Theranostics 2021; 11(16):7671-7684. doi:10.7150/thno.61881 This issue Cite
Research Paper
1. Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Unidad Asociada al CSIC, Barcelona, Spain.
2. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
3. Servei d'Anatomia Patològica, Hospital del Mar, Barcelona, Spain.
* These authors contributed equally to this work.
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.