Snail1 expression in endothelial cells controls growth, angiogenesis and differentiation of breast tumors

Cabrerizo Granados, David, 1993-; Peña Arranz, Raúl, 1976-; Palacios, Laura; Carrillo-Bosch, Laura; Lloreta, Josep, 1958-; Comerma Blesa, Laura, 1983-; Iglesias Coma, Mar; García de Herreros, Antonio

doi:http://dx.doi.org/10.7150/thno.61881

Snail1 expression in endothelial cells controls growth, angiogenesis and differentiation of breast tumors

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Cabrerizo-Granados D, Peña R, Palacios L, Carrillo-Bosch L, Lloreta-Trull J, Cormema L, Iglesias M et al. Snail1 expression in endothelial cells controls growth, angiogenesis and differentiation of breast tumors. Theranostics. 2021 Jun 16;11(16):7671-7684. DOI: 10.7150/thno.61881

Abstract

Snail1 is a transcriptional factor required for epithelial to mesenchymal transition and activation of cancer-associated fibroblasts (CAF). Apart from that, tumor endothelial cells also express Snail1. Here, we have unraveled the role of Snail1 in this tissue in a tumorigenic context. Methods: We generated transgenic mice with an endothelial-specific and inducible Snail1 depletion. This murine line was crossed with MMTV-PyMT mice that develop mammary gland tumors and the consequence of Snail1 depletion in the endothelium were investigated. We also interfere Snail1 expression in cultured endothelial cells. Results: Specific Snail1 depletion in the endothelium of adult mice does not promote an overt phenotype; however, it delays the formation of mammary gland tumors in MMTV-PyMT mice. These effects are associated to the inability of Snail1-deficient endothelial cells to undergo angiogenesis and to enhance CAF activation in a paracrine manner. Moreover, tumors generated in mice with endothelium-specific Snail1 depletion are less advanced and show a papillary phenotype. Similar changes on onset and tumor morphology are observed by pretreatment of MMTV-PyMT mice with the angiogenic inhibitor Bevacizumab. Human breast papillary carcinomas exhibit a lower angiogenesis and present lower staining of Snail1, both in endothelial and stromal cells, compared with other breast neoplasms. Furthermore, human breast tumors datasets show a strong correlation between Snail1 expression and high angiogenesis. Conclusion: These findings show a novel role for Snail1 in endothelial cell activation and demonstrate that these cells impact not only on angiogenesis, but also on tumor onset and phenotype.