Pilot Study on “Pericytic Mimicry” and Potential Embryonic/Stem Cell Properties of Angiotropic Melanoma Cells Interacting with the Abluminal Vascular Surface

Abstract

The interaction of tumor cells with the tumor vasculature is mainly studied for its role in tumor angiogenesis and intravascular metastasis of circulating tumor cells. In addition, a specific interaction of tumor cells with the abluminal surfaces of vessels, or angiotropism, may promote the migration of angiotropic tumor cells along the abluminal vascular surfaces in a pericytic location. This process has been termed extravascular migratory metastasis.The abluminal vascular surface may also provide a vascular niche inducing or sustaining stemness to angiotropic tumor cells. This pilot study investigated if angiotropic melanoma cells might represent a subset population with pericytic and embryonic or stem cell properties. Through microarray analysis, we showed that the interaction between melanoma cells and the abluminal surface of endothelial cells triggers significant differential expression of several genes. The most significantly differentially expressed genes have demonstrated properties linked to cancer cell migration (CCL2, ICAM1 and IL6), cancer progression (CCL2, ICAM1, SELE, TRAF1, IL6, SERPINB2 and CXCL6), epithelial to mesenchymal transition (CCL2 and IL6), embryonic/stem cell properties (CCL2, PDGFB, EVX1 and CFDP1) and pericytic recruitment (PDGFB). In addition, bioinformatics-based analysis of the differentially expressed genes has shown that the most significantly enriched functional groups included development, cell movement, cancer, and embryonic development. Finally, the investigation of pericyte/mesenchymal stem cells markers via immunostaining of human melanoma samples revealed expression of PDGFRB, NG2 and CD146 by angiotropic melanoma cells. Taken together, these preliminary data are supportive of the "pericytic mimicry" by angiotropic melanoma cells, and suggest that the interaction between melanoma cells and the abluminal vascular surface induce differential expression of genes linked to cancer migration and embryonic/ stem cell properties.

Review of Pericytes in Tumor Biology

“…Building on these findings, human melanoma cells were shown to localize to both endothelial tubules formed in vitro as well as invade in a perivascular fashion when injected ex vivo into the brains of mice [6,36] . Pericyte mimicry in melanoma has been confirmed at the immunophenotypic level, where angiotropic melanoma cells express pericyte antigens PDGFR-β, NG2, and CD146 [30] . Further, microarray analysis showed increased expression of PDGF-β after migration of melanoma cells along the abluminal surface of endothelial tubules during the co-culture of endothelial cells and melanoma cells [30] , indicating increased expression of a receptor key in the endothelium's recruitment of pericytes.…”

“…Pericyte mimicry in melanoma has been confirmed at the immunophenotypic level, where angiotropic melanoma cells express pericyte antigens PDGFR-β, NG2, and CD146 [30] . Further, microarray analysis showed increased expression of PDGF-β after migration of melanoma cells along the abluminal surface of endothelial tubules during the co-culture of endothelial cells and melanoma cells [30] , indicating increased expression of a receptor key in the endothelium's recruitment of pericytes. Additionally, the interaction between the abluminal endothelial tubules and angiotropic melanoma cells induced differential expression of malignancy associated genes, linked to metastasis (CCL2, ICAM1 and IL6) and disease progression (CCL2, ICAM1, SELE, TRAF1, IL6, SERPINB2 and CXCL6) [30] .…”

“…Further, microarray analysis showed increased expression of PDGF-β after migration of melanoma cells along the abluminal surface of endothelial tubules during the co-culture of endothelial cells and melanoma cells [30] , indicating increased expression of a receptor key in the endothelium's recruitment of pericytes. Additionally, the interaction between the abluminal endothelial tubules and angiotropic melanoma cells induced differential expression of malignancy associated genes, linked to metastasis (CCL2, ICAM1 and IL6) and disease progression (CCL2, ICAM1, SELE, TRAF1, IL6, SERPINB2 and CXCL6) [30] . Angiotropism has been shown to be clinically quite relevant, as angiotropism is a poor prognostic indicator in malignant melanoma [37] .…”

“…Pericyte mimicry, or angiotropism, has been most thoroughly studied in melanoma [5,6,14,[29][30][31] . Lugassy et al first described the pericyte-like position of invading melanoma cells along the blood vessel basal lamina [32][33][34] .…”

Mesenchymal cells emerge as primary contributors to fibrosis in multiple tissues

“…In cancer research there is an emerging idea of "pericyte mimicry", prompted by the finding that a subset of melanoma cells can express the classical pericyte markers PDGFRβ and NG2 and display stem cell properties (Lugassy et al 2013). This implies that these markers are not specific to pericytes, but can be expressed by various populations of stem cells in response to environmental cues.…”