Vascular channels formed by subpopulations of PECAM1+ melanoma cells

Abstract

Targeting the vasculature remains a promising approach for treating solid tumors; however, the mechanisms of tumor neovascularization are diverse and complex. Here we uncover a new subpopulation of melanoma cells that express the vascular cell adhesion molecule PECAM1, but not VEGFR-2, and participate in a PECAM1-dependent form of vasculogenic mimicry (VM). Clonally-derived PECAM1+ tumor cells coalesce to form PECAM1-dependent networks in vitro and they generate well-perfused, VEGF-independent channels in mice. The neural crest specifier AP-2α is diminished in PECAM1+ melanoma cells and is a transcriptional repressor of PECAM1. Reintroduction of AP-2α into PECAM1+ tumor cells represses PECAM1 and abolishes tube-forming ability whereas AP-2α knockdown in PECAM1− tumor cells up-regulates PECAM1 expression and promotes tube formation. Thus, VM-competent subpopulations, rather than all cells within a tumor, may instigate VM, supplant host-derived endothelium, and form PECAM1-dependent conduits that are not diminished by neutralizing VEGF.

Epithelial-to-mesenchymal transition confers pericyte properties on cancer cells

“…Recent studies show that subsets of glioma and melanoma cells (especially stem-like tumor cells) are able to switch on certain EC markers and transdifferentiate into vascular ECs (61)(62)(63)(64)(65). Such tumor-derived ECs participate in vascularization to ensure a steady supply of oxygen and nutrients for tumor growth.…”

Immunophenotyping and Transcriptomic Outcomes in PDX-Derived TNBC Tissue

“…Blood-borne cancers for example provide evidence that subclones display functional differences between each other when tested in mouse tumor models (21). Once identified, such subpopulations can be subjected to downstream analysis to elucidate cellular function (22). Some large-scale screening campaigns of cancer cell lines identified a range of potential surface markers that can be used in this fashion (23).…”

Identification and Phenotypic Plasticity of Metastatic Cells in a Mouse Model of Melanoma

“…Dudley's group described a CD31 positive cutaneous melanoma cell population that was also positive for the melanocytic marker Tyr. These CD31+/Tyr+ VM-competent tumor cells existed as stable, yet hidden subpopulations in heterogeneous melanomas [50]. The population of CD31+ cells described in this study is different in that they originally observed during heart development where a population of endocardial cells differentiated into mesenchymal heart cushion cells forming cardiac septa and valves [52].…”

“…The first evidence of EMT in cancer was noted by studies demonstrating that invasiveness and adoption of a fibroblast morphology can be achieved by down regulation of E-cadherin expression in various epithelial cancer cell lines [50,51].…”

“…In addition, re-expression of E-cadherin can reverse the invasive property of cancer cells [50,52,53]. Transforming growth factor-beta (TGF-) was shown to be a main inducer in the cancer EMT process.…”