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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.
Highlights
Angiogenesis is a normal physiological process that entails the development of new blood vessels through remodeling of a pre-existing vasculature, underpinned by endothelial cell sprouting, proliferation, and fusion [1, 2]
On the basis of the contiguous staining patterns, and given that the anti-CD31 antibody employed is human-specific, we concluded that neoangiogenesis in the core regions of these outgrowing tumors is enacted predominantly through MCF-7 cell transdifferentiation towards an endothelial phenotype
We examined the expression of kinase insert domain receptor (KDR)— known as vascular endothelial growth factor receptor 2 (VEGFR-2) or fetal liver kinase 1 (FLK1)—a well-established marker of the endothelial lineage that promotes cell proliferation and survival in response to its pro-angiogenic ligand, VEGF
Summary
Angiogenesis is a normal physiological process that entails the development of new blood vessels through remodeling of a pre-existing vasculature, underpinned by endothelial cell sprouting, proliferation, and fusion [1, 2]. Bone marrowderived endothelial progenitor cells can be mobilized to initiate de novo vessel formation in response to angiogenic signals (vasculogenesis) [7] Together, these angiogenic mechanisms facilitate the progression from avascular hyperplasia to a highly vascularized outgrowing tumor [2, 6]. Many avascular tumors can grow, at least initially, without evoking an angiogenic response through a process known as vessel co-option In this non-angiogenic mode, which mostly prevails in highly vascularized host tissues, tumor cells hijack the host vasculature and migrate along pre-existing blood vessels, invading the surrounding tissue [8, 9]. The complex mechanisms underlying neoangiogenesis differ from physiological angiogenesis and lead to the formation of dysfunctional and disorganized vessels with a defective endothelial layer, which fuels tumor progression
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