Tumor cells may have adhesion molecules whose ligands are expressed preferentially on the endothelial cells of the target organ.
Chemokines may have an important role in determining the target tissues for metastasis. For instance, many cancers express the chemokine receptor CXCR4, which has been implicated in the extravasation of circulating tumor cells originating from tumors such as breast cancer.
In some cases, the target tissue may be a nonpermissive environment, “unfavorable soil,” so to speak, for the growth of tumor seedlings. For example, although they are well vascularized, skeletal muscle and spleen are rarely sites of metastasis.
It must be admitted, however, that although particular tumors “prefer” certain metastatic sites, the precise localization of metastases cannot be predicted in individual patients with any form of cancer. Evidently, much to the dismay of medical students, many tumors have not read the relevant chapters of pathology textbooks! Although the molecular mechanisms of colonization are still being unraveled, a consistent theme seems to be that tumor cells secrete cytokines, growth factors, and proteases that act on the resident stromal cells, which in turn make the metastatic site habitable for the cancer cell. With a better molecular understanding of the mechanisms of metastasis, the clinician’s ability to target them therapeutically will be greatly enhanced.
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Of central importance in oncology is the question, why do only some tumors metastasize? It is sobering to realize that satisfying answers are still lacking. Some variation in metastasis clearly relates to inherent differences in the behavior of particular tumors; for example, small cell carcinoma of the lung virtually always metastasizes to distant sites, whereas with some tumors, such as basal cell carcinoma, metastasis is the exception rather than the rule. In general, large tumors are more likely to metastasize than small tumors, presumably because (all other things being equal) large tumors will have been present in the patient for longer periods of time, providing additional chances for metastasis to occur. However, tumor size and type cannot adequately explain the behavior of individual cancers, and it is still open to question whether metastasis is merely probabilistic (a matter of chance multiplied by tumor cell number and time) or reflects inherent differences in metastatic potential from tumor to tumor (a deterministic model).
The deterministic model proposes that metastasis is inevitable with certain tumors because the tumor harbors cells with a specific metastatic phenotype. As discussed earlier, as tumor cells grow they randomly accumulate mutations, creating subclones with distinct combinations of mutations. One possibility is that only rare tumor cells accumulate all of the mutations necessary for metastasis, and that this accounts for the inefficiency of the process. However, identification of metastasis-specific mutations and metastasis-specific patterns of gene expression has proven to be difficult. An alternative idea is that some tumors acquire all of the mutations needed for metastasis early in their development, and that these are the tumors that are fated to be “bad actors.” Metastasis, according to this view, is not dependent on the stochastic generation of metastatic subclones during tumor progression, but is an intrinsic property of the tumor that develops early on during carcinogenesis. These mechanisms are not mutually exclusive, and it could be that aggressive tumors acquire a metastasis-permissive gene expression pattern early in tumorigenesis, yet also require some additional random mutations to complete the metastatic phenotype. Nor can all blame be placed on tumor cells: as mentioned earlier, there is evidence that the makeup of the stroma, the presence of infiltrating immune cells, and the degree and quality of angiogenesis also influence metastasis.