It is an unfortunately common story. A doctor cleanly removes a tumor from a cancer patient and gives a good prognosis. Then, years later, a new tumor begins to metastasize, seemingly out of nowhere.
“The reason is, these micrometastases come out from the tumor. They can lodge in tissue somewhere else in the body, living there in a dormant state for years until something happens to make the tumor start growing,” said Lewis Cantley, the William Bosworth Castle professor of medicine at Beth Israel Deaconess Medical Center and the Medical School and an HMS professor of systems biology. “At that stage, to grow, the micrometastases need to stimulate vasculature formation.”
Cantley and colleagues examined the mechanism by which vessels form to provide oxygen and nutrients to the growing tumor. Their work, published in the July 15 Proceedings of the National Academy of Sciences, focuses on PI3 kinase (PI3K), a protein downstream of tumor-promoting growth factors such as VEGF and bFGF.
Previous studies hinted at a role for PI3K in vasculature development. To examine the protein’s function in normal development and in tumor-induced angiogenesis, the Cantley lab conducted research led by graduate student Tina Yuan. Working in mice, they genetically reduced PI3K protein in endothelial cells by about 70 percent. They injected the PI3K-depleted mice with melanoma cells and found that in animals with low PI3K levels, new vessels were leaky.
“We … injected a dye into live mice, and we were able to see that in these mutant mice, the dye was extravasating much faster than in the normal wild-type mice,” said Yuan, the first author on the paper. “We also showed that in actual tumors … there was an absence of large vessels.” The combination of leaky, smaller vessels restricted the supply of oxygen and nutrients to the tumor, leading to deceleration of tumor growth. The researchers confirmed their genetic data using a PI3K-inhibiting drug that is currently in phase 1 clinical trials.
Because decreasing PI3K seems to affect only newly forming vasculature, it predominantly affects the adult angiogenesis response to tumors. This property makes PI3K inhibitors promising in extremely early tumor formation, which is not yet widely relevant in the clinic. Until early detection methods improve, a more practical use for PI3K inhibitors might be as an adjuvant therapy with surgical removal of a tumor. Used in this way, it could prevent micrometastases from growing, making tumor removal a more permanent solution.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: The Dana Farber/Harvard Cancer Center Specialized Program Of Research Excellence and the National Institutes of Health
