Vascular endothelial growth factor receptor-2 (VEGFR2) signaling prevents senescence of colorectal cancer cells by inactivating p21, researchers report in the July issue of Gastroenterology. Inactivation of this pathway correlates with survival of patients treated with anti-VEGF cancer drug bevacizumab.
VEGF, a growth factor that has been well studied for its role in induction of angiogenesis, has been associated with inflammation-associated colorectal carcinogenesis. Activation of its receptors, VEGFR2, promotes proliferation, migration, and survival of endothelial cells.
Agents that block VEGF reduce growth of many different types of tumors; the anti-VEGF drug bevacizumab is used to treat cancer in patients.
However, there is evidence that VEGF acts on cancer cells themselves, independently of its role in angiogenesis, and also contributes to colitis-associated carcinogenesis. VEGFR2 is upregulated on intestinal epithelial cells during acute and chronic inflammation, and its activation promotes cancer cell proliferation and tumor progression.
Sebastian Foersch et al therefore investigated the link between VEGFR signaling, inflammation, and colorectal cancer using mice with conditional disruption of VEGFR2 (VEGFR2ΔIEC mice).
They found that VEGFR2 was not highly expressed by normal intestinal epithelial cells, but was upregulated during inflammation and in tumor cells. After induction of colitis, VEGFR2ΔIEC mice developed significantly fewer tumors, and smaller tumors, than control mice.
A greater number of intestinal tumor cells from VEGFR2ΔIEC mice were in senescence than tumor cells from control mice. The authors showed that VEGF signaling via VEGFR2 promoted inflammation-associated carcinogenesis by preventing senescence in intestinal epithelial cells.
Foersch et al found that in colorectal cells, VEGFR2 signaling activates the phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K) signaling via AKT , resulting in degradation of p21, which induces and maintains senescence (see figure).
VEGFR2 inhibition induced senescence in cultured colorectal cancer cells. Systemic inhibition of VEGFR2 reduced tumor growth and induced senescence of cancer cells in mice with colitis-associated cancer. Senescence induced an adaptive immune response against tumors.
What happens in patients with colorectal cancer treated with bevacizumab? Foersch et al found that numbers of senescent cells increased in colorectal tumor samples after patients were treated with this drug, based on a shift from cytoplasmatic to nuclear p21. Furthermore, patients with the greatest numbers of senescent cells had a significantly better response to bevacizumab, with significantly longer times of progression-free survival, than patients with fewer senescent cells following bevacizumab therapy.
Foersch et al conclude that VEGF signaling had important roles in colorectal cancer progression beyond its roles in angiogenesis. They say that there seems to be a connection between escape from senescence and inflammation-associated carcinogenesis. This effect might also be involved in the therapeutic effects of anti-VEGF drugs in patients.