Your question is very timely and a difficult one to answer. There are numerous mechanisms by which a cell may gain a metastatic phenotype. However in very basic terms, the acquisition of metastasis requires several fundamental steps including (1) loss of cell-cell adhesion, (2) acquisition of motility and (3) the ability to digest through the basement membrane to enter the circulation. The process of epithelial mesenchymal transition (EMT) is thought to be a primary mechanism underlying the development of metastatic potential.

Cancer stem cells (CSCs) are also thought to play a critical role in cancer progression, metastasis and the development of therapeutic resistance. The process of EMT has been linked to CSCs.

Metastasis suppressors are genes that inhibit metastasis formation without altering primary tumor formation. Loss of expression of these genes promotes metastasis (reviewed in: Nat Rev Clin Oncol. 2011 Jun;8(6):333-42).

Hopefully this will give you a starting point in your quest to answer the important question as to how cancer cells learn to become metastatic.

http://www.gentaurpub.com/metastasis/bWV0YXN0YXNpcw==.html

Your question is very timely and a difficult one to answer. There are numerous mechanisms by which a cell may gain a metastatic phenotype. However in very basic terms, the acquisition of metastasis requires several fundamental steps including (1) loss of cell-cell adhesion, (2) acquisition of motility and (3) the ability to digest through the basement membrane to enter the circulation. The process of epithelial mesenchymal transition (EMT) is thought to be a primary mechanism underlying the development of metastatic potential.

Cancer stem cells (CSCs) are also thought to play a critical role in cancer progression, metastasis and the development of therapeutic resistance. The process of EMT has been linked to CSCs.

Metastasis suppressors are genes that inhibit metastasis formation without altering primary tumor formation. Loss of expression of these genes promotes metastasis (reviewed in: Nat Rev Clin Oncol. 2011 Jun;8(6):333-42).

Hopefully this will give you a starting point in your quest to answer the important question as to how cancer cells learn to become metastatic.

To the above, I would add a recommendation to read the very informative paper "Circulating Tumor Cells" (2013) by Plaks, Koopman, and Werb, Science 341(6151), 1186-1188. It gives a very nice overview of the role of blood circulation in tumor metastasis. One of the aspects it emphasizes is that "circulating tumor cell genomics" is still in its infancy, in part due to technological inability to isolate enough cells to analyze somatic mutations that would help explain the underlying mechanisms.

Well the answer is going to be contextual. Cancer cells acquire mutations and within which arose a population capable of leaving the primary site-dislodge in the circulation - cells then adhere to capillaries - intravasate in the target organ - and grow - resulting in clinically detectable metastasis. Hence metastasis is a process - an evolving "inefficient" process. So the cancer cells so called “learn” a large proportion in the primary site.

For example Breast cancer, when depict a signature at the primary site {MMP1, CXCL1, PTGS2, ID1, VCAM1 and EREG (validated genes of extensive list)} (Minn AJ et al Nature 2005) they metastasize to the lung. Whereas primary breast cancer cells when display a signature that comprise of ST6GALNAC5, COX2, HBEGF appear to metastasize to the brain (again 3 out of extensive list) (Bos et al., 2009 Nature). Further Bone metastasis is mediated partly by IL11 and CTGF expression in primary tumors (Kang et al., 2003 Cancer Cell).

To reiterate, the cells “learn” to invade, extravasate the primary site by expression of invasion markers may be common to a lot of cancers, but it’s highly likely that the primary tumor gene expression, will determine the seeding in the distant organs. Lets say for example if ST6GALNAC5 is overexpressed in primary tumors then the cells are able to adhere to the endothelial capillaries of the brain- and intravasate and colonize the brain tissue (Bos et al., Nature). Its also important to note that all the cells that adhere to the capillary will not survive (remember metastasis is inefficient), so the cells that are able to express markers that will help their survival in the foreign environment will survive. For this – Serpins (SERPINEB2 and Neuroserpin) it is important to overexpress these markers by Breast/Lung cancer in order for them to metastasize to the brain (Valiente M. et al 2014 Cell).

This being said there is not going to be a correlation always, of the primary tumor expressing genes that will mediate metastasis, in fact there may not be any correlation (Nolte S et al., 2013 JNCI). This is reasoned (theoretically) by virtue of a primary tumor which is evolving, metastasized to a certain organ first- then the cells are seeded again -seeded cells later gave the target metastasis which “we” study (Valiente M. et al., 2014 Cell, Vanharanta and Massague 2013 Cancer Cell). Hence the gene signature of metastatic site may not be in correlation with the primary tumor.

I would highly recommend this review (Vanharanta and Massague 2013 Cancer Cell) which is an outstanding piece in understanding the “up-todate” fundamentals of mediating metastasis largely in a breast cancer context.

One could describe the process (in its basic terms) as either "pleomorphism" or "Darwin in action." Most cancers evolve when normal cells go haywire - I.e., by forming daughters genetically unlike themselves. In general, the more pleomorphic a tumor (the greater the variation in shape/size/genetic structures/etc. from cell to cell.) the more malignant its behavior. (I showed this with ocular melanomas.) Eventually, in certain cases, one or more daughters acquires the capacities needed to metastasize, and by survival of the fittest these come to dominate the tumor population. We might get more insight by studying basal cell cancer, which (no matter how aggressive its local extension) NEVER metastasizes.

John Gamel

In addition - because of hypoxia and of changed microenvironment.

Regarding metastasis:  Cancer cells have clonally flexible karyotypes.  As a result karyotypic variants are generated spontaneously, which have a new or variant host range and thus grow in non-native tissues.  See attached paper for, details: "Origin of metastases, Subspecies of cancers generated by intrinsic karyotypic variations" Cell Cycle, 2012.

Peter Duesberg

University of California at Berkeley