KRAS activation in gastric cancer stem-like cells promotes tumor angiogenesis and metastasis

Our previous work showed that KRAS activation in gastric cancer cells leads to activation of an epithelial-to-mesenchymal transition (EMT) program and generation of cancer stem-like cells (CSCs). Here we analyze how this KRAS activation in gastric CSCs promotes tumor angiogenesis and metastasis. Gastric cancer CSCs were found to secrete proangiogenic factors such as vascular endothelial growth factor A (VEGF-A), and inhibition of KRAS markedly reduced secretion of these factors. In a genetically engineered mouse model, gastric tumorigenesis was markedly attenuated when both KRAS and VEGF-A signaling were blocked. In orthotropic implant and experimental metastasis models, silencing of KRAS and VEGF-A using shRNA in gastric CSCs abrogated primary tumor formation, lymph node metastasis, and lung metastasis far greater than individual silencing of KRAS or VEGF-A. Analysis of gastric cancer patient samples using RNA sequencing revealed a clear association between high expression of the gastric CSC marker CD44 and expression of both KRAS and VEGF-A, and high CD44 and VEGF-A expression predicted worse overall survival. In conclusion, KRAS activation in gastric CSCs enhances secretion of pro-angiogenic factors and promotes tumor progression and metastasis.

Automated summary

This study reveals that KRAS activation in gastric cancer stem-like cells (CSCs) enhances the secretion of pro-angiogenic factors and promotes tumor progression and metastasis. Inhibition of KRAS significantly reduces the secretion of factors such as VEGF-A, which are important for tumor angiogenesis. Additionally, high expression of the gastric CSC marker CD44 is associated with expression of both KRAS and VEGF-A, and predicts worse overall survival in gastric cancer patients.