A pre-metastatic niche is an environment in a secondary organ that can be conducive to the

metastasis 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, ...

of a primary tumor. Such a niche provides favorable conditions for growth, and eventual metastasis, in an otherwise foreign and hostile environment for the primary tumor cells. This concept demonstrated the fundamental role of the microenvironment in regulating tumor growth and metastasis. The discovery of the pre-metastatic niche has fostered new research regarding the potential treatment of metastases, including targeting myeloid derived suppressor cells, and stromal cell plasticity including

fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...

and

pericytes Pericytes (previously known as Rouget cells) are multi-functional mural cells of the microcirculation that wrap around the Endothelium, endothelial cells that line the Capillary, capillaries throughout the body. Pericytes are embedded in the basem ...

and perivascular smooth muscle cells and (attempts to stop the flow of

vesicles Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features o ...

from primary tumors to pre-metastatic niches in secondary organs and different combinations of microenvironment targeted therapies.

Pre-metastatic niche formation

Tumors metastasize to particular organs due to the migration of

hematopoietic Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...

bone marrow cells expressing

VEGFR1 Vascular endothelial growth factor receptor 1 is a protein that in humans is encoded by the ''FLT1'' gene. Function ''FLT1'' is a member of VEGF receptor gene family. It encodes a receptor tyrosine kinase which is activated by VEGF-A, VEGF-B, ...

(vascular endothelial growth factor receptor 1) and

stromal cell Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucos ...

s to these particular sites prior to the formation of clinically relevant metastasis. These cells along with changes in the extracellular matrix form pre-metastatic niches that support disseminated tumor cells and allow these cells to gather and more easily colonize the organ. Pre-metastatic niche formation is influenced by many different bodily processes, including the suppression of the immune system and an increase in the presence of

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

s and other growth factors. and extracellular matrix deposition and remodeling

Hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...

in the primary tumor and the movement of exosomes from the primary tumor to the secondary organ are additional phenomena that are partially responsible for the formation of pre-metastatic niches.

Role in metastasis

In order to metastasize, tumor cells should arrive at an organ with an environment conducive to their growth, such as a pre-metastatic niche. The creation of this environment is accomplished by factors from the primary tumor that alter the structure of the secondary organ in order to allow cells from the primary tumor to more easily colonize the secondary organ. Tumor cells release factors that cause bone cells to resorb and therefore increase the rate of metastasis. Bone is conducive to the metastatic process given its composition of many different kinds of cells and its ability to grow skeletal structures. Without the process of pre-metastatic niche formation, metastases are less likely to occur. There are often tumor cell deposits found in organs without a metastasis, indicating that metastases do not always proliferate in the tissues that they enter after leaving the circulatory system.

Role of the immune system

Pre-metastatic niche formation is possible due in large part to active immune suppression. Primary tumors recruit myeloid derived suppressor cells, which are myeloid cells that can inhibit

antigen presentation Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment, now ...

and

T cells A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...

mediated cytotoxicity, in order to allow the tumor cells to avoid detection by the immune system as they metastasize, and thus allows the metastasis to flourish. As the primary tumors release tumor cells into the bloodstream, myeloid cells that have been recruited by the tumor, can protect the cancer cells from detection by the adaptive immune system, which would otherwise be halting metastasis.

Myeloid progenitor cells Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...

, recruited at various different stages in their cell development, are believed to constitute much of the pre-metastatic niche, as they can protect the tumor cells from the standard immune response as the cancer cells attempt to colonize the pre-metastatic niche. Given their important role not only in protecting the growing metastasis from immune system attacks, but also in enabling

extravasation __NOTOC__ Extravasation is the leakage of a fluid out of its container into the surrounding area, especially blood or blood cells from vessels. In the case of inflammation, it refers to the movement of white blood cells from the capillaries to th ...

, myeloid cells are a key factor in the development of the pre-metastatic niche, and thus eventually in promoting metastases.

Chemokine 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 additio ...

s, a class of signaling molecules, also play a significant role in the creation of pre-metastatic niches and metastases. The primary tumor, in an attempt to evade detection by the immune system, uses chemokines in order to increase recruitment of bone marrow-derived myeloid cells to secondary organs. In addition, cancer cells from the primary tumor can be used to induce inflammation in the future site of the pre-metastatic niche in the secondary organ, which is similar to the immune response created by an infection. Thus, the large presence of immune cells allows the pre-metastatic niche to ward off attacks by the immune system and therefore allow the tumor to metastasize without inhibition. Immune suppression, combined with

hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...

and ECM, among other processes, are essential steps in allowing a primary tumor to metastasize, as they allow tumor cells to grow in a foreign and hostile environment without being destroyed by the typical response of the immune system. Specifically, necessary

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

s are depleted and

lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...

movement is decreased while

regulatory T cell The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosup ...

s, which suppress the immune system, and

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 ...

are increased.

Discovery of the pre-metastatic niche

Metastasis has typically been condensed into a few simple steps, namely that the tumor cells leave the primary tumor and travel to secondary organs via the circulatory system in an attempt to invade the foreign environment of the pre-metastatic organ. Since tumor growth is often difficult in a new and relatively hostile environment, metastasis had been considered by many to be an inefficient process, despite its high mortality rate. Although

Stephen Paget Stephen Paget (17 July 1855 – 8 May 1926) was an English surgeon and pro-vivisection campaigner. The concept of the pre-metastatic niche was discovered in David Lyden's laboratory, by Drs. David Lyden and Stergios Zacharoulis, and the pre-metastatic niche was first described and characterized by Drs. Rosandra Kaplan, Rebecca Riba, Stergios Zacharoulis et al., in 2005.

Implications for cancer treatment

The recognition of the concept of the pre-metastatic niche allows researchers to consider several new possibilities for treating cancer. One such possibility is employing methods that attempt to limit the expression of VEGFR1 in cells, thereby combating metastasis by delaying the creation of or eradicating the pre-metastatic niche altogether. Targeting hypoxia in the primary tumor and the suppression of the immune system could also stop the creation of pre-metastatic niches. Factors from the primary tumor that structurally alter the secondary organ in order to facilitate its colonization by tumor cells could also potentially be targeted in an attempt to stop metastasis. Tumor cells grown in different microenvironments yield different types of protein, indicating that varying types of oncological treatments are needed for tumors in distinct locales. It is easier to target later stages of metastasis because cancer is often not found until the earlier stages of metastasis have been completed. Thus, a combination of primary therapies and drugs that combat metastasis could be used to arrest the colonization of a secondary organ by tumor cells, as this would stop both the cells flowing from the tumor and the formation of the pre-metastatic niche. Alternatively, using drugs to stop tumor cells from migrating to pre-metastatic niches could be an effective method of halting metastases.

References

{{reflist Cancer