Carcinoma cells that have undergone an epithelial-mesenchymal transition differentiate into endothelial cells and contribute to tumor growth

Abstract

Hypoxia stimulates neoangiogenesis, promoting tumor outgrowth, and triggers the epithelial-mesenchymal transition (EMT), which bestows cells with mesenchymal traits and multi-lineage differentiation potential. Here, we investigated whether EMT can confer endothelial attributes upon carcinoma cells, augmenting tumor growth and vascularization. Following orthotopic implantation of MCF-7 human epithelial breast cancer cells into mice, tumors of different sizes were immunostained for markers of hypoxia and EMT. Larger tumors were well-vascularized with CD31-positive cells of human origin. Hypoxic regions, demarcated by HIF-1α staining, exhibited focal areas of E-cadherin loss and elevated levels of vimentin and the EMT-mediator FOXC2. Implantation of MCF-7 cells, co-mixed with human mammary epithelial (HMLE) cells overexpressing the EMT-inducer Snail, markedly potentiated tumor growth and vascularization, compared with MCF-7 cells injected alone or co-mixed with HMLE-vector cells. Intra-tumoral vessels contained CD31-positive cells derived from either donor cell type. FOXC2 knockdown abrogated the potentiating effects of HMLE-Snail cells on MCF-7 tumor growth and vascularization, and compromised endothelial transdifferentiation of mesenchymal cells cultured in endothelial growth medium. Hence, cells that have undergone EMT can promote tumor growth and neovascularization either indirectly, by promoting endothelial transdifferentiation of carcinoma cells, or directly, by acquiring an endothelial phenotype, with FOXC2 playing key roles in these processes.

FOXC2 Promotes Vasculogenic Mimicry in Ovarian Cancer

“…Induction of EMT in a weakly tumorigenic MCF-7 breast cancer cel line promoted trans-differentiation of cancer cells into CD31-positive endothelial cells which facilitated vascularization and growth of tumor xenografts in mice [92]. Mechanis tically, FOXC2 was shown to be a key factor in the acquisition of endothelial phenotypic and functional characteristics in vitro and in vivo (path B in Figure 7) [92]. In addition to the well-documented paracrine effects of FOXC2 on endothelial cells, it has been shown that FOXC2-expressing cancer cells are capable of trans-differentiation into endothelial cells.…”

“…In addition to the well-documented paracrine effects of FOXC2 on endothelial cells, it has been shown that FOXC2-expressing cancer cells are capable of trans-differentiation into endothelial cells. Induction of EMT in a weakly tumorigenic MCF-7 breast cancer cell line promoted trans-differentiation of cancer cells into CD31-positive endothelial cells, which facilitated vascularization and growth of tumor xenografts in mice [92]. Mechanistically, FOXC2 was shown to be a key factor in the acquisition of endothelial phenotypic and functional characteristics in vitro and in vivo (path B in Figure 7) [92].…”

“…Induction of EMT in a weakly tumorigenic MCF-7 breast cancer cell line promoted trans-differentiation of cancer cells into CD31-positive endothelial cells, which facilitated vascularization and growth of tumor xenografts in mice [92]. Mechanistically, FOXC2 was shown to be a key factor in the acquisition of endothelial phenotypic and functional characteristics in vitro and in vivo (path B in Figure 7) [92].…”