Figure 6. Models to Explain the Acquisition of Molecular Alterations in Metastasis Virulence Genes.

A number of models have recently been proposed in order to explain how tumor cell populations evolve to acquire molecular alterations in metastasis virulence genes. (A) The normal differentiation programs of the cells-of-origin from which certain primary tumors are derived may already dictate the altered activity of various metastasis virulence genes (depicted in gray). Upon subsequent oncogenic transformation and systemic dissemination, these cells may therefore be capable of completing the process of metastatic colonization. (B) Cells that are only partially metastasis-competent (i.e., tumor cells that have acquired a series of mutations that confer the capacity to disseminate systemically, but are initially unable to colonize foreign microenvironments) may arrive at distant organs, where they then undergo further genetic and/or epigenetic evolution within these foreign microenvironments in order to achieve full metastatic competence. Such molecular evolution would likely include alterations in metastasis virulence genes. (C) Purely by chance, mutations in metastasis virulence genes may accumulate stochastically as “passenger mutations” within tumor cell clones that bear unrelated “driver mutations” that serve to fuel the clonal expansion of these cells within primary tumors. (D) The phenomenon of tumor self-seeding indicates that already-metastasized cells are capable of re-infiltrating the primary tumor from which they originated. Hence, carcinoma cells present in metastases (which have come to acquire molecular alterations in metastasis virulence genes via either of the models proposed above – as indicated by the asterisk) may become increasingly represented within their primary-tumor-of-origin (re-infiltrating cells are depicted in blue). (E) The parallel progression model asserts that quasi-normal epithelial cells (depicted in orange) disseminate very early from pre-neoplastic lesions. Subsequently, these cells undergo molecular evolution at future sites of metastasis formation. Notably, such sites represent locations where mutations in metastasis virulence genes are now selectively advantageous. Carcinoma cells are depicted in red.