Obesity is linked to prostate cancer, scientists know, but it’s not clear why. On Monday, researchers reported a surprising connection.
When prostate cancers lose a particular gene, they become tiny fat factories, a team at Beth Israel Deaconess Medical Center in Boston reported in a paper published in Nature Genetics.
Then the cancers spread from the prostate, often with deadly effect. Prostate cancers that have not lost that gene also can spread, or metastasize — in mice, at least — but only if they have a ready source of fat from the diet.
That finding suggests that dietary fat can substitute for the loss of the gene, fueling prostate cancer. Moreover, the investigators found, an obesity drug that blocks fat production can make metastatic prostate cancers regress in mice and prevent them from spreading.
“What this paper suggests is that fat or high-fat diets promote more aggressive prostate cancer,” said Cory Abate-Shen, interim director of the Herbert Irving Comprehensive Cancer Center at Columbia University in New York, who was not involved with the research.
Now the scientists are planning a clinical trial in men with prostate cancer to see if the obesity drug may be an effective treatment for this cancer.
“That’s really important,” Abate-Shen said. “Aggressive prostate cancer is lethal, and there are no curative drugs right now.”
The American Cancer Society estimates that prostate cancer will be diagnosed in about 165,000 U.S. men this year, making it the second-most common cancer in U.S. men, behind only skin cancer.
The tumors often remain in the prostate and do not kill, but when the cancer spreads, it is lethal. About 29,500 men die of prostate cancer each year. Researchers have been struggling to find new ways to help men with metastatic cancer.
Geneticists knew prostate cancers often start when a protective gene, PTEN, shuts down. But the tumors in men that lose only PTEN tend to languish, rarely spreading beyond the prostate and rarely becoming lethal.
The cancers change, though, if a second gene, called PML, also shuts down. Suddenly, indolent cells become cancers that spread and kill. But why?
In the new study, researchers found that when PML was lost, cancerous cells — in petri dishes and in mice — started churning out fat, which may protect the cells from certain toxic molecules. But the fat also may help the cancers spread, the researchers suggested.
PML is also lost in human metastatic prostate cancer, but it has never been clear what the consequences might be.
“This is all cool molecular genetics,” said Dr. Pier Paolo Pandolfi, director of the Cancer Center and Cancer Research Institute at Beth Israel Deaconess and lead author of the new study.
Pandolfi has long tried to study prostate cancer spread in mice, but the rodents were not much help. Few genetic manipulations made prostate cancers spread in the animals as they do in humans.
Then one day, at a meeting with colleagues, Pandolfi had an idea: “What are the mice eating?” he asked. It was mouse chow, his co-workers said — a low-fat, vegetarian concoction.
“Why don’t we try a simple experiment?” Pandolfi recalled asking. “Why don’t we put our mice on a high-fat Western diet?”
It was the missing link. Mice with prostate cancers that had lost PTEN and that were fed a high-fat diet quickly developed tumors that grew rapidly and spread. It was as if fat in the diet had an effect similar to the loss of PML, the protective gene.
Then the group asked a bigger question: Could they could protect mice from metastatic cancer by blocking fat production? That led to the experiment with a new obesity drug, fatostatin. It not only halted the cancer’s spread in the animals but also made it regress.
The work leaves plenty of questions for future studies, Abate-Shen said.
High-sugar diets also cause obesity. Are the prostate tumors in men who became fat by eating high-sugar diets equally susceptible to metastasis? If they are, what is the mechanism?
And, she and others noted, the studies so far involved human cells in petri dishes and cancers in mice. It remains to be seen if the provocative findings hold for humans.
Pandolfi and his colleagues are planning a clinical trial with fatostatin to treat prostate cancer in humans.
They also wonder if low-fat diets might help these patients, and what kinds of dietary fat might fuel prostate cancers.
“You cannot just say, ‘Don’t eat fat,'” Pandolfi said.
- New York Times