The Microenvironment of Site-Specific Metastasis

Solid tumors can be visualized as an ecosystem composed of cancer and non-cancerous cells and their products, extra cellular matrix, metabolites, and numerous other factors. The cellular components of this ecosystem (termed tumor microenvironment) form an evolving signaling network. The cross talk between cancer and non-cancerous cells brings about a progressing phenotype reprograming of the interacting cells culminating either in tumor demise, dormancy, or progression. The progression of solid tumors on the road to metastasis is a stepwise process comprising well-defined steps. An early step is the formation of a pre-metastatic niche in selected organs that will ultimately host metastasis. Other progression steps are: acquisition of a migratory capacity by a subpopulation of tumor cells resulting in their detachment from the tumor mass, penetration into the circulation, extravasation into organs hosting a pre-metastatic niche, and finally the establishment of a metastatic lesion. Particular cancers usually metastasize to multiple but favored organ sites. The factors that determine organ-specific metastasis are: reciprocal recognition elements, such as integrins expressed by tumor cells as well as by the endothelium of the target organ and survival and growth factors expressed by this organ. The realization that interactions between tumors and their microenvironments play pivotal roles in driving or inhibiting tumor progression is being translated to the clinical setting in efforts to boost tumor-microenvironment interactions that inhibit tumor progression and/or oppose interactions that promote tumor progression.