Editing Metastasis (section)

=== 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" />