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

BMC Cancer. 2023 Jul 22;23(1):690. doi: 10.1186/s12885-023-11170-0.

Abstract

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 pro-angiogenic 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.

Keywords: Cancer stem cells; Epithelial-to-mesenchymal transition; Gastric adenocarcinoma; KRAS.

Publication types

  • Retracted Publication

MeSH terms

  • Animals
  • Lymphatic Metastasis
  • Mice
  • Proto-Oncogene Proteins p21(ras)
  • Stomach Neoplasms*
  • Vascular Endothelial Growth Factor A

Substances

  • Vascular Endothelial Growth Factor A
  • Proto-Oncogene Proteins p21(ras)