Editing Metastasis (section)

== 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 [[lung]]s, [[liver]], [[brain]], and the [[bone]]s<ref name="nci" />

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).<ref name="Olteanu_2020" /> Understanding the enigma of cancer cell spread to distant sites, which accounts for over 90% of cancer-related deaths, necessitates comprehensive investigation. Key outstanding questions revolve around the survival and migration of cancer cells, such as the nucleus, as they face challenges in passage through capillary valves and hydrodynamic shear forces in the circulation system, making CTCs an unlikely source of metastasis. Moreover, understanding how cancer cells adapt to the metastatic niche and remain dormant (tumor dormancy) for extended periods presents difficult questions that require further investigation.<ref name="Olteanu_2020">{{Cite journal |vauthors=Olteanu GE, Mihai IM, Bojin F, Gavriliuc O, Paunescu V |date=August 2020 |title=The natural adaptive evolution of cancer: The metastatic ability of cancer cells |journal=Bosnian Journal of Basic Medical Sciences |volume=20 |issue=3 |pages=303–309 |doi=10.17305/bjbms.2019.4565 |pmc=7416172 |pmid=32020846}}</ref>

=== 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]]s that make up the surrounding [[extracellular matrix]] (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.<ref name="Nguyen_2007">{{Cite journal |author-link2=Joan Massagué |vauthors=Nguyen DX, Massagué J |date=May 2007 |title=Genetic determinants of cancer metastasis |journal=Nature Reviews. Genetics |volume=8 |issue=5 |pages=341–352 |doi=10.1038/nrg2101 |pmid=17440531 |s2cid=17745552}}</ref> 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]]<ref name="Zlotnik_2011">{{Cite journal |vauthors=Zlotnik A, Burkhardt AM, Homey B |date=August 2011 |title=Homeostatic chemokine receptors and organ-specific metastasis |journal=Nature Reviews. Immunology |volume=11 |issue=9 |pages=597–606 |doi=10.1038/nri3049 |pmid=21866172 |s2cid=34438005}}</ref> and [[transforming growth factor beta]].<ref name="Drabsch_2011">{{Cite journal |vauthors=Drabsch Y, ten Dijke P |date=June 2011 |title=TGF-β signaling in breast cancer cell invasion and bone metastasis |journal=Journal of Mammary Gland Biology and Neoplasia |volume=16 |issue=2 |pages=97–108 |doi=10.1007/s10911-011-9217-1 |pmc=3095797 |pmid=21494783}}</ref> The body resists metastasis by a variety of mechanisms through the actions of a class of proteins known as [[metastasis suppressor]]s, of which about a dozen are known.<ref>{{Cite journal |author-link3=Danny Welch |vauthors=Yoshida BA, Sokoloff MM, Welch DR, Rinker-Schaeffer CW |date=November 2000 |title=Metastasis-suppressor genes: a review and perspective on an emerging field |journal=Journal of the National Cancer Institute |volume=92 |issue=21 |pages=1717–1730 |doi=10.1093/jnci/92.21.1717 |pmid=11058615 |doi-access=free}}</ref>

Human cells exhibit different kinds of motion: collective [[motility]], [[mesenchyme|mesenchymal]]-type movement, and [[amoeboid movement]]. 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.<ref>{{Cite journal |vauthors=Parri M, Chiarugi P |date=September 2010 |title=Rac and Rho GTPases in cancer cell motility control |journal=Cell Communication and Signaling |volume=8 |issue=1 |pages=23 |doi=10.1186/1478-811X-8-23 |pmc=2941746 |pmid=20822528 |doi-access=free}}</ref><ref>{{Cite journal |vauthors=Friedl P, Wolf K |date=May 2003 |title=Tumour-cell invasion and migration: diversity and escape mechanisms |journal=Nature Reviews. Cancer |volume=3 |issue=5 |pages=362–374 |doi=10.1038/nrc1075 |pmid=12724734 |s2cid=5547981}}</ref>

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.<ref>{{Cite journal |vauthors=Escribano J, Chen MB, Moeendarbary E, Cao X, Shenoy V, Garcia-Aznar JM, Kamm RD, Spill F |date=May 2019 |title=Balance of mechanical forces drives endothelial gap formation and may facilitate cancer and immune-cell extravasation |journal=PLOS Computational Biology |volume=15 |issue=5 |pages=e1006395 |arxiv=1811.09326 |bibcode=2019PLSCB..15E6395E |doi=10.1371/journal.pcbi.1006395 |pmc=6497229 |pmid=31048903 |doi-access=free}}</ref> Besides forces, the regulation of various types of cell-cell and cell-matrix adhesions is crucial during metastasis.{{citation needed|date=September 2024}}

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]],<ref>{{Cite journal |vauthors=Weidner N, Semple JP, Welch WR, Folkman J |date=January 1991 |title=Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma |journal=The New England Journal of Medicine |volume=324 |issue=1 |pages=1–8 |doi=10.1056/NEJM199101033240101 |pmid=1701519 |doi-access=free}}</ref> is a crucial [[The Hallmarks of Cancer|hallmark of cancer.]] It has therefore been suggested that [[angiogenesis inhibitor]]s would prevent the growth of metastases.<ref name="Robbins" /> [[Endothelial progenitor cell]]s have been shown to have a strong influence on metastasis and angiogenesis.<ref name="pmid18187653">{{Cite journal |vauthors=Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V |date=January 2008 |title=Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis |journal=Science |volume=319 |issue=5860 |pages=195–198 |bibcode=2008Sci...319..195G |doi=10.1126/science.1150224 |pmid=18187653 |s2cid=12577022}}</ref><ref name="pmid17575055">{{Cite journal |vauthors=Nolan DJ, Ciarrocchi A, Mellick AS, Jaggi JS, Bambino K, Gupta S, Heikamp E, McDevitt MR, Scheinberg DA, Benezra R, Mittal V |date=June 2007 |title=Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization |journal=Genes & Development |volume=21 |issue=12 |pages=1546–1558 |doi=10.1101/gad.436307 |pmc=1891431 |pmid=17575055}}</ref> Endothelial progenitor cells are important in tumor growth, angiogenesis and metastasis, and can be marked using the [[ID1|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.<ref>{{Cite journal |vauthors=Mellick AS, Plummer PN, Nolan DJ, Gao D, Bambino K, Hahn M, Catena R, Turner V, McDonnell K, Benezra R, Brink R, Swarbrick A, Mittal V |date=September 2010 |title=Using the transcription factor inhibitor of DNA binding 1 to selectively target endothelial progenitor cells offers novel strategies to inhibit tumor angiogenesis and growth |journal=Cancer Research |volume=70 |issue=18 |pages=7273–7282 |doi=10.1158/0008-5472.CAN-10-1142 |pmc=3058751 |pmid=20807818}}</ref> The immune system is typically deregulated in cancer and affects many stages of tumor progression, including metastasis.{{citation needed|date=September 2024}}

[[Epigenetics|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.<ref>{{Cite journal |vauthors=Franci C, Zhou J, Jiang Z, Modrusan Z, Good Z, Jackson E, Kouros-Mehr H |year=2013 |title=Biomarkers of residual disease, disseminated tumor cells, and metastases in the MMTV-PyMT breast cancer model |journal=PLOS ONE |volume=8 |issue=3 |pages=e58183 |bibcode=2013PLoSO...858183F |doi=10.1371/journal.pone.0058183 |pmc=3592916 |pmid=23520493 |doi-access=free}}</ref>  These epigenetic modifications in metastases may allow the proliferation and survival of disseminated tumor cells in distant organs.<ref>{{Cite journal |vauthors=Lujambio A, Esteller M |date=February 2009 |title=How epigenetics can explain human metastasis: a new role for microRNAs |journal=Cell Cycle |volume=8 |issue=3 |pages=377–382 |doi=10.4161/cc.8.3.7526 |pmid=19177007 |doi-access=free}}</ref>

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.<ref name="pmid29048609">{{Cite journal |vauthors=Ratnayake WS, Apostolatos AH, Ostrov DA, Acevedo-Duncan M |date=November 2017 |title=Two novel atypical PKC inhibitors; ACPD and DNDA effectively mitigate cell proliferation and epithelial to mesenchymal transition of metastatic melanoma while inducing apoptosis |journal=International Journal of Oncology |volume=51 |issue=5 |pages=1370–1382 |doi=10.3892/ijo.2017.4131 |pmc=5642393 |pmid=29048609}}</ref>

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.<ref name="Syn_2016" />

=== 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 cavity|peritoneal]], [[pleural cavity|pleural]], pericardial, or subarachnoid spaces. For example, [[ovarian cancer|ovarian tumors]] can spread transperitoneally to the surface of the liver.{{citation needed|date=September 2024}}

==== Lymphatic spread ====

Lymphatic spread allows the transport of tumor cells to regional [[lymph node]]s 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]].
Lymphatic spread is the most common route of initial metastasis for [[carcinoma]]s.<ref name="Robbins" /> In contrast, it is uncommon for a [[sarcoma]] 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 [[prognosis|outcome]].
The lymphatic system does eventually drain from the [[thoracic duct]] and [[right lymphatic duct]] into the systemic venous system at the [[venous angle]] and into the [[brachiocephalic vein]]s, and therefore these metastatic cells can also eventually spread through the haematogenous route.{{citation needed|date=September 2024}}

[[File:Lymph node with metastatic melanoma.jpg|thumb|Lymph node with almost complete replacement by metastatic melanoma. The brown pigment is focal deposition of melanin]]

==== 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]] originating in the [[kidney]] 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 blood|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.{{citation needed|date=September 2024}}

==== Canalicular spread ====

Some tumors, especially [[carcinoma]]s 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]]).{{citation needed|date=September 2024}}

===Organ-specific targets===
[[File:Metastasis sites for common cancers.svg|thumb|240px|Main sites of metastases for some common cancer types. Primary cancers are denoted by "''...cancer''" and their main metastasis sites are denoted by "''...metastases''".<ref>List of included entries and references is found on main image page in Commons: [[Commons:File:Metastasis sites for common cancers.svg#Summary]]</ref>]]
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.<ref>{{Cite journal |vauthors=Ribatti D, Mangialardi G, Vacca A |date=December 2006 |title=Stephen Paget and the 'seed and soil' theory of metastatic dissemination |journal=Clinical and Experimental Medicine |volume=6 |issue=4 |pages=145–149 |doi=10.1007/s10238-006-0117-4 |pmid=17191105 |s2cid=26736196}}</ref> 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]].{{citation needed|date=September 2024}}

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.<ref name="Hart_1982">{{Cite journal |vauthors=Hart IR |year=1982 |title='Seed and soil' revisited: mechanisms of site-specific metastasis |journal=Cancer and Metastasis Reviews |volume=1 |issue=1 |pages=5–16 |doi=10.1007/BF00049477 |pmid=6764375 |s2cid=19573769}}</ref> For example, breast tumor cells, which gather calcium [[ion]]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 [[melanocyte]]s arise from the same [[cell line]] in the [[embryo]].<ref>{{Cite book |title=The Biology of Cancer |vauthors=Weinberg RA |date=2007 |publisher=Taylor & Francis |isbn=978-0-8153-4076-8 |location=New York}} quoted in {{cite news | vauthors = Angier N | url = https://www.nytimes.com/2007/04/03/health/03angi.html | title = Basics: A mutinous group of cells on a greedy, destructive task | work = [[The New York Times]] | date = 3 April 2007}}</ref>

In 1928, [[James Ewing (pathologist)|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.<ref name="filterflow">{{Cite journal |vauthors=Scott J, Kuhn P, Anderson AR |date=July 2012 |title=Unifying metastasis--integrating intravasation, circulation and end-organ colonization |journal=Nature Reviews. Cancer |volume=12 |issue=7 |pages=445–446 |doi=10.1038/nrc3287 |pmc=4533867 |pmid=22912952}}</ref> However, contemporary evidences indicate that the primary tumour may dictate organotropic metastases by inducing the formation of [[pre-metastatic niche]]s at distant sites, where incoming metastatic cells may engraft and colonise.<ref name="Syn_2016">{{Cite journal |vauthors=Syn N, Wang L, Sethi G, Thiery JP, Goh BC |date=July 2016 |title=Exosome-Mediated Metastasis: From Epithelial-Mesenchymal Transition to Escape from Immunosurveillance |journal=Trends in Pharmacological Sciences |volume=37 |issue=7 |pages=606–617 |doi=10.1016/j.tips.2016.04.006 |pmid=27157716}}</ref> 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.<ref name="Syn_2016" />

=== 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 unit]]s 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]] (CUP) or [[unknown primary tumors]] (UPT).<ref>{{Cite journal |vauthors=Ettinger DS, Agulnik M, Cates JM, Cristea M, Denlinger CS, Eaton KD, Fidias PM, Gierada D, Gockerman JP, Handorf CR, Iyer R, Lenzi R, Phay J, Rashid A, Saltz L, Shulman LN, Smerage JB, Varadhachary GR, Zager JS, Zhen WK |date=December 2011 |title=NCCN Clinical Practice Guidelines Occult primary |journal=Journal of the National Comprehensive Cancer Network |volume=9 |issue=12 |pages=1358–1395 |doi=10.6004/jnccn.2011.0117 |pmid=22157556 |doi-access=free}}</ref> It is estimated that 3% of all cancers are of unknown primary origin.<ref name="CUP-Oncologist">{{Cite journal |vauthors=Briasoulis E, Pavlidis N |year=1997 |title=Cancer of Unknown Primary Origin |journal=The Oncologist |volume=2 |issue=3 |pages=142–152 |doi=10.1634/theoncologist.2-3-142 |pmid=10388044 |doi-access=free}}</ref> Studies have shown that, if simple questioning does not reveal the cancer's source (coughing up blood—"probably [[lung cancer|lung]]", urinating blood—"probably [[bladder cancer|bladder]]"), complex imaging will not either.<ref name="CUP-Oncologist" /> In some of these cases a primary tumor may appear later.{{citation needed|date=September 2024}}

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.{{citation needed|date=September 2024}}