Sphyris Nathalie, King Cody, Hoar Jonathan, Werden Steven J, Vijay Geraldine V, Miura Naoyuki, Gaharwar Akhilesh, Sarkar Tapasree Roy
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Present address: Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
Oncotarget. 2021 Apr 13;12(8):823-844. doi: 10.18632/oncotarget.27940.
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.
缺氧刺激新血管生成，促进肿瘤生长，并引发上皮-间质转化（EMT），赋予细胞间质特性和多谱系分化潜能。在此，我们研究了EMT是否能赋予癌细胞内皮细胞属性，从而增强肿瘤生长和血管生成。将MCF-7人上皮性乳腺癌细胞原位植入小鼠体内后，对不同大小的肿瘤进行缺氧和EMT标志物的免疫染色。较大的肿瘤血管丰富，有人类来源的CD31阳性细胞。通过HIF-1α染色界定的缺氧区域，出现了E-钙黏蛋白缺失的局部区域，波形蛋白和EMT介导因子FOXC2水平升高。与单独注射的MCF-7细胞或与HMLE-载体细胞共混的MCF-7细胞相比，将MCF-7细胞与过表达EMT诱导因子Snail的人乳腺上皮（HMLE）细胞共混植入，显著增强了肿瘤生长和血管生成。瘤内血管含有来自两种供体细胞类型的CD31阳性细胞。FOXC2基因敲低消除了HMLE-Snail细胞对MCF-7肿瘤生长和血管生成的增强作用，并损害了在内皮生长培养基中培养的间充质细胞的内皮转分化。因此，经历EMT的细胞可以通过促进癌细胞的内皮转分化间接促进肿瘤生长和新生血管形成，或者通过获得内皮表型直接促进肿瘤生长和新生血管形成，FOXC2在这些过程中起关键作用。
