New research from Belgium, published in Nature this week, reveals that VEGF, a signalling protein that is known to regulate the formation of new blood vessels, has a dual role in helping cancer cells grow and form tumors in skin squamous cell carcinoma, a common cancer in humans. The study finds that VEGF helps grow a blood supply for the tumor, and it also helps replenish and renew the stem cancer cells that differentiate to become skin cancer cells.
Recent studies have shown that like many cancers, skin squamous cell carcinoma, a common cancer in humans, contains cancer stem cells that differentiate into cancer cells. They are also able to renew themselves and thereby fuel tumor growth. However, we know little about the underlying biology that helps this to happen.
First author Benjamin Beck, from the Institute for Interdisciplinary Research on Human and Molecular Biology (IRIBHM) at the Université Libre de Bruxelles, and colleagues, decided to tackle the problem by looking at the genes that are more strongly expressed by cancer stem cells in skin tumors.
They discovered that the genes that code for vascular endothelial growth factor (VEGF), a signalling protein that is already known to be involved in organizing the growth of new blood vessels (the process of “angiogenesis”), were expressed at a high level by skin cancer stem cells.
They then did tests on mice with skin tumors. They gave the mice an antibody that reduces new blood vessel growth and found this reduced the pool of cancer stem cells and shrank the tumors, showing that skin cancer stem cells rely on the presence of blood vessel cells.
This could be viewed as an indirect effect of VEGF on the stem cancer cells, and indeed there are already some anti-cancer drugs that target this effect by blocking VEGF and its receptors. But what if VEGF also has a direct effect on stem cancer cells? Might this account for the efficiency with which the VEGF blockers work, as has been suggested in other studies, asked the authors?
To test for this, Beck and colleagues removed the genes that code for VEGF from the tumor cells and found that when the VEGF disappeared, the skin cancer cells couldn’t function properly and quickly died off, causing the tumors to shrink.
Beck told the press:
“It was extremely exciting to see the complete disappearance of these tumors only two weeks after the treatment.”
Beck and colleagues also found that Neuropilin 1, a VEGF receptor, is highly expressed by skin cancer stem cells, and after further investigation, found it also plays a critical role in promoting cancer stem cell renewal and tumor growth.
Thus the authors concluded their study offers two new and important findings: one showing an indirect effect and the other showing a direct effect of VEGF on tumors.
First, VEGF signalling in endothelial cells (the cells that line blood vessels) is crucial for helping form the “vascular niche” which indirectly promotes the renewal of skin cancer stem cells.
Second, VEGF secretion by cancer stem cells acts directly on cancer stem cells, via a mechanism that involves the Neuropilin 1 receptor, to stimulate cancer stem renewal and tumor growth.
Senior and corresponding author Cédric Blanpain, from Wellbio, IRIBHM, Université Libre de Bruxelles, said:
“Anti-VEGF therapies are currently used to treat cancers. These new results have important implications for the prevention and treatment of different epithelial cancers, as new therapies blocking VEGF and/or Neuropilin 1 functions in cancer cells may be more effective for the treatment of certain cancers compared to the therapeutic strategies blocking VEGF function only in endothelial cells.”
Written by Catharine Paddock PhD