Metastasis is a
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 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
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 ...
ous tumor.
The newly pathological sites, then, are metastases (mets). It is generally distinguished from
cancer invasion
For cancer, invasion is the direct extension and penetration by cancer cells into neighboring tissues. It is generally distinguished from metastasis, which is the spread of cancer cells through the circulatory system or the lymphatic system to m ...
, which is the direct extension and penetration by cancer cells into neighboring tissues.
Cancer occurs after cells are genetically altered to proliferate rapidly and indefinitely. This uncontrolled proliferation by
mitosis produces a
primary heterogeneic tumour. The cells which constitute the tumor eventually undergo
metaplasia
Metaplasia ( gr, "change in form") is the transformation of one differentiated cell type to another differentiated cell type. The change from one type of cell to another may be part of a normal maturation process, or caused by some sort of abno ...
, followed by
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 microscopi ...
then
anaplasia
Anaplasia (from grc, ἀνά ''ana'', "backward" + πλάσις ''plasis'', "formation") is a condition of cells with poor cellular differentiation, losing the morphological characteristics of mature cells and their orientation with respect to e ...
, resulting in a
malignant
Malignancy () is the tendency of a medical condition to become progressively worse.
Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...
phenotype. This malignancy allows for invasion into the circulation, followed by invasion to a second site for
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 abnor ...
.
Some cancer cells known as
circulating tumor cells acquire the ability to penetrate the walls of
lymphatic
Lymph (from Latin, , meaning "water") is the fluid that flows through the lymphatic system, a system composed of lymph vessels (channels) and intervening lymph nodes whose function, like the venous system, is to return fluid from the tissues to ...
or
blood vessel
The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away ...
s, after which they are able to circulate through the bloodstream to other sites and tissues in the body. This process is known (respectively) as ''lymphatic'' or ''hematogenous'' spread. After the tumor cells come to rest at another site, they re-penetrate the vessel or walls and continue to multiply, eventually forming another clinically detectable tumor. This new tumor is known as a metastatic (or ''secondary'') tumor. Metastasis is one of the
hallmarks of cancer
The hallmarks of cancer were originally six biological capabilities acquired during the multistep development of human tumors and have since been increased to eight capabilities and two enabling capabilities. The idea was coined by Douglas Hanah ...
, distinguishing it from
benign tumor
A benign tumor is a mass of cells (tumor) that does not invade neighboring tissue or metastasize (spread throughout the body). Compared to malignant (cancerous) tumors, benign tumors generally have a slower growth rate. Benign tumors have re ...
s.
[
] Most cancers can metastasize, although in varying degrees.
Basal cell carcinoma
Basal-cell carcinoma (BCC), also known as basal-cell cancer, is the most common type of skin cancer. It often appears as a painless raised area of skin, which may be shiny with small blood vessels running over it. It may also present as a raise ...
for example rarely metastasizes.
When tumor cells metastasize, the new tumor is called a ''secondary'' or ''metastatic'' tumor, and its cells are similar to those in the original or
primary tumor A primary tumor is a tumor growing at the anatomical site where tumor progression began and proceeded to yield a cancerous mass. Most cancers develop at their primary site but then go on to metastasize or spread to other parts of the body. These fur ...
. This means that if
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...
metastasizes to the lungs, the secondary tumor is made up of abnormal breast cells, not of abnormal lung cells. The tumor in the lung is then called ''metastatic breast cancer'', not ''lung cancer''. Metastasis is a key element in
cancer staging
Cancer staging is the process of determining the extent to which a cancer has developed by growing and spreading. Contemporary practice is to assign a number from I to IV to a cancer, with I being an isolated cancer and IV being a cancer that ha ...
systems such as the
TNM staging system
The TNM Classification of Malignant Tumors (TNM) is a globally recognised standard for classifying the extent of spread of cancer. It is a classification system of the anatomical extent of tumor cancers. It has gained wide international acceptance ...
, where it represents the "M". In
overall stage grouping, metastasis places a cancer in Stage IV. The possibilities of curative treatment are greatly reduced, or often entirely removed when a cancer has metastasized.
Signs and symptoms
![Secondary tumor deposits in the liver from a primary cancer of the pancreas](https://upload.wikimedia.org/wikipedia/commons/5/53/Secondary_tumor_deposits_in_the_liver_from_a_primary_cancer_of_the_pancreas.jpg)
Initially, nearby lymph nodes are struck early.
[ The ]lungs
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side ...
, liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
, brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...
, and bone
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...
s are the most common metastasis locations from solid tumors.[
* In ]lymph node metastasis Lymph node metastasis is the spread (metastasis) of cancer cells into a lymph node.
Lymph node metastasis is different from malignant lymphoma. Lymphoma is a cancer ''of'' lymph node, rather than cancer ''in'' the lymph node, because lymphoma or ...
, a common symptom is lymphadenopathy
* Lung metastasis: cough
A cough is a sudden expulsion of air through the large breathing passages that can help clear them of fluids, irritants, foreign particles and microbes. As a protective reflex, coughing can be repetitive with the cough reflex following three ph ...
, hemoptysis
Hemoptysis is the coughing up of blood or blood-stained mucus from the bronchi, larynx, trachea, or lungs. In other words, it is the airway bleeding. This can occur with lung cancer, infections such as tuberculosis, bronchitis, or pneumonia, a ...
and dyspnea
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...
[ (shortness of breath)
* ]Liver metastasis
A liver metastasis is a malignant tumor in the liver that has spread from another organ affected by cancer. The liver is a common site for metastatic disease because of its rich, dual blood supply (the liver receives blood via the hepatic artery a ...
: hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdo ...
(enlarged liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
), nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
[ and jaundice][
* ]Bone metastasis
Bone metastasis, or osseous metastatic disease, is a category of cancer metastases that results from primary tumor invasion to bone. Bone-originating primary tumors such as osteosarcoma, chondrosarcoma, and Ewing's sarcoma are rare; the most com ...
: bone pain,[National Cancer Institute: Metastatic Cancer: Questions and Answers](_blank)
Retrieved on 2008-11-01 fracture of affected bones[
* ]Brain metastasis
A brain metastasis is a cancer that has metastasized (spread) to the brain from another location in the body and is therefore considered a secondary brain tumor. The metastasis typically shares a cancer cell type with the original site of the c ...
: neurological
Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
symptoms such as headaches,[ seizures,][ and ]vertigo
Vertigo is a condition where a person has the sensation of movement or of surrounding objects moving when they are not. Often it feels like a spinning or swaying movement. This may be associated with nausea, vomiting, sweating, or difficulties w ...
[
Although advanced cancer may cause pain, it is often not the first symptom.
Some patients, however, do not show any symptoms.][
When the organ gets a metastatic disease it begins to shrink until its ]lymph nodes
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...
burst, or undergo lysis.
Pathophysiology
Metastatic tumors are very common in the late stages of cancer. The spread of metastasis may occur via the blood or the lymphatics or through both routes. The most common sites of metastases are the lungs, liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
, brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...
, and the bone
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...
s.
Currently, three main theories have been proposed to explain the metastatic pathway of cancer: the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) hypothesis (1), the cancer stem cell hypothesis (2), and the macrophage–cancer cell fusion hybrid hypothesis (3). Some new hypotheses were suggested as well, i.e., under the effect of particular biochemical and/or physical stressors, cancer cells can undergo nuclear expulsion with subsequent macrophage engulfment and fusion, with the formation of cancer fusion cells (CFCs).
Factors involved
Metastasis involves a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via the bloodstream, via the lymphatic system, or by direct extension. To do so, malignant cells break away from the primary tumor and attach to and degrade 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, res ...
s that make up the surrounding extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...
(ECM), which separates the tumor from adjoining tissues. By degrading these proteins, cancer cells are able to breach the ECM and escape. The location of the metastases is not always random, with different types of cancer tending to spread to particular organs and tissues at a rate that is higher than expected by statistical chance alone. Breast cancer, for example, tends to metastasize to the bones and lungs. This specificity seems to be mediated by soluble signal molecules such as chemokines
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition ...
and transforming growth factor beta
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...
. The body resists metastasis by a variety of mechanisms through the actions of a class of proteins known as metastasis suppressor
A metastasis suppressor is a protein that acts to slow or prevent metastases (secondary tumors) from spreading in the body of an organism with cancer. Metastasis is one of the most lethal cancer processes. This process is responsible for about nine ...
s, of which about a dozen are known.
Human cells exhibit different kinds of motion: collective motility
Motility is the ability of an organism to move independently, using metabolic energy.
Definitions
Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...
, mesenchymal
Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every ...
-type movement, and amoeboid movement
Amoeboid movement is the most typical mode of locomotion in adherent eukaryotic cells. It is a crawling-like type of movement accomplished by protrusion of cytoplasm of the cell involving the formation of pseudopodia ("false-feet") and posterior ...
. Cancer cells often opportunistically switch between different kinds of motion. Some cancer researchers hope to find treatments that can stop or at least slow down the spread of cancer by somehow blocking some necessary step in one or more kinds of motion.
All steps of the metastatic cascade involve a number of physical processes. Cell migration requires the generation of forces, and when cancer cells transmigrate through the vasculature, this requires physical gaps in the blood vessels to form. Besides forces, the regulation of various types of cell-cell and cell-matrix adhesions is crucial during metastasis.
The metastatic steps are critically regulated by various cell types, including the blood vessel cells (endothelial cells), immune cells or stromal cells. The growth of a new network of blood vessels, called tumor angiogenesis, is a crucial hallmark of cancer. It has therefore been suggested that angiogenesis inhibitor An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels ( angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical ...
s would prevent the growth of metastases. Endothelial progenitor cell
Endothelial progenitor cell (or EPC) is a term that has been applied to multiple different cell types that play roles in the regeneration of the endothelial lining of blood vessels. Outgrowth endothelial cells are an EPC subtype committed to endot ...
s have been shown to have a strong influence on metastasis and angiogenesis. Endothelial progenitor cells are important in tumor growth, angiogenesis and metastasis, and can be marked using the Inhibitor of DNA Binding 1 (ID1). This novel finding meant that investigators gained the ability to track endothelial progenitor cells from the bone marrow to the blood to the tumor-stroma and even incorporated in tumor vasculature. Endothelial progenitor cells incorporated in tumor vasculature suggests that this cell type in blood-vessel development is important in a tumor setting and metastasis. Furthermore, ablation of the endothelial progenitor cells in the bone marrow can lead to a significant decrease in tumor growth and vasculature development. Therefore, endothelial progenitor cells are important in tumor biology and present novel therapeutic targets. The immune system is typically deregulated in cancer and affects many stages of tumor progression, including metastasis.
Epigenetic regulation also plays an important role in the metastatic outgrowth of disseminated tumor cells. Metastases display alterations in histone modifications, such as H3K4-methylation and H3K9-methylation, when compared to matching primary tumors. These epigenetic modifications in metastases may allow the proliferation and survival of disseminated tumor cells in distant organs.
A recent study shows that PKC-iota promotes melanoma cell invasion by activating Vimentin during EMT. PKC-iota inhibition or knockdown resulted in an increase in E-cadherin and RhoA levels while decreasing total Vimentin, phosphorylated Vimentin (S39) and Par6 in metastatic melanoma cells. These results suggested that PKC-ι is involved in signaling pathways which upregulate EMT in melanoma thereby directly stimulates metastasis.
Recently, a series of high-profile experiments suggests that the co-option of intercellular cross-talk mediated by exosome vesicles is a critical factor involved in all steps of the invasion-metastasis cascade.
Routes
Metastasis occurs by the following four routes:
Transcoelomic
The spread of a malignancy into body cavities can occur via penetrating the surface of the peritoneal
The peritoneum is the serous membrane forming the lining of the abdominal cavity or coelom in amniotes and some invertebrates, such as annelids. It covers most of the intra-abdominal (or coelomic) organs, and is composed of a layer of meso ...
, pleural, pericardial, or subarachnoid spaces. For example, ovarian tumors
Ovarian tumors, or ovarian neoplasms, are tumors arising from the ovary. They can be benign or malignant (ovarian cancer). They consist of mainly solid tissue, while ovarian cysts contain fluid.
Histopathologic classification
Ovarian tumors ar ...
can spread transperitoneally to the surface of the liver.
Lymphatic spread
Lymphatic spread allows the transport of tumor cells to regional lymph nodes near the primary tumor and ultimately, to other parts of the body. This is called nodal involvement, positive nodes, or regional disease. "Positive nodes" is a term that would be used by medical specialists to describe regional lymph nodes that tested positive for malignancy. It is common medical practice to test by biopsy at least one lymph node near a tumor site when carrying out surgery to examine or remove a tumor. This lymph node is then called a sentinel lymph node
The sentinel lymph node is the hypothetical first lymph node or group of nodes draining a cancer. In case of established cancerous dissemination it is postulated that the sentinel lymph nodes are the target organs primarily reached by metastasiz ...
.
Lymphatic spread is the most common route of initial metastasis for carcinomas. In contrast, it is uncommon for a sarcoma
A sarcoma is a malignant tumor, a type of cancer that arises from transformed cells of mesenchymal ( connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sar ...
to metastasize via this route. Localized spread to regional lymph nodes near the primary tumor is not normally counted as a metastasis, although this is a sign of a worse outcome.
The lymphatic system does eventually drain from the thoracic duct
In human anatomy, the thoracic duct is the larger of the two lymph ducts of the lymphatic system. It is also known as the ''left lymphatic duct'', ''alimentary duct'', ''chyliferous duct'', and ''Van Hoorne's canal''. The other duct is the righ ...
and right lymphatic duct
The right lymphatic duct is an important lymphatic vessel that drains the right upper quadrant of the body. It forms various combinations with the right subclavian vein and right internal jugular vein.
Structure
The right lymphatic duct course ...
into the systemic venous system at the venous angle
The venous angle, also known as Pirogoff's angle and in Latin as angulus venosus, is the junction where the internal jugular (Latin: ''v. jugularis interna'') and subclavian (Latin: ''v. subclavia'') veins at each side of the neck merge to form t ...
and into the brachiocephalic vein
The left and right brachiocephalic veins (previously called innominate veins) are major veins in the upper chest, formed by the union of each corresponding internal jugular vein and subclavian vein. This is at the level of the sternoclavicular j ...
s, and therefore these metastatic cells can also eventually spread through the haematogenous route.
Hematogenous spread
This is typical route of metastasis for sarcomas, but it is also the favored route for certain types of carcinoma, such as renal cell carcinoma
Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the Proximal tubule, proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cance ...
originating in the kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
and follicular carcinomas of the thyroid. Because of their thinner walls, veins are more frequently invaded than are arteries, and metastasis tends to follow the pattern of venous flow. That is, hematogenous spread often follows distinct patterns depending on the location of the primary tumor. For example, colorectal cancer spreads primarily through the portal vein to the liver.
Canalicular spread
Some tumors, especially carcinomas may metastasize along anatomical canalicular spaces. These spaces include for example the bile ducts, the urinary system, the airways and the subarachnoid space. The process is similar to that of transcoelomic spread. However, often it remains unclear whether simultaneously diagnosed tumors of a canalicular system are one metastatic process or in fact independent tumors caused by the same agent (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 ...
).
Organ-specific targets
There is a propensity for certain tumors to seed in particular organs. This was first discussed as the "seed and soil" theory by Stephen Paget in 1889. The propensity for a metastatic cell to spread to a particular organ is termed 'organotropism'. For example, prostate cancer usually metastasizes to the bones. In a similar manner, colon cancer has a tendency to metastasize to the liver. Stomach cancer often metastasises to the ovary in women, when it is called a Krukenberg tumor.
According to the "seed and soil" theory, it is difficult for cancer cells to survive outside their region of origin, so in order to metastasize they must find a location with similar characteristics. For example, breast tumor cells, which gather calcium ion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
s from breast milk, metastasize to bone tissue, where they can gather calcium ions from bone. Malignant melanoma spreads to the brain, presumably because neural tissue and melanocytes arise from the same cell line in the embryo.
In 1928, James Ewing challenged the "seed and soil" theory and proposed that metastasis occurs purely by anatomic and mechanical routes. This hypothesis has been recently utilized to suggest several hypotheses about the life cycle of circulating tumor cells (CTCs) and to postulate that the patterns of spread could be better understood through a 'filter and flow' perspective. However, contemporary evidences indicate that the primary tumour may dictate organotropic metastases by inducing the formation of pre-metastatic niches at distant sites, where incoming metastatic cells may engraft and colonise. Specifically, exosome vesicles secreted by tumours have been shown to home to pre-metastatic sites, where they activate pro-metastatic processes such as angiogenesis and modify the immune contexture, so as to foster a favourable microenvironment for secondary tumour growth.
Metastasis and primary cancer
It is theorized that metastasis always coincides with a primary cancer, and, as such, is a tumor that started from a cancer cell or cells in another part of the body. However, over 10% of patients presenting to oncology units will have metastases without a primary tumor found. In these cases, doctors refer to the primary tumor as "unknown" or "occult," and the patient is said to have cancer of unknown primary origin
Cancer of unknown primary origin (CUP) is a cancer that is determined to be at the metastatic stage at the time of diagnosis, but a primary tumor cannot be identified. A diagnosis of CUP requires a clinical picture consistent with metastatic di ...
(CUP) or unknown primary tumors (UPT). It is estimated that 3% of all cancers are of unknown primary origin. Studies have shown that, if simple questioning does not reveal the cancer's source (coughing up blood—"probably lung", urinating blood—"probably bladder
The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine enters ...
"), complex imaging will not either. In some of these cases a primary tumor may appear later.
The use of immunohistochemistry has permitted pathologists to give an identity to many of these metastases. However, imaging of the indicated area only occasionally reveals a primary. In rare cases (e.g., of melanoma), no primary tumor is found, even on autopsy. It is therefore thought that some primary tumors can regress completely, but leave their metastases behind. In other cases, the tumor might just be too small and/or in an unusual location to be diagnosed.
Diagnosis
The cells in a metastatic tumor resemble those in the primary tumor. Once the cancerous tissue is examined under a microscope to determine the cell type, a doctor can usually tell whether that type of cell is normally found in the part of the body from which the tissue sample was taken.
For instance, breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...
cells look the same whether they are found in the breast or have spread to another part of the body. So, if a tissue sample taken from a tumor in the lung contains cells that look like breast cells, the doctor determines that the lung tumor is a secondary tumor. Still, the determination of the primary tumor can often be very difficult, and the pathologist may have to use several adjuvant techniques, such as immunohistochemistry, FISH ( fluorescent in situ hybridization), and others. Despite the use of techniques, in some cases the primary tumor remains unidentified.
Metastatic cancers may be found at the same time as the primary tumor, or months or years later. When a second tumor is found in a patient that has been treated for cancer in the past, it is more often a metastasis than another primary tumor.
It was previously thought that most cancer cells have a low metastatic potential and that there are rare cells that develop the ability to metastasize through the development of somatic mutations. According to this theory, diagnosis of metastatic cancers is only possible after the event of metastasis. Traditional means of diagnosing cancer (e.g. a biopsy
A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a dise ...
) would only investigate a subpopulation of the cancer cells and would very likely not sample from the subpopulation with metastatic potential.
The somatic mutation theory of metastasis development has not been substantiated in human cancers. Rather, it seems that the genetic state of the primary tumor reflects the ability of that cancer to metastasize. Research comparing gene expression between primary and metastatic adenocarcinomas
Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ) (AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or ...
identified a subset of genes whose expression could distinguish primary tumors from metastatic tumors, dubbed a "metastatic signature." Up-regulated genes in the signature include: SNRPF
Small nuclear ribonucleoprotein F is a protein that in humans is encoded by the ''SNRPF'' gene.
Interactions
Small nuclear ribonucleoprotein polypeptide F has been shown to interact with DDX20, Small nuclear ribonucleoprotein D2 and Small nucl ...
, HNRPAB
Heterogeneous nuclear ribonucleoprotein A/B, also known as HNRNPAB, is a protein which in humans is encoded by the ''HNRNPAB'' gene. Although this gene is named ''HNRNPAB'' in reference to its first cloning as an RNA binding protein with similarit ...
, DHPS
Deoxyhypusine synthase is an enzyme that in humans is encoded by the ''DHPS'' gene.
The unusual amino acid hypusine is formed posttranslationally and is only found in a single cellular protein, eukaryotic translation initiation factor 5A (EIF5A, ...
and securin Securin is a protein involved in control of the metaphase-anaphase transition and anaphase onset. Following bi-orientation of chromosome pairs and inactivation of the spindle checkpoint system, the underlying regulatory system, which includes secu ...
. Actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
, myosin and MHC class II
MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial ce ...
down-regulation was also associated with the signature. Additionally, the metastatic-associated expression of these genes was also observed in some primary tumors, indicating that cells with the potential to metastasize could be identified concurrently with diagnosis of the primary tumor. Recent work identified a form of genetic instability in cancer called chromosome instability (CIN) as a driver of metastasis. In aggressive cancer cells, loose DNA fragments from unstable chromosomes spill in the cytosol leading to the chronic activation of innate immune pathways, which are hijacked by cancer cells to spread to distant organs.
Expression of this metastatic signature has been correlated with a poor prognosis and has been shown to be consistent in several types of cancer. Prognosis was shown to be worse for individuals whose primary tumors expressed the metastatic signature. Additionally, the expression of these metastatic-associated genes was shown to apply to other cancer types in addition to adenocarcinoma. Metastases of breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...
, medulloblastoma
Medulloblastoma is a common type of primary brain cancer in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the cerebellum, or posterior fossa.
The brain is divided into two ...
and prostate cancer all had similar expression patterns of these metastasis-associated genes.
The identification of this metastasis-associated signature provides promise for identifying cells with metastatic potential within the primary tumor and hope for improving the prognosis of these metastatic-associated cancers. Additionally, identifying the genes whose expression is changed in metastasis offers potential targets to inhibit metastasis.
File:Bone metastasis.jpg, Cut surface of a humerus sawn lengthwise, showing a large 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 ...
ous metastasis (the whitish tumor between the head and the shaft of the bone)
File:Lymph node with papillary thyroid carcinoma.jpg, Micrograph
A micrograph or photomicrograph is a photograph or digital image taken through a microscope or similar device to show a magnified image of an object. This is opposed to a macrograph or photomacrograph, an image which is also taken on a m ...
of thyroid cancer (papillary thyroid carcinoma
Papillary thyroid cancer or papillary thyroid carcinoma is the most common type of thyroid cancer, representing 75 percent to 85 percent of all thyroid cancer cases.Chapter 20 in: 8th edition. It occurs more frequently in women and presents in th ...
) in a lymph node of the neck. H&E stain
Hematoxylin and eosin stain ( or haematoxylin and eosin stain or hematoxylin-eosin stain; often abbreviated as H&E stain or HE stain) is one of the principal tissue stains used in histology. It is the most widely used stain in medical diagnos ...
File:MultipleLiverMets2008.jpg, CT image of multiple liver metastases
File:LungMets2008.jpg, CT image of a lung metastasis
File:Adenocarcinoma liver metastasis.jpg, Metastasis proven by liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
biopsy
A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a dise ...
(tumor ( adenocarcinoma)—lower two-thirds of image). H&E stain
Hematoxylin and eosin stain ( or haematoxylin and eosin stain or hematoxylin-eosin stain; often abbreviated as H&E stain or HE stain) is one of the principal tissue stains used in histology. It is the most widely used stain in medical diagnos ...
.
File:MetsToLungs.png, Metastatic cancer in the lungs
File:MetstoBrain(LungPri)Mark.png, Metastases from the lungs to the brain
File:Metstopancrease.png, Metastases from the lungs to the pancreas
Management
Treatment and survival is determined, to a great extent, by whether or not a cancer remains localized or spreads to other locations in the body. If the cancer metastasizes to other tissues or organs it usually dramatically increases a patient's likelihood of death. Some cancers—such as some forms 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 ...
, a cancer of the blood, or malignancies in the brain—can kill without spreading at all.
Once a cancer has metastasized it may still be treated with radiosurgery, chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
, radiation therapy
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. Radi ...
, biological therapy, hormone therapy, surgery, or a combination of these interventions ("multimodal therapy"). The choice of treatment depends on many factors, including the type of primary 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 ...
, the size and location of the metastases, the patient's age and general health, and the types of treatments used previously. In patients diagnosed with CUP it is often still possible to treat the disease even when the primary tumor cannot be located.
Current treatments are rarely able to cure metastatic cancer though some tumors, such as testicular cancer
Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system. Symptoms may include a lump in the testicle, or swelling or pain in the scrotum. Treatment may result in infertility.
Risk factors include an ...
and thyroid cancer
Thyroid cancer is cancer that develops from the tissues of the thyroid gland. It is a disease in which cells grow abnormally and have the potential to spread to other parts of the body. Symptoms can include swelling or a lump in the neck. C ...
, are usually curable.
Palliative care
Palliative care (derived from the Latin root , or 'to cloak') is an interdisciplinary medical caregiving approach aimed at optimizing quality of life and mitigating suffering among people with serious, complex, and often terminal illnesses. Wit ...
, care aimed at improving the quality of life of people with major illness, has been recommended as part of management programs for metastasis. Results from a systematic review of the literature on radiation therapy for brain metastases found that there is little evidence to inform comparative effectiveness and patient-centered outcomes on quality of life, functional status, and cognitive effects.
Research
Although metastasis is widely accepted to be the result of the tumor cells migration, there is a hypothesis
A hypothesis (plural hypotheses) is a proposed explanation for a phenomenon. For a hypothesis to be a scientific hypothesis, the scientific method requires that one can test it. Scientists generally base scientific hypotheses on previous obse ...
saying that some metastases are the result of inflammatory processes by abnormal immune cells. The existence of metastatic cancers in the absence of primary tumors also suggests that metastasis is not always caused by malignant cells that leave primary tumors.
The research done by Sarna's team proved that heavily pigmented melanoma cells have Young's modulus
Young's modulus E, the Young modulus, or the modulus of elasticity in tension or compression (i.e., negative tension), is a mechanical property that measures the tensile or compressive stiffness of a solid material when the force is applied le ...
about 4.93, when in non-pigmented ones it was only 0.98. In another experiment they found that elasticity of melanoma cells is important for its metastasis and growth: non-pigmented tumors were bigger than pigmented and it was much easier for them to spread. They shown that there are both pigmented and non-pigmented cells in melanoma tumors
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 ...
, so that they can both be drug-resistant and metastatic.
History
In March 2014 researchers discovered the oldest complete example of a human with metastatic cancer. The tumors had developed in a 3,000-year-old skeleton found in 2013 in a tomb in Sudan dating back to 1200 BC. The skeleton was analyzed using radiography and a scanning electron microscope. These findings were published in the ''Public Library of Science
PLOS (for Public Library of Science; PLoS until 2012 ) is a nonprofit publisher of open-access journals in science, technology, and medicine and other scientific literature, under an open-content license. It was founded in 2000 and laun ...
'' journal.
Etymology
Metastasis is a Greek
Greek may refer to:
Greece
Anything of, from, or related to Greece, a country in Southern Europe:
*Greeks, an ethnic group.
*Greek language, a branch of the Indo-European language family.
**Proto-Greek language, the assumed last common ancestor ...
word meaning "displacement", from μετά, ''meta'', "next", and στάσις, ''stasis'', "placement".
See also
* Abscopal effect
The abscopal effect is a hypothesis in the treatment of metastatic cancer whereby shrinkage of untreated tumors occurs concurrently with shrinkage of tumors within the scope of the localized treatment. R.H. Mole proposed the term “abscopal” ( ...
* Brain metastasis
A brain metastasis is a cancer that has metastasized (spread) to the brain from another location in the body and is therefore considered a secondary brain tumor. The metastasis typically shares a cancer cell type with the original site of the c ...
* Brown-Séquard syndrome
Brown-Séquard syndrome (also known as Brown-Séquard's hemiplegia, Brown-Séquard's paralysis, hemiparaplegic syndrome, hemiplegia et hemiparaplegia spinalis, or spinal hemiparaplegia) is caused by damage to one half of the spinal cord, i.e. hem ...
(Sections on cavernous malformation, germinoma, renal cell carcinoma and lung cancer)
* Collective cell migration Collective cell migration describes the movements of group of cells and the emergence of collective behavior from cell-environment interactions and cell-cell communication. Collective cell migration is an essential process in the lives of multicellu ...
* Contact normalization
* Disseminated disease
Disseminated disease refers to a diffuse disease-process, generally either infectious or neoplastic. The term may sometimes also characterize connective tissue disease.
A disseminated infection, for example, has extended beyond its origin or nidus ...
* Micrometastasis
A micrometastasis is a small collection of cancer cells that has been shed from the original tumor and spread to another part of the body through the lymphovascular system. Micrometastases are too few, in size and quantity, to be picked up in a sc ...
* Mouse models of breast cancer metastasis
Breast cancer metastatic mouse models are experimental approaches in which mice are genetically manipulated to develop a mammary tumor leading to distant focal lesions of mammary epithelium created by metastasis. Mammary cancers in mice can be ca ...
* Positron emission tomography (PET)
* Urogenital pelvic malignancy
References
External links
Q&A: Metastatic Cancer
from the National Cancer Institute
The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...
How does cancer spread - the route by TED-Ed
{{Authority control
Cancer pathology
Oncology