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

• Published in: BMC cancer 2023-07, Vol.23 (1), p.690-690
• Main Authors: Yoon, Changhwan, Lu, Jun, Jun, Yukyung, Suh, Yun-Suhk, Kim, Bang-Jin, Till, Jacob E, Kim, Jong Hyun, Keshavjee, Sara H, Ryeom, Sandra, Yoon, Sam S
• Format: Article
• Language: English
• Subjects: Analysis; Angiogenesis; Animal models; Animals; Antibodies; Cancer; Cancer therapies; Care and treatment; CD44 antigen; Cell activation; Chemotherapy; Development and progression; Epidermal growth factor; Fibroblasts; Gastric cancer; Gene mutations; Genetic aspects; Genetic engineering; Genetically modified organisms; Health aspects; K-Ras protein; Kinases; Lymph nodes; Lymphatic Metastasis; Lymphatic system; Manufacturers; Medical research; Metastases; Metastasis; Mice; Neovascularization; Patient outcomes; Penicillin; Pharmaceutical industry; Prevention; Proteins; Proto-Oncogene Proteins p21(ras); R&D; Research & development; Risk factors; RNA sequencing; Secretion; Spheroids; Stem cells; Stomach cancer; Stomach Neoplasms; Tumorigenesis; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A; Veins & arteries
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-023-11170-0

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.