Loss of two tumor suppressor genes – PTEN and PML – in prostate cancer appears to trigger the progression of disease by turning the cells into fat-producing factories, new research shows.
These findings reveal the genetic link between aggressive types of prostate cancer and dietary habits and suggest new therapies for halting disease progression.
The study, “An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer,” was published in the journal Nature Genetics.
Fat-rich diets and obesity are established factors that promote cancer progression, including prostate cancer.
Epidemiological data supports this claim and actually shows that metastatic prostate cancer is much higher in nations where high-fat diets are common, such as the United States. In fact, while in Asia only 10 percent of men develop prostate cancer, the rates are four times higher (40 percent) among Asian immigrants that come to live in the U.S. – similar to those of native-born U.S. men. This suggests that fat consumption is a key environmental trigger for aggressive forms of prostate cancer.
“The progression of cancer to the metastatic stage represents a pivotal event that influences patient outcomes and the therapeutic options available to patients,” the study’s lead author, Pier Paolo Pandolfi, said in a press release.
“Our data provide a strong genetic foundation for the mechanisms underlying metastatic progression, and we also demonstrated how environmental factors can boost these mechanisms to promote progression from primary to advanced metastatic cancer,” added Pandolfi, a group leader at the Cancer Research Institute, Beth Israel Deaconess Cancer Center (BIDMC) in Boston.
Tumor suppressor genes are key to protecting our cells from growing uncontrollably and forming tumors. One of these genes, PTEN, is partially lost in about 70 percent of non-metastatic prostate tumors. Total loss of PTEN is found in the advanced or metastatic stages of the disease.
However, studies with animal models of prostate cancer show that absence of PTEN alone is not sufficient to promote the transition between local to spreading (metastatic) prostate cancer.
Pandolfi and his team set out to identify what other genes or pathways underlie the switch toward metastasis. They compared the genomes of localized, or non-metastatic, and metastatic prostate tumors and saw that another tumor suppressor gene, PML, was absent in a third of metastatic prostate tumors.
About 20 percent of the tumors lacked both PTEN and PML, while PML was expressed in all non-metastatic prostate tumors.
In tumors lacking both PTEN and PML, researchers saw that the cells turned to fat-producing factories.
“It was as though we’d found the tumors’ lipogenic, or fat production, switch,” Pandolfi said. “The implication is, if there’s a switch, maybe there’s a drug with which we can block this switch and maybe we can prevent metastasis or even cure metastatic prostate cancer.”
Next, the team tested a molecule – called fatostatin – that’s being investigated as a possible treatment for obesity.
Researchers gave fatostatin to mice and saw that “the obesity drug blocked the lipogenesis fantastically and the tumors regressed and didn’t metastasize.”
Overall, “our data provide a strong genetic foundation elucidating the mechanisms underlying metastatic progression, and they demonstrate how environmental dietary factors can boost progression from primary to metastatic cancer, intertwining with the genetic makeup of cancer,” the study concluded.
These findings suggest a potential new therapeutic avenue for metastatic prostate cancer. It also means that physicians should analyze early-stage prostate cancer patients looking for those who lack PTEN and PML tumor suppressing genes – those at higher risk for metastasis – and ask whether changing their diet may impact the risk of disease progression.
“The data are tremendously actionable, and they surely will convince you to change your lifestyle,” Pandolfi said.
The findings may also help researchers develop better mouse models for metastatic prostate cancer. Mice in the lab are grown in standardized conditions, eating a vegetable-based chow, which is miles away from the high-fat content of many Americans’ diet.
Feeding mice with a saturated fat-rich diet, similar to fast food like cheeseburgers and fries, made them develop aggressive, metastatic tumors, researchers said.
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