VEGF Drives Cancer-Initiating Stem Cells Through VEGFR-2/Stat3 Signaling to Upregulate Myc and Sox2

摘要: Vascular endothelial growth factor-A (VEGF), a potent angiogenic factor, is also implicated in self-renewal several normal tissue types. VEGF has been shown to drive malignant stem cells but mechanisms thereof and tumor types affected are not fully characterized. Here, we show promotes breast lung cancer cell (CSC) via receptor-2 (VEGFR-2)/STAT3-mediated upregulation of Myc Sox2. increased spheres aldehyde dehydrogenase activity, both proxies for function vitro, triple-negative (TNBC) lines dissociated primary cancers, lines. exposure before injection cancer-initiating abundance vivo yielding orthotopic tumors, metastasis from primaries following tail vein without further treatment. rapidly stimulated VEGFR-2/JAK2/STAT3 binding activated STAT3 bind MYC SOX2 promoters induce their expression. VEGFR-2 knockdown or inhibition abrogated VEGF-mediated activation, induction sphere formation. Notably, either STAT3, impaired VEGF-upregulation pSTAT3, expression Each transcription once upregulated, appears promote sustained activation the others, creating feed-forward loop self-renewal. Thus, addition effects, tumor-initiating through VEGFR-2/STAT3 signaling. Analysis cancers (>1300 each) showed high expression, was prognostic poor outcome strongly associated with supporting link between CSC High-VEGF tumors may be most likely escape anti-angiogenics by upregulating VEGF, driving re-populate post-treatment. Our work highlights need better define VEGF-driven subsets supports investigation combined therapeutic blockade JAK2/STAT3.