Carcinoma cells that have undergone an epithelial-mesenchymal transition differentiate into endothelial cells and contribute to tumor growth
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Nathalie Sphyris1,6,*, Cody King2, Jonathan Hoar3, Steven J. Werden1, Geraldine V. Vijay1, Naoyuki Miura4, Akhilesh Gaharwar5 and Tapasree Roy Sarkar1,3,*
1 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2 Department of Biochemistry, Texas A&M University, College Station, TX, USA
3 Department of Biology, Texas A&M University, College Station, TX, USA
4 Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan
5 Department of Biomedical Engineering, Texas A&M University, College Station, TX, USA
6 Present address: Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK
* These authors contributed equally to this work
|Tapasree Roy Sarkar,||email:||[email protected]|
Keywords: angiogenesis; endothelial transdifferentiation; epithelial-mesenchymal transition; vasculogenic mimicry; FOXC2
Received: December 11, 2020 Accepted: March 25, 2021 Published: April 13, 2021
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.
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