Angiotropism, Pericytic Mimicry and Extravascular Migratory Metastasis in Melanoma: An Alternative to Intravascular Cancer Dissemination

Abstract

For more than 15 years, angiotropism in melanoma has been emphasized as a marker of extravascular migration of tumor cells along the abluminal vascular surface, unveiling an alternative mechanism of tumor spread distinct from intravascular dissemination. This mechanism has been termed extravascular migratory metastasis (EVMM). During EVMM, angiotropic tumor cells migrate in a 'pericytic-like' manner (pericytic mimicry) along the external surfaces of vascular channels, without intravasation. Through this pathway, melanoma cells may spread to nearby or more distant sites. Angiotropism is a prognostic factor predicting risk for metastasis in human melanoma, and a marker of EVMM in several experimental models. Importantly, analogies of EVMM and pericytic mimicry include neural crest cell migration, vasculogenesis and angiogenesis, and recent studies have suggested that the interaction between melanoma cells and the abluminal vascular surface induce differential expression of genes reminiscent of cancer migration and embryonic/stem cell state transitions. A recent work revealed that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression via angiotropism and migration along the abluminal vascular surface. Finally, recent data using imaging of melanoma cells in a murine model have shown the progression of tumor cells along the vascular surfaces. Taken together, these data provide support for the biological phenomenon of angiotropism and EVMM, which may open promising new strategies for reducing or preventing melanoma metastasis.

Cancer cell motility: lessons from migration in confined spaces

“…An increasing amount of evidence generated using intravital microscopy reveals that migration tracks are not created solely by matrix remodelling but also occur naturally in healthy tissues 6,11 . Examples include tracks along ECM fibres in the interstitial space 7,9,11 , between muscle and nerve fibres 11 , along or within blood vessels 23,24 and in the vasculature of target organs 25,26 . The different forms of migration tracks are illustrated schematically in FIG.…”

Lymphatic invasion and angiotropism in primary cutaneous melanoma

“…[53][54][55][56][57] It has been hypothesized that the interaction of melanoma cells with the abluminal vascular surface recapitulates embryonic migration of neural crest cells through pericyte mimicry. [58][59][60] Prior studies have shown that neural crest cells migrate along the external surface of microvascular channels during embryogenesis. 61,62 Interestingly, angiotropism has been identified in many congenital nevi, suggesting that EVMM may be an important mechanism for the development of these benign melanocytic lesions.…”

Replacement and desmoplastic histopathological growth patterns: A pilot study of prediction of outcome in patients with uveal melanoma liver metastases

“…Angiotropic tumour cells can spread along the abluminal surfaces of vessels without entering the vascular channels (intravasation), therefore making use of the blood vascular network as a track . As mentioned earlier, this tumour cell migration has been termed EVMM and is believed to represent a mechanism of tumour spread independent of intravasation and haematogenous dissemination .…”