The researchers found that when a mutation is used to permanently turn “off” this so-called PI3K pathway, tumors grow and spread independent of the amount of food consumed. But when the PI3K pathway operates normally, dietary restriction – defined as 60 percent or less of a person’s normal intake of calories – leads to smaller and less frequent tumors.
“Our findings indicate that each tumor cell bears a signature that determines whether or not that cell will be affected by dietary restriction,” said Nada Kalaany, first author of the paper and a postdoctoral researcher in the lab of Whitehead member David Sabatini. “We think that mutations in the PI3K pathway are a major determinant of the sensitivity of tumors to dietary restriction.”
Scientists first noted early in the 20th century that dietary restriction (DR) had a dampening effect on the size and prevalence of tumors. But, for unknown reasons, there were always some cancers that were resistant to calorie-cutting.
In the recent study, Kalaany and her associates first injected mice with cells from human prostate, breast, brain and colon cancers to confirm that some tumors were DR-resistant while others were DR-sensitive. The scientists then grew cells from these same tumor types in vitro and determined that the DR-sensitive cancers were shrunk by growing in an environment poor in insulin and insulin-like growth factor 1 (IGF1), which are hormones related to food. These hormones, or the lack thereof, had no effect on the growth of DR-resistant tumors.
Because of this, and because insulin and IGF1 activate the set of cellular reactions that is the PI3K pathway, the researchers postulated that the pathway in the insensitive tumors is somehow defective. They then looked for mutations in two genes in the PI3K pathway (known as PI3KCA and PTEN) that are frequently associated with cancer. Lo and behold! The DR-resistant cells contained mutations in one or the other of the two genes, while DR-sensitive cells were not mutated.
The scientists then found that DR-resistant tumor cells in which the PTEN gene was switched off were, as expected, resistant to dietary restriction – but when PTEN was turned on, re-establishing a normal PI3K pathway, the cells became sensitive to DR and tumor size diminished.