Resumen de Endothelial snail1 in angiogenesis and tumorigenesis
Snail1 is a transcriptional factor with a great relevance in tumor development as it is required for epithelial-to-mesenchymal transition and activation of cancer-associated fibroblasts (CAF). In this thesis, we reported that tumor endothelial cells did also express Snail1, being key for angiogenesis, by promoting endothelial cell migration, invasion and tubulogenesis in vitro. Those roles are associated to Snail1 induction by FGF2 and VEGF-A, leading to gene expression profile change in endothelial cells and increasing their activation status. Specific Snail1 depletion in the endothelium of adult mice does not promote an overt phenotype; however, it controls angiogenesis and vessel morphology in Matrigel plug assay. Moreover, endothelium-specific Snail1 depletion in the MMTV-PyMT breast cancer murine model delays the initiation of neoplasms, being less advanced and with a papillary morphology, which was corroborated by orthotopic breast tumor inoculation model. These in vivo effects are associated to the inability of Snail1-deficient endothelial cells to promote a full in vitro and in vivo activation of fibroblasts through a reduced FGF2 and CXCL12 signaling; as well as to sustain a complete in vivo angiogenesis, resulting in wider and less invasive neo-vessels. Similar changes on tumor onset and morphology are observed by pretreatment on MMTV-PyMT mice with the angiogenic inhibitor Bevacizumab. Checking those results in human breast tumor samples, papillary carcinomas are less advanced and exhibit lower levels of Snail1 expression both in vessels and in associated stromal cells, compared to no special type breast carcinomas. Furthermore, TCGA consortium breast tumors datasets show a strong correlation between vasculature and stromal activation, as well as better survival and prognosis in tumors mimicking the molecular profile of breast tumor endothelium-Snail1 depletion mice. Altogether, these findings establish a new role for Snail1 in endothelial cells, not only in angiogenesis but also in tumor onset, development and phenotype.
