![Cancer requires multiple mutations from NIHen](https://upload.wikimedia.org/wikipedia/commons/7/73/Cancer_requires_multiple_mutations_from_NIHen.png)
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, whereby normal
cells are
transformed into
cancer cell
Cancer cells are cells that divide continually, forming solid tumors or flooding the blood with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these d ...
s. The process is characterized by changes at the cellular,
genetic, and
epigenetic levels and abnormal
cell division
Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...
. Cell division is a physiological process that occurs in almost all
tissues and under a variety of circumstances. Normally, the balance between proliferation and programmed cell death, in the form of
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, is maintained to ensure the integrity of tissues and
organs
In biology, an organ is a collection of tissues joined in a structural unit to serve a common function. In the hierarchy of life, an organ lies between tissue and an organ system. Tissues are formed from same type cells to act together in a f ...
. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory,
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s in
DNA and
epimutations that lead to cancer disrupt these orderly processes by interfering with the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and the
evolution of those cells by
natural selection
Natural selection is the differential survival and reproduction of individuals due to differences in phenotype. It is a key mechanism of evolution, the change in the heritable traits characteristic of a population over generations. Charle ...
in the body. Only certain mutations lead to cancer whereas the majority of mutations do not.
Variants of inherited genes may predispose individuals to cancer. In addition, environmental factors such as
carcinogen
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...
s and radiation cause mutations that may contribute to the development of cancer. Finally random mistakes in normal DNA replication may result in cancer causing mutations.
A series of several mutations to certain classes of genes is usually required before a normal cell will transform into a
cancer cell
Cancer cells are cells that divide continually, forming solid tumors or flooding the blood with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these d ...
.
Recent comprehensive patient-level classification and quantification of driver events in
TCGA cohorts revealed that there are on average 12 driver events per tumor, of which 0.6 are
point mutations
A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequence ...
in
oncogenes
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. , 1.5 are
amplifications of oncogenes, 1.2 are point mutations in
tumor suppressors, 2.1 are
deletions of tumor suppressors, 1.5 are driver
chromosome losses, 1 is a driver
chromosome gain, 2 are driver
chromosome arm losses, and 1.5 are driver
chromosome arm gains. Mutations in genes that regulate cell division,
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
(cell death), and
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
may result in uncontrolled cell proliferation and cancer.
Cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
is fundamentally a disease of regulation of tissue growth. In order for a normal cell to
transform
Transform may refer to:
Arts and entertainment
* Transform (scratch), a type of scratch used by turntablists
* ''Transform'' (Alva Noto album), 2001
* ''Transform'' (Howard Jones album) or the title song, 2019
* ''Transform'' (Powerman 5000 album ...
into a cancer cell,
genes
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
that regulate cell growth and differentiation must be altered. Genetic and epigenetic changes can occur at many levels, from gain or loss of entire chromosomes, to a mutation affecting a
single DNA nucleotide, or to silencing or activating a microRNA that controls expression of 100 to 500 genes.
There are two broad categories of genes that are affected by these changes.
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. s may be normal genes that are expressed at inappropriately high levels, or altered genes that have novel properties. In either case, expression of these genes promotes the malignant phenotype of cancer cells.
Tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
s are genes that inhibit cell division, survival, or other properties of cancer cells. Tumor suppressor genes are often disabled by cancer-promoting genetic changes. Finally
Oncovirinae,
virus
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
es that contain an
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. , are categorized as oncogenic because they trigger the growth of tumorous tissues in the
host
A host is a person responsible for guests at an event or for providing hospitality during it.
Host may also refer to:
Places
* Host, Pennsylvania, a village in Berks County
People
*Jim Host (born 1937), American businessman
* Michel Host ...
. This process is also referred to as
viral transformation.
Causes
Genetic and epigenetic
There is a diverse classification scheme for the various genomic changes that may contribute to the generation of
cancer cell
Cancer cells are cells that divide continually, forming solid tumors or flooding the blood with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these d ...
s. Many of these changes are
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s, or changes in the
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
sequence of genomic DNA. There are also many epigenetic changes that alter whether genes are expressed or not expressed.
Aneuploidy
Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any ...
, the presence of an abnormal number of chromosomes, is one genomic change that is not a mutation, and may involve either gain or loss of one or more
chromosomes
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
through errors in
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
. Large-scale mutations involve either the
deletion or
duplication
Duplication, duplicate, and duplicator may refer to:
Biology and genetics
* Gene duplication, a process which can result in free mutation
* Chromosomal duplication, which can cause Bloom and Rett syndrome
* Polyploidy, a phenomenon also known ...
of a portion of a chromosome.
Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal region, usually containing one or more oncogenes and adjacent genetic material.
Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the
Philadelphia chromosome
The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...
, or translocation of chromosomes 9 and 22, which occurs in
chronic myelogenous leukemia, and results in production of the
BCR-
abl fusion protein
Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this ''fusion gene'' r ...
, an oncogenic
tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cla ...
. Small-scale mutations include
point mutations
A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequence ...
,
deletions, and
insertions, which may occur in the
promoter of a gene and affect its
expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, o ...
, or may occur in the gene's
coding sequence
The coding region of a gene, also known as the coding sequence (CDS), is the portion of a gene's DNA or RNA that codes for protein. Studying the length, composition, regulation, splicing, structures, and functions of coding regions compared to n ...
and alter the function or stability of its
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
product. Disruption of a single gene may also result from
integration of genomic material from a
DNA virus
A DNA virus is a virus that has a genome made of deoxyribonucleic acid (DNA) that is replicated by a DNA polymerase. They can be divided between those that have two strands of DNA in their genome, called double-stranded DNA (dsDNA) viruses, and ...
or
retrovirus
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...
, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants.
DNA damage
![Diagram Damage to Cancer Wiki 300dpi](https://upload.wikimedia.org/wikipedia/commons/9/9d/Diagram_Damage_to_Cancer_Wiki_300dpi.svg)
DNA damage is considered to be the primary cause of cancer.
More than 60,000 new naturally-occurring instances of DNA damage arise, on average, per human cell, per day, due to endogenous cellular processes (see article
DNA damage (naturally occurring)
DNA damage is an alteration in the chemical structure of DNA, such as a break in a strand of DNA, a nucleobase missing from the backbone of DNA, or a chemically changed base such as 8-OHdG. DNA damage can occur naturally or via environmental fac ...
).
Additional DNA damage can arise from exposure to
exogenous
In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system.
Economics
In an economic model, an exogeno ...
agents. As one example of an
exogenous
In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system.
Economics
In an economic model, an exogeno ...
carcinogenic agent, tobacco smoke causes increased DNA damage, and this DNA damage likely cause the increase of lung cancer due to smoking.
In other examples, UV light from solar radiation causes DNA damage that is important in
melanoma
Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
, ''
Helicobacter pylori
''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, microaerophilic, spiral (helical) bacterium usually found in the stomach. Its helical shape (from which the genus name, helicobacter, derives) is though ...
'' infection produces high levels of
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
that damage DNA and contribute to
gastric cancer
Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lymph ...
, and the ''
Aspergillus flavus
''Aspergillus flavus'' is a saprotrophic and pathogenic fungus with a cosmopolitan distribution. It is best known for its colonization of cereal grains, legumes, and tree nuts. Postharvest rot typically develops during harvest, storage, and/or t ...
'' metabolite
aflatoxin
Aflatoxins are various poisonous carcinogens and mutagens that are produced by certain molds, particularly ''Aspergillus'' species. The fungi grow in soil, decaying vegetation and various staple foodstuffs and commodities such as hay, sweetcorn ...
is a DNA damaging agent that is causative in liver cancer.
DNA damage can also be caused by
substances produced in the body. Macrophages and neutrophils in an inflamed colonic epithelium are the source of reactive oxygen species causing the DNA damage that initiates colonic
tumorigenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
, and bile acids, at high levels in the colons of humans eating a high-fat diet, also cause DNA damage and contribute to colon cancer.
Such exogenous and endogenous sources of DNA damage are indicated in the boxes at the top of the figure in this section. The central role of DNA damage in progression to cancer is indicated at the second level of the figure. The central elements of DNA damage,
epigenetic alterations and deficient DNA repair in progression to cancer are shown in red.
A deficiency in DNA repair would cause more DNA damage to accumulate, and increase the risk for cancer. For example, individuals with an inherited impairment in any of 34
DNA repair genes
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
(see article
DNA repair-deficiency disorder
A DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair.
DNA repair defects can cause an accelerated aging disease or an increased risk of cancer, or sometimes both.
DNA repair defects and accelerated a ...
) are at increased risk of cancer, with some defects causing an up to 100% lifetime chance of cancer (e.g.
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
mutations). Such
germline mutation
A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and ova). Mutations in these cells are the only mutations that can be passed on to offspring, when either a mu ...
s are shown in a box at the left of the figure, with an indication of their contribution to DNA repair deficiency. However, such germline mutations (which cause highly
penetrant cancer syndromes) are the cause of only about ''one percent'' of cancers.
The majority of cancers are called non-hereditary or "sporadic cancers". About 30% of sporadic cancers do have some hereditary component that is currently undefined, while the majority, or 70% of sporadic cancers, have no hereditary component.
In sporadic cancers, a deficiency in DNA repair is occasionally due to a mutation in a DNA repair gene; much more frequently, reduced or absent expression of DNA repair genes is due to
epigenetic alteration
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
s that reduce or
silence gene expression. This is indicated in the figure at the 3rd level from the top. For example, for 113 colorectal cancers examined in sequence, only four had a
missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense m ...
in the DNA repair gene
MGMT
MGMT () is an American indie rock band formed in 2002 in Middletown, Connecticut. It was founded by multi-instrumentalists Andrew VanWyngarden and Ben Goldwasser. Alongside VanWyngarden and Goldwasser, MGMT's live lineup currently consists of ...
, while the majority had reduced MGMT expression due to
methylation
In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
of the MGMT
promoter region
In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can have a function in and of ...
(an epigenetic alteration).
When expression of DNA repair genes is reduced, this causes a DNA repair deficiency. This is shown in the figure at the 4th level from the top. With a DNA repair deficiency, DNA damage persists in cells at a higher than typical level (5th level from the top in figure); this excess damage causes an increased frequency of mutation and/or
epimutation
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are " ...
(6th level from top of figure). Experimentally, mutation rates increase substantially in cells defective in
DNA mismatch repair
DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of nucleobase, bases that can arise during DNA replication and Genetic recombination, recombination, as well as DNA repair, r ...
or in
Homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
al repair (HRR).
Chromosomal rearrangement
In genetics, a chromosomal rearrangement is a mutation that is a type of chromosome abnormality involving a change in the structure of the native chromosome. Such changes may involve several different classes of events, like deletions, duplica ...
s and
aneuploidy
Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any ...
also increase in HRR-defective cells During repair of DNA double-strand breaks, or repair of other DNA damage, incompletely-cleared repair sites can cause epigenetic gene silencing.
The somatic mutations and epigenetic alterations caused by DNA damage and deficiencies in DNA repair accumulate in
field defects. Field defects are normal-appearing tissues with multiple alterations (discussed in the section below), and are common precursors to development of the disordered and over-proliferating clone of tissue in a cancer. Such field defects (second level from bottom of figure) may have numerous mutations and epigenetic alterations.
It is impossible to determine the initial cause for most specific cancers. In a few cases, only one cause exists: for example, the virus
HHV-8
Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ICTV) is ''Human gammaherpesvirus 8'', or HHV-8 in short. Like other herpesviru ...
causes all
Kaposi's sarcoma
Kaposi's sarcoma (KS) is a type of cancer that can form masses in the skin, in lymph nodes, in the mouth, or in other organs. The skin lesions are usually painless, purple and may be flat or raised. Lesions can occur singly, multiply in a limite ...
s. However, with the help of
cancer epidemiology
The epidemiology of cancer is the study of the factors affecting cancer, as a way to infer possible trends and causes. The study of cancer epidemiology uses epidemiological methods to find the cause of cancer and to identify and develop improve ...
techniques and information, it is possible to produce an estimate of a likely cause in many more situations. For example,
lung cancer
Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissue (biology), tissues of the lung. Lung carcinomas derive from tran ...
has several causes, including tobacco use and
radon gas
Radon is a chemical element with the symbol Rn and atomic number 86. It is a radioactive, colourless, odourless, tasteless noble gas. It occurs naturally in minute quantities as an intermediate step in the normal radioactive decay chains through ...
. Men who currently smoke tobacco develop lung cancer at a rate 14 times that of men who have never smoked tobacco: the chance of lung cancer in a current smoker being caused by smoking is about 93%; there is a 7% chance that the smoker's lung cancer was caused by radon gas or some other, non-tobacco cause.
These statistical correlations have made it possible for researchers to infer that certain substances or behaviors are carcinogenic. Tobacco smoke causes increased
exogenous
In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system.
Economics
In an economic model, an exogeno ...
DNA damage, and this DNA damage is the likely cause of lung cancer due to smoking. Among the more than 5,000 compounds in tobacco smoke, the
genotoxic Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with mutagenicity, all mutagens are genotoxic, but some genotoxic s ...
DNA-damaging agents that occur both at the highest concentrations, and which have the strongest mutagenic effects are
acrolein
Acrolein (systematic name: propenal) is the simplest unsaturated aldehyde. It is a colorless liquid with a piercing, acrid smell. The smell of burnt fat (as when cooking oil is heated to its smoke point) is caused by glycerol in the burning fa ...
,
formaldehyde
Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...
,
acrylonitrile
Acrylonitrile is an organic compound with the formula and the structure . It is a colorless, volatile liquid although commercial samples can be yellow due to impurities. It has a pungent odor of garlic or onions. In terms of its molecular ...
,
1,3-butadiene
1,3-Butadiene () is the organic compound with the formula (CH2=CH)2. It is a colorless gas that is easily condensed to a liquid. It is important industrially as a precursor to synthetic rubber. The molecule can be viewed as the union of two viny ...
,
acetaldehyde
Acetaldehyde (IUPAC systematic name ethanal) is an organic chemical compound with the formula CH3 CHO, sometimes abbreviated by chemists as MeCHO (Me = methyl). It is a colorless liquid or gas, boiling near room temperature. It is one of the mos ...
,
ethylene oxide
Ethylene oxide is an organic compound with the chemical formula, formula . It is a cyclic ether and the simplest epoxide: a three-membered Ring (chemistry), ring consisting of one oxygen atom and two carbon atoms. Ethylene oxide is a colorless a ...
and
isoprene
Isoprene, or 2-methyl-1,3-butadiene, is a common volatile organic compound with the formula CH2=C(CH3)−CH=CH2. In its pure form it is a colorless volatile liquid. Isoprene is an unsaturated hydrocarbon. It is produced by many plants and animals ...
.
Using
molecular biological
Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
techniques, it is possible to characterize the mutations, epimutations or chromosomal aberrations within a tumor, and rapid progress is being made in the field of predicting certain cancer patients'
prognosis
Prognosis (Greek: πρόγνωσις "fore-knowing, foreseeing") is a medical term for predicting the likely or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) or remain stabl ...
based on the spectrum of mutations. For example, up to half of all tumors have a defective p53 gene. This mutation is associated with poor prognosis, since those tumor cells are less likely to go into
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
or
programmed cell death
Programmed cell death (PCD; sometimes referred to as cellular suicide) is the death of a cell (biology), cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers ...
when damaged by therapy.
Telomerase
Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most euka ...
mutations remove additional barriers, extending the number of times a cell can divide. Other mutations enable the tumor to
grow new blood vessels to provide more nutrients, or to
metastasize
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
, spreading to other parts of the body. However, once a cancer is formed it continues to evolve and to produce sub-clones. It was reported in 2012 that a single renal cancer specimen, sampled in nine different areas, had 40 "ubiquitous" mutations, found in all nine areas, 59 mutations shared by some, but not all nine areas, and 29 "private" mutations only present in one area.
The lineages of cells in which all these DNA alterations accumulate are difficult to trace, but two recent lines of evidence suggest that normal
stem cell
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
s may be the cells of origin in cancers.
First, there exists a highly positive correlation (Spearman's rho = 0.81; P < 3.5 × 10−8) between the risk of developing cancer in a tissue and the number of normal stem cell divisions taking place in that same tissue. The correlation applied to 31 cancer types and extended across five
orders of magnitude
An order of magnitude is an approximation of the logarithm of a value relative to some contextually understood reference value, usually 10, interpreted as the base of the logarithm and the representative of values of magnitude one. Logarithmic dis ...
. This correlation means that if normal stem cells from a tissue divide once, the cancer risk in that tissue is approximately 1X. If they divide 1,000 times, the cancer risk is 1,000X. And if the normal stem cells from a tissue divide 100,000 times, the cancer risk in that tissue is approximately 100,000X. This strongly suggests that the main factor in cancer initiation is the fact that "normal" stem cells divide, which implies that cancer originates in normal, healthy stem cells.
Second, statistics show that most human cancers are diagnosed in older people. A possible explanation is that cancers occur because cells accumulate damage through time. DNA is the only cellular component that can accumulate damage over the entire course of a life, and stem cells are the only cells that can transmit DNA from the zygote to cells late in life. Other cells, derived from stem cells, do not keep DNA from the beginning of life until a possible cancer occurs. This implies that most cancers arise from normal stem cells.
Contribution of field defects
The term "
field cancerization
Field cancerization or field effect (also termed field change, field change cancerization, field carcinogenesis, cancer field effect or premalignant field defect) is a biological process in which large areas of cells at a tissue surface or within ...
" was first used in 1953 to describe an area or "field" of epithelium that has been preconditioned by (at that time) largely unknown processes so as to predispose it towards development of cancer. Since then, the terms "field cancerization" and "field defect" have been used to describe pre-malignant tissue in which new cancers are likely to arise.
Field defects have been identified in association with cancers and are important in progression to cancer.
However, it was pointed out by Rubin that "the vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neoplastic foci in vitro. Yet there is evidence that more than 80% of the somatic mutations found in
mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion…" More than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells. It would also be expected that many of the epigenetic alterations present in tumors may have occurred in pre-neoplastic field defects.
In the colon, a field defect probably arises by natural selection of a mutant or epigenetically altered cell among the stem cells at the base of one of the
intestinal crypts on the inside surface of the colon. A mutant or epigenetically altered stem cell may replace the other nearby stem cells by natural selection. This may cause a patch of abnormal tissue to arise. The figure in this section includes a photo of a freshly
resected and lengthwise-opened segment of the colon showing a colon cancer and four polyps. Below the photo there is a schematic diagram of how a large patch of mutant or epigenetically altered cells may have formed, shown by the large area in yellow in the diagram. Within this first large patch in the diagram (a large clone of cells), a second such mutation or epigenetic alteration may occur, so that a given stem cell acquires an advantage compared to its neighbors, and this altered stem cell may expand clonally, forming a secondary patch, or sub-clone, within the original patch. This is indicated in the diagram by four smaller patches of different colors within the large yellow original area. Within these new patches (sub-clones), the process may be repeated multiple times, indicated by the still smaller patches within the four secondary patches (with still different colors in the diagram) which clonally expand, until stem cells arise that generate either small polyps or else a malignant neoplasm (cancer). In the photo, an apparent field defect in this segment of a colon has generated four polyps (labeled with the size of the polyps, 6mm, 5mm, and two of 3mm, and a cancer about 3 cm across in its longest dimension). These neoplasms are also indicated (in the diagram below the photo) by 4 small tan circles (polyps) and a larger red area (cancer). The cancer in the photo occurred in the cecal area of the colon, where the colon joins the small intestine (labeled) and where the appendix occurs (labeled). The fat in the photo is external to the outer wall of the colon. In the segment of colon shown here, the colon was cut open lengthwise to expose its inner surface and to display the cancer and polyps occurring within the inner epithelial lining of the colon.
If the general process by which sporadic colon cancers arise is the formation of a pre-neoplastic clone that spreads by natural selection, followed by formation of internal sub-clones within the initial clone, and sub-sub-clones inside those, then colon cancers generally should be associated with, and be preceded by, fields of increasing abnormality, reflecting the succession of premalignant events. The most extensive region of abnormality (the outermost yellow irregular area in the diagram) would reflect the earliest event in formation of a malignant neoplasm.
In experimental evaluation of specific DNA repair deficiencies in cancers, many specific DNA repair deficiencies were also shown to occur in the field defects surrounding those cancers. The table below gives examples for which the DNA repair deficiency in a cancer was shown to be caused by an epigenetic alteration, and the somewhat lower frequencies with which the same epigenetically caused DNA repair deficiency was found in the surrounding field defect.
Some of the small polyps in the field defect shown in the photo of the opened colon segment may be relatively benign neoplasms. In a 1996 study of polyps less than 10mm in size found during colonoscopy and followed with repeat colonoscopies for 3 years, 25% remained unchanged in size, 35% regressed or shrank in size and 40% grew in size.
Genome instability
Cancers are known to exhibit
genome instability
Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneu ...
or a "mutator phenotype". The protein-coding DNA within the nucleus is about 1.5% of the total genomic DNA. Within this protein-coding DNA (called the
exome
The exome is composed of all of the exons within the genome, the sequences which, when transcribed, remain within the mature RNA after introns are removed by RNA splicing. This includes untranslated regions of messenger RNA (mRNA), and coding r ...
), an average cancer of the breast or colon can have about 60 to 70 protein altering mutations, of which about 3 or 4 may be "driver" mutations, and the remaining ones may be "passenger" mutations.
However, the average number of DNA sequence mutations in the entire genome (including
non-protein-coding regions) within a breast cancer tissue sample is about 20,000. In an average melanoma tissue sample (melanomas have a higher
exome
The exome is composed of all of the exons within the genome, the sequences which, when transcribed, remain within the mature RNA after introns are removed by RNA splicing. This includes untranslated regions of messenger RNA (mRNA), and coding r ...
mutation frequency),
) the total number of DNA sequence mutations is about 80,000. These high frequencies of mutations in the total nucleotide sequences within cancers suggest that often an early alteration in the field defect giving rise to a cancer (e.g. yellow area in the diagram in the preceding section) is a deficiency in DNA repair. Large field defects surrounding colon cancers (extending to about 10 cm on each side of a cancer) are found
to frequently have epigenetic defects in two or three DNA repair proteins (
ERCC1
DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ''ERCC1'' gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
Many aspects of these two gene ...
,
ERCC4
ERCC4 is a protein designated as DNA repair endonuclease XPF that in humans is encoded by the ''ERCC4'' gene. Together with ERCC1, ERCC4 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
The nuclease enz ...
(XPF) and/or
PMS2
Mismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the ''PMS2'' gene.
Function
This gene is one of the PMS2 gene family members which are found in clusters on chromosome 7. Human PMS2 related genes are located at bands ...
) in the entire area of the field defect. When expression of DNA repair genes is reduced, DNA damage accumulates in cells at a higher than normal rate, and this excess damage causes an increased frequency of mutation and/or epimutation. Mutation rates strongly increase in cells defective in
DNA mismatch repair
DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of nucleobase, bases that can arise during DNA replication and Genetic recombination, recombination, as well as DNA repair, r ...
or in
homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
al repair (HRR).
A deficiency in DNA repair, itself, can allow DNA damage to accumulate, and error-prone
translesion synthesis
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dama ...
of some of the damaged areas may give rise to mutations. In addition, faulty repair of this accumulated DNA damage may give rise to epimutations. These new mutations and/or epimutations may provide a proliferative advantage, generating a field defect. Although the mutations/epimutations in DNA repair genes do not, themselves, confer a selective advantage, they may be carried along as passengers in cells when the cell acquires an additional mutation/epimutation that does provide a proliferative advantage.
Non-mainstream theories
There are a number of theories of carcinogenesis and cancer treatment that fall outside the mainstream of scientific opinion, due to lack of scientific rationale, logic, or evidence base. These theories may be used to justify various alternative cancer treatments. They should be distinguished from those theories of carcinogenesis that have a logical basis within mainstream cancer biology, and from which conventionally testable hypotheses can be made.
Several alternative theories of carcinogenesis, however, are based on scientific evidence and are increasingly being acknowledged. Some researchers believe that cancer may be caused by
aneuploidy
Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any ...
(numerical and structural abnormalities in chromosomes) rather than by mutations or epimutations. Cancer has also been considered as a metabolic disease, in which the cellular metabolism of oxygen is diverted from the pathway that generates energy (
oxidative phosphorylation
Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...
) to the pathway that generates
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
.
This causes an energy switch from oxidative phosphorylation to aerobic glycolysis (
Warburg's hypothesis), and the accumulation of
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
leading to
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
("oxidative stress theory of cancer").
Another concept of cancer development is based on exposure to weak
magnetic
Magnetism is the class of physical attributes that are mediated by a magnetic field, which refers to the capacity to induce attractive and repulsive phenomena in other entities. Electric currents and the magnetic moments of elementary particle ...
and
electromagnetic fields
An electromagnetic field (also EM field or EMF) is a classical (i.e. non-quantum) field produced by (stationary or moving) electric charges. It is the field described by classical electrodynamics (a classical field theory) and is the classical co ...
and their effects on
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
, known as magnetocarcinogenesis.
A number of authors have questioned the assumption that cancers result from sequential random mutations as oversimplistic, suggesting instead that cancer results from a failure of the body to inhibit an innate, programmed proliferative tendency. A related theory suggests that cancer is an
atavism
In biology, an atavism is a modification of a biological structure whereby an ancestral genetic trait reappears after having been lost through evolutionary change in previous generations. Atavisms can occur in several ways; one of which is when ...
, an evolutionary throwback to an earlier form of
multicellular life. The genes responsible for uncontrolled cell growth and cooperation between
cancer cell
Cancer cells are cells that divide continually, forming solid tumors or flooding the blood with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these d ...
s are very similar to those that enabled the first multicellular life forms to group together and flourish. These genes still exist within the genomes of more complex
metazoans
Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage in ...
, such as humans, although more recently evolved genes keep them in check. When the newer controlling genes fail for whatever reason, the cell can revert to its more primitive programming and reproduce out of control. The theory is an alternative to the notion that cancers begin with rogue cells that undergo evolution within the body. Instead, they possess a fixed number of primitive genes that are progressively activated, giving them finite variability. Another evolutionary theory puts the roots of cancer back to the origin of the
eukaryote
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
(nucleated) cell by massive
horizontal gene transfer
Horizontal gene transfer (HGT) or lateral gene transfer (LGT) is the movement of genetic material between Unicellular organism, unicellular and/or multicellular organisms other than by the ("vertical") transmission of DNA from parent to offsprin ...
, when the genomes of infecting viruses were cleaved (and thereby attenuated) by the host, but their fragments integrated into the host genome as immune protection. Cancer thus originates when a rare somatic mutation recombines such fragments into a functional driver of cell proliferation.
Cancer cell biology
![Cancer progression from NIH](https://upload.wikimedia.org/wikipedia/commons/f/f6/Cancer_progression_from_NIH.png)
Often, the multiple genetic changes that result in cancer may take many years to accumulate. During this time, the biological behavior of the pre-malignant cells slowly changes from the properties of normal cells to cancer-like properties. Pre-malignant tissue can have a
distinctive appearance under the microscope. Among the distinguishing traits of a pre-malignant lesion are an increased
number of dividing cells, variation in
nuclear
Nuclear may refer to:
Physics
Relating to the nucleus of the atom:
* Nuclear engineering
*Nuclear physics
*Nuclear power
*Nuclear reactor
*Nuclear weapon
*Nuclear medicine
*Radiation therapy
*Nuclear warfare
Mathematics
*Nuclear space
*Nuclear ...
size and shape, variation in cell
size
Size in general is the Magnitude (mathematics), magnitude or dimensions of a thing. More specifically, ''geometrical size'' (or ''spatial size'') can refer to linear dimensions (length, width, height, diameter, perimeter), area, or volume ...
and
shape
A shape or figure is a graphics, graphical representation of an object or its external boundary, outline, or external Surface (mathematics), surface, as opposed to other properties such as color, Surface texture, texture, or material type.
A pl ...
, loss of
specialized cell features, and loss of normal tissue organization.
Dysplasia
Dysplasia is any of various types of abnormal growth or development of cells (microscopic scale) or organs (macroscopic scale), and the abnormal histology or anatomical structure(s) resulting from such growth. Dysplasias on a mainly microscopic ...
is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure in pre-malignant cells. These early
neoplastic
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
changes must be distinguished from
hyperplasia
Hyperplasia (from ancient Greek ὑπέρ ''huper'' 'over' + πλάσις ''plasis'' 'formation'), or hypergenesis, is an enlargement of an organ or tissue caused by an increase in the amount of organic tissue that results from cell proliferati ...
, a reversible increase in cell division caused by an external stimulus, such as a hormonal imbalance or chronic irritation.
The most severe cases of dysplasia are referred to as ''
carcinoma in situ
Carcinoma ''in situ'' (CIS) is a group of abnormal cells. While they are a form of neoplasm, there is disagreement over whether CIS should be classified as cancer. This controversy also depends on the exact CIS in question (i.e. cervical, skin, bre ...
.'' In Latin, the term ''in situ'' means "in place"; ''carcinoma in situ'' refers to an uncontrolled growth of dysplastic cells that remains in its original location and has not shown
invasion
An invasion is a military offensive in which large numbers of combatants of one geopolitical entity aggressively enter territory owned by another such entity, generally with the objective of either: conquering; liberating or re-establishing con ...
into other tissues. Carcinoma in situ may develop into an invasive malignancy and is usually removed surgically when detected.
Clonal evolution
Just as a population of animals undergoes
evolution
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
, an unchecked population of cells also can undergo "evolution". This undesirable process is called
somatic evolution Somatic evolution is the accumulation of mutations and epimutations in somatic cells (the cells of a body, as opposed to germ plasm and stem cells) during a lifetime, and the effects of those mutations and epimutations on the fitness of those c ...
, and is how cancer arises and becomes more malignant over time.
Most changes in cellular metabolism that allow cells to grow in a disorderly fashion lead to cell death. However, once cancer begins,
cancer cell
Cancer cells are cells that divide continually, forming solid tumors or flooding the blood with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these d ...
s undergo a process of
natural selection
Natural selection is the differential survival and reproduction of individuals due to differences in phenotype. It is a key mechanism of evolution, the change in the heritable traits characteristic of a population over generations. Charle ...
: the few cells with new genetic changes that enhance their survival or reproduction multiply faster, and soon come to dominate the growing tumor as cells with less favorable genetic change are out-competed.
This is the same mechanism by which
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
ic species such as
MRSA
Methicillin-resistant ''Staphylococcus aureus'' (MRSA) is a group of Gram-positive bacteria that are genetically distinct from other strains of ''Staphylococcus aureus''. MRSA is responsible for several difficult-to-treat infections in humans. ...
can become
antibiotic-resistant
Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...
and by which
HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
can become
drug-resistant), and by which plant diseases and insects can become
pesticide-resistant. This evolution explains why a cancer
relapse
In internal medicine, relapse or recidivism is a recurrence of a past (typically medical) condition. For example, multiple sclerosis and malaria often exhibit peaks of activity and sometimes very long periods of dormancy, followed by relapse or r ...
often involves cells that have acquired
cancer-drug resistance or resistance to
radiotherapy
Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radia ...
).
Biological properties of cancer cells
In a 2000 article by
Hanahan and
Weinberg, the biological properties of malignant tumor cells were summarized as follows:
* Acquisition of self-sufficiency in
growth signals, leading to unchecked growth.
* Loss of sensitivity to anti-growth signals, also leading to unchecked growth.
* Loss of capacity for
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, allowing growth despite genetic errors and external anti-growth signals.
* Loss of capacity for
senescence
Senescence () or biological aging is the gradual deterioration of functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence inv ...
, leading to limitless replicative potential (immortality)
* Acquisition of
sustained angiogenesis, allowing the tumor to grow beyond the limitations of passive nutrient diffusion.
* Acquisition of ability to invade neighbouring
tissues, the defining property of invasive carcinoma.
* Acquisition of ability to seed
metastases
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
at distant sites, a late-appearing property of some malignant tumors (carcinomas or others).
The completion of these multiple steps would be a very rare event without:
* Loss of capacity to repair genetic errors, leading to an increased
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
rate (genomic instability), thus accelerating all the other changes.
These biological changes are classical in
carcinoma
Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesodermal ...
s; other malignant tumors may not need to achieve them all. For example, given that tissue invasion and displacement to distant sites are normal properties of
leukocytes
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
, these steps are not needed in the development of
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
. Nor do the different steps necessarily represent individual mutations. For example, inactivation of a single gene, coding for the
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
protein, will cause genomic instability, evasion of apoptosis and increased angiogenesis. Further, not all the
cancer cell
Cancer cells are cells that divide continually, forming solid tumors or flooding the blood with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these d ...
s are dividing. Rather, a subset of the cells in a tumor, called
cancer stem cell
Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. ...
s, replicate themselves as they generate differentiated cells.
Cancer as a defect in cell interactions
Normally, once a tissue is injured or infected, damaged cells elicit inflammation by stimulating specific patterns of enzyme activity and cytokine gene expression in surrounding cells. Discrete clusters ("cytokine clusters") of molecules are secreted, which act as mediators, inducing the activity of subsequent cascades of biochemical changes. Each cytokine binds to specific receptors on various cell types, and each cell type responds in turn by altering the activity of intracellular signal transduction pathways, depending on the receptors that the cell expresses and the signaling molecules present inside the cell. Collectively, this reprogramming process induces a stepwise change in cell phenotypes, which will ultimately lead to restoration of tissue function and toward regaining essential structural integrity. A tissue can thereby heal, depending on the productive communication between the cells present at the site of damage and the immune system. One key factor in healing is the regulation of cytokine gene expression, which enables complementary groups of cells to respond to inflammatory mediators in a manner that gradually produces essential changes in tissue physiology. Cancer cells have either permanent (genetic) or reversible (epigenetic) changes to their genome, which partly inhibit their communication with surrounding cells and with the immune system. Cancer cells do not communicate with their tissue microenvironment in a manner that protects tissue integrity; instead, the movement and the survival of cancer cells become possible in locations where they can impair tissue function. Cancer cells survive by "rewiring" signal pathways that normally protect the tissue from the immune system. This alteration of the immune response is evident in early stages of malignancy too.
One example of tissue function rewiring in cancer is the activity of transcription factor
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
.
NF-κB activates the expression of numerous genes involved in the transition between inflammation and regeneration, which encode cytokines, adhesion factors, and other molecules that can change cell fate. This reprogramming of cellular phenotypes normally allows the development of a fully functional intact tissue. NF-κB activity is tightly controlled by multiple proteins, which collectively ensure that only discrete clusters of genes are induced by NF-κB in a given cell and at a given time. This tight regulation of signal exchange between cells protects the tissue from excessive inflammation, and ensures that different cell types gradually acquire complementary functions and specific positions. Failure of this mutual regulation between genetic reprogramming and cell interactions allows cancer cells to give rise to metastasis. Cancer cells respond aberrantly to cytokines, and activate signal cascades that can protect them from the immune system.
In fish
The role of iodine in marine fish (rich in iodine) and freshwater fish (iodine-deficient) is not completely understood, but it has been reported that freshwater fish are more susceptible to infectious and, in particular, neoplastic and atherosclerotic diseases, than marine fish. Marine elasmobranch fishes such as sharks, stingrays etc. are much less affected by cancer than freshwater fishes, and therefore have stimulated medical research to better understand carcinogenesis.
Mechanisms
In order for cells to start dividing uncontrollably, genes that regulate cell growth must be dysregulated.
Proto-oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. s are genes that promote cell growth and
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
, whereas
tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
s discourage cell growth, or temporarily halt cell division to carry out
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
. Typically, a series of several
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s to these genes is required before a normal cell transforms into a
cancer cell
Cancer cells are cells that divide continually, forming solid tumors or flooding the blood with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these d ...
.
This concept is sometimes termed "oncoevolution." Mutations to these genes provide the signals for tumor cells to start dividing uncontrollably. But the uncontrolled cell division that characterizes cancer also requires that the dividing cell duplicates all its cellular components to create two daughter cells. The activation of anaerobic glycolysis (the
Warburg effect), which is not necessarily induced by mutations in proto-oncogenes and tumor suppressor genes, provides most of the building blocks required to duplicate the cellular components of a dividing cell and, therefore, is also essential for carcinogenesis.
Oncogenes
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. s promote cell growth through a variety of ways. Many can produce
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
s, a "chemical messenger" between cells that encourage
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
, the effect of which depends on the
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
of the receiving tissue or cells. In other words, when a hormone receptor on a recipient cell is stimulated, the signal is conducted from the surface of the cell to the
cell nucleus
The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
to affect some change in gene transcription regulation at the nuclear level. Some oncogenes are part of the signal transduction system itself, or the signal
receptors
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
in cells and tissues themselves, thus controlling the sensitivity to such hormones. Oncogenes often produce
mitogen
A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a ...
s, or are involved in
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
of DNA in
protein synthesis
Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside Cell (biology), cells, homeostasis, balancing the loss of cellular proteins (via Proteolysis, degradation or Protein targeting, export) through the product ...
, which creates the
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s and
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s responsible for producing the products and
biochemicals cells use and interact with.
Mutations in proto-oncogenes, which are the normally quiescent counterparts of
oncogenes
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. , can modify their
expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, o ...
and function, increasing the amount or activity of the product protein. When this happens, the proto-oncogenes become
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. s, and this transition upsets the normal balance of
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
regulation in the cell, making uncontrolled growth possible. The chance of cancer cannot be reduced by removing proto-oncogenes from the
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
, even if this were possible, as they are critical for growth, repair and
homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
of the organism. It is only when they become mutated that the signals for growth become excessive.
One of the first
oncogenes
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. to be defined in
cancer research
Cancer research is research into cancer to identify causes and develop strategies for prevention, diagnosis, treatment, and cure.
Cancer research ranges from epidemiology, molecular bioscience to the performance of clinical trials to evaluate and ...
is the
ras oncogene. Mutations in the Ras family of
proto-oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. s (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours. Ras was originally identified in the Harvey sarcoma virus genome, and researchers were surprised that not only is this gene present in the human genome but also, when ligated to a stimulating control element, it could induce cancers in cell line cultures.
Proto-oncogenes
Proto-oncogenes promote cell growth in a variety of ways. Many can produce
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
s, "chemical messengers" between cells that encourage mitosis, the effect of which depends on the
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
of the receiving tissue or cells. Some are responsible for the signal transduction system and signal
receptors
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
in cells and tissues themselves, thus controlling the sensitivity to such hormones. They often produce
mitogen
A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a ...
s, or are involved in
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
of DNA in
protein synthesis
Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside Cell (biology), cells, homeostasis, balancing the loss of cellular proteins (via Proteolysis, degradation or Protein targeting, export) through the product ...
, which create the
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s and
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s responsible for producing the products and
biochemicals cells use and interact with.
Mutations in proto-oncogenes can modify their
expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, o ...
and function, increasing the amount or activity of the product protein. When this happens, they become
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. s, and, thus, cells have a higher chance of dividing excessively and uncontrollably. The chance of cancer cannot be reduced by removing proto-oncogenes from the
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
, as they are critical for growth, repair and
homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
of the body. It is only when they become mutated that the signals for growth become excessive.
It is important to note that a gene possessing a growth-promoting role may increase the carcinogenic potential of a cell, under the condition that all necessary cellular mechanisms that permit growth are activated. This condition also includes the inactivation of specific tumor suppressor genes (see below). If the condition is not fulfilled, the cell may cease to grow and can proceed to die. This makes identification of the stage and type of
cancer cell
Cancer cells are cells that divide continually, forming solid tumors or flooding the blood with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these d ...
that grows under the control of a given oncogene crucial for the development of treatment strategies.
Tumor suppressor genes
Tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
s code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally, tumor suppressors are
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
s that are activated by cellular
stress
Stress may refer to:
Science and medicine
* Stress (biology), an organism's response to a stressor such as an environmental condition
* Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phrase ...
or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways that lead to the activation of
tumor suppressor genes
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
. The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. The
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
protein, one of the most important studied tumor suppressor genes, is a transcription factor activated by many cellular stressors including Hypoxia (medical), hypoxia and ultraviolet radiation damage.
Despite nearly half of all cancers possibly involving alterations in p53, its tumor suppressor function is poorly understood. p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis.
The Warburg hypothesis is the preferential use of glycolysis for energy to sustain cancer growth. p53 has been shown to regulate the shift from the respiratory to the glycolytic pathway.
However, a mutation can damage the tumor suppressor gene itself, or the signal pathway that activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer.
Mutations of tumor suppressor genes that occur in germline cells are passed along to offspring, and increase the likelihood for cancer diagnoses in subsequent generations. Members of these families have increased incidence and decreased latency of multiple tumors. The tumor types are typical for each type of tumor suppressor gene mutation, with some mutations causing particular cancers, and other mutations causing others. The mode of inheritance of mutant tumor suppressors is that an affected member inherits a defective copy from one parent, and a normal copy from the other. For instance, individuals who inherit one mutant ''
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
'' allele (and are therefore heterozygote, heterozygous for mutated ''p53'') can develop melanomas and pancreatic cancer, known as Li-Fraumeni syndrome. Other inherited tumor suppressor gene syndromes include ''Retinoblastoma protein, Rb'' mutations, linked to retinoblastoma, and ''Familial adenomatous polyposis#Pathophysiology, APC'' gene mutations, linked to Familial adenomatous polyposis, adenopolyposis colon cancer. Adenopolyposis colon cancer is associated with thousands of polyps in colon while young, leading to Colorectal cancer, colon cancer at a relatively early age. Finally, inherited mutations in ''BRCA1'' and ''BRCA2'' lead to early onset of breast cancer.
Development of cancer was proposed in 1971 to depend on at least two mutational events. In what became known as the Alfred G. Knudson, Knudson Knudson hypothesis, two-hit hypothesis, an inherited, germ-line mutation in a
tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
would cause cancer only if another mutation event occurred later in the organism's life, inactivating the other allele of that
tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
.
Usually, oncogenes are dominant gene, dominant, as they contain gain-of-function mutations, while mutated tumor suppressors are recessive gene, recessive, as they contain loss-of-function mutations. Each cell has two copies of the same gene, one from each parent, and under most cases gain of function mutations in just one copy of a particular proto-oncogene is enough to make that gene a true oncogene. On the other hand, loss of function mutations need to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one mutated copy of a
tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
can render the other, wild-type copy non-functional. This phenomenon is called the ''dominant negative effect'' and is observed in many p53 mutations.
Knudson's two hit model has recently been challenged by several investigators. Inactivation of one allele of some tumor suppressor genes is sufficient to cause tumors. This phenomenon is called haploinsufficiency and has been demonstrated by a number of experimental approaches. Tumors caused by haploinsufficiency usually have a later age of onset when compared with those by a two hit process.
Multiple mutations
![Multi Onco](https://upload.wikimedia.org/wikipedia/commons/c/c7/Multi_Onco.jpg)
In general, mutations in both types of genes are required for cancer to occur. For example, a mutation limited to one oncogene would be suppressed by normal mitosis control and tumor suppressor genes, first hypothesised by the Knudson hypothesis.
A mutation to only one tumor suppressor gene would not cause cancer either, due to the presence of many "backup" genes that duplicate its functions. It is only when enough proto-oncogenes have mutated into oncogenes, and enough tumor suppressor genes deactivated or damaged, that the signals for cell growth overwhelm the signals to regulate it, that cell growth quickly spirals out of control.
Often, because these genes regulate the processes that prevent most damage to genes themselves, the rate of mutations increases as one gets older, because DNA damage forms a feedback loop.
Mutation of tumor suppressor genes that are passed on to the next generation of not merely cells, but their offspring, can cause increased likelihoods for cancers to be inherited. Members within these families have increased incidence and decreased latency of multiple tumors. The mode of inheritance of mutant tumor suppressors is that affected member inherits a defective copy from one parent, and a normal copy from another. Because mutations in tumor suppressors act in a recessive manner (note, however, there are exceptions), the loss of the normal copy creates the cancer phenotype. For instance, individuals that are heterozygote, heterozygous for p53 mutations are often victims of Li-Fraumeni syndrome, and that are heterozygous for Retinoblastoma protein, Rb mutations develop retinoblastoma. In similar fashion, mutations in the Familial adenomatous polyposis#Pathophysiology, adenomatous polyposis coli gene are linked to Familial adenomatous polyposis, adenopolyposis colon cancer, with thousands of polyps in the colon while young, whereas mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.
A new idea announced in 2011 is an extreme version of multiple mutations, called ''chromothripsis'' by its proponents. This idea, affecting only 2–3% of cases of cancer, although up to 25% of bone cancers, involves the catastrophic shattering of a chromosome into tens or hundreds of pieces and then being patched back together incorrectly. This shattering probably takes place when the chromosomes are compacted during mitosis, normal cell division, but the trigger for the shattering is unknown. Under this model, cancer arises as the result of a single, isolated event, rather than the slow accumulation of multiple mutations.
Non-mutagenic carcinogens
Many mutagens are also
carcinogen
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...
s, but some carcinogens are not mutagens. Examples of carcinogens that are not mutagens include alcohol (drug), alcohol and estrogen. These are thought to promote cancers through their stimulating effect on the rate of cell
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
. Faster rates of mitosis increasingly leave fewer opportunities for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells' receiving the wrong number of
chromosomes
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
, which leads to
aneuploidy
Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any ...
and may lead to cancer.
Role of infections
Bacterial
''
Helicobacter pylori
''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, microaerophilic, spiral (helical) bacterium usually found in the stomach. Its helical shape (from which the genus name, helicobacter, derives) is though ...
'' can cause stomach cancer, gastric cancer. Although the data varies between different countries, overall about 1% to 3% of people infected with ''Helicobacter pylori'' develop gastric cancer in their lifetime compared to 0.13% of individuals who have had no ''H. pylori'' infection.
''H. pylori'' infection is very prevalent. As evaluated in 2002, it is present in the gastric tissues of 74% of middle-aged adults in developing countries and 58% in developed countries.
Since 1% to 3% of infected individuals are likely to develop gastric cancer,
''H. pylori''-induced gastric cancer is the third highest cause of worldwide cancer mortality as of 2018.
Infection by ''H. pylori'' causes no symptoms in about 80% of those infected.
About 75% of individuals infected with ''H. pylori'' develop gastritis.
Thus, the usual consequence of ''H. pylori'' infection is chronic asymptomatic gastritis.
Because of the usual lack of symptoms, when gastric cancer is finally diagnosed it is often fairly advanced. More than half of gastric cancer patients have lymph node metastasis when they are initially diagnosed.
The gastritis caused by ''H. pylori'' is accompanied by inflammation, characterized by infiltration of neutrophils and macrophages to the gastric epithelium, which favors the accumulation of inflammatory cytokine, pro-inflammatory cytokines and
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
/reactive nitrogen species (ROS/RNS).
The substantial presence of ROS/RNS causes DNA damage including 8-oxo-2'-deoxyguanosine (8-OHdG).
If the infecting ''H. pylori'' carry the cytotoxic cagA gene (present in about 60% of Western isolates and a higher percentage of Asian isolates), they can increase the level of 8-OHdG in gastric cells by 8-fold, while if the ''H. pylori'' do not carry the cagA gene, the increase in 8-OHdG is about 4-fold.
In addition to the DNA oxidation, oxidative DNA damage 8-OHdG, ''H. pylori'' infection causes other characteristic DNA damages including DNA double-strand breaks.
''H. pylori'' also causes many Cancer epigenetics, epigenetic alterations linked to cancer development.
These Cancer epigenetics, epigenetic alterations are due to ''H. pylori''-induced CpG site#Promoter CpG hyper/hypo-methylation in cancer, methylation of CpG sites in promoters of genes
and ''H. pylori''-induced altered expression of multiple microRNAs.
As reviewed by Santos and Ribeiro
''H. pylori'' infection is associated with epigenetically reduced efficiency of the DNA repair machinery, which favors the accumulation of mutations and genomic instability as well as gastric carcinogenesis. In particular, Raza et al.
showed that expression of two DNA repair proteins,
ERCC1
DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ''ERCC1'' gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
Many aspects of these two gene ...
and
PMS2
Mismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the ''PMS2'' gene.
Function
This gene is one of the PMS2 gene family members which are found in clusters on chromosome 7. Human PMS2 related genes are located at bands ...
, was severely reduced once ''H. pylori'' infection had progressed to cause Indigestion, dyspepsia. Dyspepsia occurs in about 20% of infected individuals.
In addition, as reviewed by Raza et al.,
human gastric infection with ''H. pylori'' causes epigenetically reduced protein expression of DNA repair proteins MLH1,
MGMT
MGMT () is an American indie rock band formed in 2002 in Middletown, Connecticut. It was founded by multi-instrumentalists Andrew VanWyngarden and Ben Goldwasser. Alongside VanWyngarden and Goldwasser, MGMT's live lineup currently consists of ...
and MRE11A, MRE11. Reduced DNA repair in the presence of increased DNA damage increases carcinogenic mutations and is likely a significant cause of ''H. pylori'' carcinogenesis.
Viral
Furthermore, many cancers originate from a virus, viral infection; this is especially true in animals such as birds, but less so in humans. 12% of human cancers can be attributed to a viral infection. The mode of virally induced tumors can be divided into two, ''acutely transforming'' or ''slowly transforming''. In acutely transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly transforming viruses, the virus genome is inserted, especially as viral genome insertion is an obligatory part of
retrovirus
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...
es, near a proto-oncogene in the host genome. The viral Promoter (biology), promoter or other transcription regulation elements, in turn, cause over-expression of that proto-oncogene, which, in turn, induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly transforming viruses have very long tumor latency compared to acutely transforming virus, which already carries the viral-oncogene.
Viruses that are known to cause cancer such as HPV (cervical cancer), Hepatitis B (liver cancer), and Epstein-Barr virus, EBV (a type of lymphoma), are all DNA viruses. It is thought that when the virus infects a cell, it inserts a part of its own DNA near the cell growth genes, causing cell division. The group of changed cells that are formed from the first cell dividing all have the same viral DNA near the cell growth genes. The group of changed cells are now special because one of the normal controls on growth has been lost.
Depending on their location, cells can be damaged through radiation, chemicals from cigarette smoke, and inflammation from bacterial infection or other viruses. Each cell has a chance of damage. Cells often die if they are damaged, through failure of a vital process or the immune system, however, sometimes damage will knock out a single cancer gene. In an old person, there are thousands, tens of thousands, or hundreds of thousands of knocked-out cells. The chance that any one would form a cancer is very low.
When the damage occurs in any area of changed cells, something different occurs. Each of the cells has the potential for growth. The changed cells will divide quicker when the area is damaged by physical, chemical, or viral agents. A vicious circle has been set up: Damaging the area will cause the changed cells to divide, causing a greater likelihood that they will experience knock-outs.
This model of carcinogenesis is popular because it explains why cancers grow. It would be expected that cells that are damaged through radiation would die or at least be worse off because they have fewer genes working; viruses increase the number of genes working.
One thought is that we may end up with thousands of vaccines to prevent every virus that can change our cells. Viruses can have different effects on different parts of the body. It may be possible to prevent a number of different cancers by immunizing against one viral agent. It is likely that HPV, for instance, has a role in cancers of the mucous membranes of the mouth.
Helminthiasis
Certain parasitic worms are known to be carcinogenic.
These include:
* ''Clonorchis sinensis'' (the organism causing Clonorchiasis) and ''Opisthorchis viverrini'' (causing Opisthorchiasis) are associated with cholangiocarcinoma.
* ''Schistosoma species'' (the organisms causing Schistosomiasis) is associated with bladder cancer.
Epigenetics
Epigenetics is the study of the regulation of gene expression through chemical, non-mutational changes in DNA structure. The theory of epigenetics in cancer pathogenesis is that non-mutational changes to DNA can lead to alterations in gene expression. Normally,
oncogenes
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. are silent, for example, because of DNA methylation. Loss of that methylation can induce the aberrant expression of
oncogenes
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. , leading to cancer pathogenesis. Known mechanisms of epigenetic change include DNA methylation, and methylation or acetylation of histone proteins bound to chromosomal DNA at specific locations. Classes of medications, known as Histone deacetylase inhibitor, HDAC inhibitors and DNA methyltransferase inhibitors, can re-regulate the epigenetic signaling in the
cancer cell
Cancer cells are cells that divide continually, forming solid tumors or flooding the blood with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these d ...
.
Epigenetics, Epimutations include methylations or demethylations of the CpG islands of the Promoter (genetics), promoter regions of genes, which result in repression or de-repression, respectively of gene expression. Epimutations can also occur by acetylation, methylation, phosphorylation or other alterations to histones, creating a histone code that represses or activates gene expression, and such histone epimutations can be important epigenetic factors in cancer. In addition, carcinogenic epimutation can occur through alterations of chromosome architecture caused by proteins such as HMGA2. A further source of epimutation is due to increased or decreased expression of microRNAs (miRNAs). For example, extra expression of miR-137 can cause downregulation of expression of 491 genes, and miR-137 is epigenetically silenced in 32% of colorectal cancers>
Cancer stem cells
A new way of looking at carcinogenesis comes from integrating the ideas of developmental biology into oncology. The
cancer stem cell
Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. ...
hypothesis proposes that the different kinds of cells in a heterogeneous tumor arise from a single cell, termed Cancer Stem Cell. Cancer stem cells may arise from transformation of adult stem cells or Cellular differentiation, differentiated cells within a body. These cells persist as a subcomponent of the tumor and retain key stem cell properties. They give rise to a variety of cells, are capable of self-renewal and homeostatic control. Furthermore, the
relapse
In internal medicine, relapse or recidivism is a recurrence of a past (typically medical) condition. For example, multiple sclerosis and malaria often exhibit peaks of activity and sometimes very long periods of dormancy, followed by relapse or r ...
of cancer and the emergence of metastasis are also attributed to these cells. The
cancer stem cell
Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. ...
hypothesis does not contradict earlier concepts of carcinogenesis. The cancer stem cell hypothesis has been a proposed mechanism that contributes to tumour heterogeneity.
Clonal evolution
While genetic and epigenetic alterations in tumor suppressor genes and oncogenes change the behavior of cells, those alterations, in the end, result in cancer through their effects on the population of Neoplasm, neoplastic cells and their microenvironment.
Mutant cells in neoplasms compete for space and resources. Thus, a clone with a mutation in a tumor suppressor gene or oncogene will expand only in a neoplasm if that mutation gives the clone a competitive advantage over the other clones and normal cells in its microenvironment.
Thus, the process of carcinogenesis is formally a process of Darwinian
evolution
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
, known as Somatic evolution in cancer, somatic or clonal evolution.
Furthermore, in light of the Darwinistic mechanisms of carcinogenesis, it has been theorized that the various forms of cancer can be categorized as pubertal and gerontological. Anthropological research is currently being conducted on cancer as a natural evolutionary process through which natural selection destroys environmentally inferior phenotypes while supporting others. According to this theory, cancer comes in two separate types: from birth to the end of puberty (approximately age 20) teleologically inclined toward supportive group dynamics, and from mid-life to death (approximately age 40+) teleologically inclined away from overpopulated group dynamics.
See also
* Cancer cell
* Armitage–Doll multistage model of carcinogenesis
* Linear no-threshold model
* Oncogenic retroviridae protein
References
Further reading
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