Carcinoma cells that have undergone an epithelial-mesenchymal transition differentiate into endothelial cells and contribute to tumor growth
Open Access
- 13 April 2021
- journal article
- Published by Impact Journals, LLC in Oncotarget
- Vol. 12 (8), 823-844
- https://doi.org/10.18632/oncotarget.27940
Abstract
// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> 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 Correspondence to: Tapasree Roy Sarkar, email: tsarkar@bio.tamu.edu Keywords: angiogenesis; endothelial transdifferentiation; epithelial-mesenchymal transition; vasculogenic mimicry; FOXC2 Received: December 11, 2020 Accepted: March 25, 2021 Published: April 13, 2021 Copyright: © 2021 Sphyris et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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.Keywords
This publication has 73 references indexed in Scilit:
- Hypoxia-inducible factor 1: Regulator of mitochondrial metabolism and mediator of ischemic preconditioningBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2011
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Deconstructing the molecular portraits of breast cancerMolecular Oncology, 2010
- Epithelial-Mesenchymal Transition-Derived Cells Exhibit Multilineage Differentiation Potential Similar to Mesenchymal Stem CellsThe International Journal of Cell Cloning, 2010
- Expression and significance of hypoxia-inducible factor-1 alpha and MDR1/P-glycoprotein in human colon carcinoma tissue and cellsZeitschrift für Krebsforschung und Klinische Onkologie, 2010
- The Foxc2 transcription factor regulates tumor angiogenesisBiochemical and Biophysical Research Communications, 2010
- The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem CellsCell, 2008
- Forkhead transcription factors regulate expression of the chemokine receptor CXCR4 in endothelial cells and CXCL12-induced cell migrationBiochemical and Biophysical Research Communications, 2008
- HIF1α Induces the Recruitment of Bone Marrow-Derived Vascular Modulatory Cells to Regulate Tumor Angiogenesis and InvasionCancer Cell, 2008
- Abrogation of TGFβ Signaling in Mammary Carcinomas Recruits Gr-1+CD11b+ Myeloid Cells that Promote MetastasisCancer Cell, 2008