Supply lines and escape routes are key strategic considerations in a war between nations, and the same can be said of the war on cancer. As a tumor grows, its demand for oxygen and nutrients increases.
To meet their metabolic needs, cancer cells can secrete factors that stimulate blood vessel formation—also known as angiogenesis. As blood vessels also give cancer cells access to the general blood circulation and opportunities to spread throughout the body, targeting tumor angiogenesis could prevent cancer progression.
In the present study, researchers led by Sayan Chakraborty, Senior Research Scientist at A*STAR’s Institute of Molecular and Cell Biology (IMCB), have identified Agrin—a secreted protein with sugar chains attached to it—as a key promoter of tumor angiogenesis. The team observed that Agrin is produced in large quantities by liver cancer cells and associated with increased recruitment of endothelial cells within tumors engrafted onto mice. Endothelial cells line the blood vessels and are important for angiogenesis.
Not only does Agrin directly support primary liver tumor growth, it also helps endothelial cells adhere to the liver cancer cells, which increases the likelihood of the cancer cells escaping into the bloodstream. Probing deeper, the researchers found that focal adhesion kinase (FAK) was central to the adhesion process.
When they used a drug to inhibit the activity of FAK in endothelial cells, they noted that the cells failed to form micro-vessels. This inhibition could not be overcome even by increasing the levels of Agrin exposure, indicating that FAK is a critical signaling node for Agrin’s pro-tumor angiogenesis effects. Furthermore, the team demonstrated that Agrin stabilizes a key receptor on the endothelial cells—vascular endothelial growth factor receptor-2 (VEGFR2)—which is required for blood vessel formation.
“Both FAK and VEGFR2 are important for many cancers, and there are extensive ongoing clinical trials with FAK inhibitors to prevent blood vessel formation and shrink tumors. Based on our mechanistic studies, we perceive that the combined targeting of Agrin, FAK and VEGFR2 would produce better outcomes in inhibiting liver tumor growth,” said Sayan.
His team is currently collaborating with colleagues at A*STAR’s Experimental Drug Development Centre (EDDC) to develop antibodies that specifically bind to and block the activity of Agrin. They will also investigate Agrin’s role in blood vessel architecture, tumor stiffness and cancer drug resistance.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).
