VEGFR2 Signaling Prevents Colorectal Cancer Cell Senescence to Promote Tumorigenesis in Mice With Colitis

Area of Science:

• Oncology
• Cell Biology
• Cancer Research

Background:

• Cellular senescence is a critical mechanism that prevents uncontrolled cell proliferation and tumor formation.
• Vascular Endothelial Growth Factor (VEGF) signaling plays a role in tumor progression and angiogenesis.

Purpose of the Study:

• To investigate the role of VEGF receptor 2 (VEGFR2) signaling in regulating tumor cell senescence and proliferation within the context of colitis-associated cancer (CAC).
• To elucidate the molecular mechanisms by which VEGFR2 influences senescence and to assess its clinical relevance in colorectal cancer patients.

Main Methods:

• Colitis-associated cancer (CAC) was induced in mice with specific VEGFR2 gene deletions in the intestinal epithelium (VEGFR2(ΔIEC)) and control mice (VEGFR2(fl/fl)).
• Tumor development and inflammation were assessed via endoscopy, and colorectal tissues underwent molecular analyses (immunoblot, immunohistochemistry, qPCR).
• Findings in mice were validated in human colorectal cancer cells (HCT116) and patient tumor samples treated with bevacizumab.

Main Results:

• VEGFR2(ΔIEC) mice exhibited significantly fewer tumors and a higher proportion of senescent tumor cells compared to controls.
• VEGFR2 signaling activates phosphatidylinositol-4,5-bisphosphate-3-kinase and AKT, leading to the inactivation of the cell cycle inhibitor p21.
• Inhibition of VEGFR2 or AKT induced senescence in cancer cells, and tumor cell senescence promoted an anti-tumor immune response mediated by CD8(+) T cells.
• Patients treated with bevacizumab showed longer progression-free survival when their tumors exhibited increased senescence post-treatment.

Conclusions:

• Inhibition of VEGFR2 signaling effectively induces senescence in both mouse and human colorectal cancer cells.
• VEGFR2's interaction with phosphatidylinositol-4,5-bisphosphate-3-kinase and AKT leads to p21 inactivation, a key pathway in regulating senescence.
• Colorectal tumor cell senescence and p21 levels are significant biomarkers correlating with patient survival during bevacizumab therapy.