Pericyte mimicry: an embryogenesis-derived program of extravascular tumor cell migration

Abstract Intravascular dissemination of tumor cells is the accepted mechanism of cancer metastasis. However, the field of angiotropism, pericyte mimicry (PM), and extravascular migratory metastasis (EVMM) has questioned this thesis that tumor cells metastasize exclusively by circulating within vascular channels. This new paradigm of cancer spread and metastasis suggests that metastatic cells employ embryogenesis-derived mechanisms for attachment to the abluminal surfaces of blood vessels (angiotropism) and spread via progressive migration, competing with and replacing pericytes, that is, PM. This is an entirely extravascular phenomenon (i.e., EVMM) without entry (intravasation) into vascular channels. PM and EVMM have mainly been studied in melanoma but also in other cancers. PM and EVMM appear to be a reversion to an embryogenesis-derived program. There are many analogies between embryogenesis and cancer progression, including the importance of laminins, epithelial–mesenchymal transition, and the reactivation of embryonic signals by “cancer stem cells.” Furthermore, there is no circulation of blood during the first trimester of embryogenesis, despite the fact that there is extensive migration of cells to distant sites and formation of organs and tissues during this period. Embryonic migration therefore is a progressive and extravascular migration as are PM and EVMM, supporting the concept that these embryonic migratory events appear to recur abnormally during the metastatic process of many tumors. Finally, the perivascular location of tumor cells intrinsically links PM to vascular co-option. Taken together, these two new paradigms may greatly influence the development of new effective therapeutics for metastasis. In particular, targeting embryonic factors linked to migration that are detected during cancer metastasis may be particularly relevant to PM/EVMM.