Imaging of Angiotropism/Vascular Co-Option in a Murine Model of Brain Melanoma: Implications for Melanoma Progression along Extravascular Pathways.

Laurent A Bentolila,Madhuri Wadehra,Bruno Péault,Raymond L Barnhill,Roshini Prakash,Hynda K Kleinman,Claire Lugassy,Thomas S Carmichael,Daniela Mihic-Probst

doi:10.1038/srep23834

Abstract

Angiotropism/pericytic mimicry and vascular co-option involve tumor cell interactions with the abluminal vascular surface. These two phenomena may be closely related. However, investigations of the two processes have developed in an independent fashion and different explanations offered as to their biological nature. Angiotropism describes the propensity of tumor cells to spread distantly via continuous migration along abluminal vascular surfaces, or extravascular migratory metastasis (EVMM). Vascular co-option has been proposed as an alternative mechanism by which tumors cells may gain access to a blood supply. We have used a murine brain melanoma model to analyze the interactions of GFP human melanoma cells injected into the mouse brain with red fluorescent lectin-labeled microvascular channels. Results have shown a striking spread of melanoma cells along preexisting microvascular channels and features of both vascular co-option and angiotropism/pericytic mimicry. This study has also documented the perivascular expression of Serpin B2 by angiotropic melanoma cells in the murine brain and in human melanoma brain metastases. Our findings suggest that vascular co-option and angiotropism/pericytic mimicry are closely related if not identical processes. Further studies are needed in order to establish whether EVMM is an alternative form of cancer metastasis in addition to intravascular cancer dissemination.

Highlights

Mortality from cancer is directly related to its invasion and metastatic potential
We have examined the expression of Serpin B2 in this murine brain melanoma model, as well as in a series of human melanoma brain metastases
In order to characterize the capacity of tumor cells to spread along external vascular surfaces, we examined early stages of brain tumor formation after injecting human melanoma cells directly into the brain of immuno-compromised Nu/J mice

Summary

Introduction

Mortality from cancer is directly related to its invasion and metastatic potential. Metastasis is defined by end points (metastatic lesions detected in specific organs distant from a primary tumor), but the dynamic aspect of the metastatic process to distant organs is still a subject of intense interest in cancer biology[1]. While the propensity for tumor cells to migrate along anatomic structures, such as nerves and skin appendages has been recognized for many years[6,7] this same capacity of tumor cells to spread along the external vascular surfaces had received almost no attention in the literature until recently. This extravascular tumor spread represents another interaction of tumor cells with vessels in addition to tumor angiogenesis and intravasation. It has been demonstrated that during vascular co-option in lung metastases tumor cells anchor themselves to the endothelial basement membrane of vascular channels[12]

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