Western high dietary fat and changes in that fat metabolism may promote metastasis of prostate cancer
- A typical high-fat diet may promote prostate cancer progression.
- The tumor suppressor gene PTEN or PML or in combination have shown to play an important role in containing the spread of prostate cancer.
. The findings have shown a strong association between dietary lipids and prostate cancer. The results were published in the Nature Genetics
"Although it is widely postulated that a Western diet can promote prostate cancer progression, direct evidence supporting a strong association between dietary lipids and prostate cancer has been lacking," said first author Ming Chen, PhD, a research fellow in the laboratory of Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center and Cancer Research Institute at BIDMC.
‘Prostate tumors have been found to be lipogenic or fat producing so new drugs can now be developed to block this lipogenic switch to prevent their metastasis.’
Epidemiological data links dietary fats (and obesity) to many types of cancer, and rates of cancer deaths from metastatic cancers including prostate cancer are much higher in the United States than in nations where lower fat diets are more common. While prostate cancer affects about ten percent of men in Asian nations, that rate climbs to about 40 percent when they immigrate to the U.S., mirroring the rates among the native-born U.S. population. That points to an environmental culprit that may work in concert with genetic factors to drive this aggressive, fatal disease.
"The progression of cancer to the metastatic stage represents a pivotal event that influences patient outcomes and the therapeutic options available to patients," said senior author Pandolfi. "Our data provide a strong genetic foundation for the mechanisms underlying metastatic progression, and we also demonstrated how environmental factors could boost these mechanisms to promote progression from primary to advanced metastatic cancer."
The tumor suppressor gene PTEN is known to play a major role in prostate cancer; its partial loss occurs in up to 70 percent of primary prostate tumors. Its complete loss is linked to metastatic prostate disease
, but animal studies suggest the loss of PTEN alone is not enough to trigger progression. Pandolfi and colleagues sought to identify an additional tumor-suppressing gene or pathway that may work in concert with PTEN to drive metastasis.
Another tumor suppressor gene, called PML, tended to be present in localized (non-metastatic) prostate tumors
, but was absent in about a third of metastatic prostate tumors. Moreover, about 20 percent of metastatic prostate tumors lack both PML and PTEN.
When they compared the two types of tumor - the localized ones were lacking only the PTEN gene versus the metastatic tumors lacking both genes - the researchers found that the metastatic tumors produced huge amounts of lipids or fats. In tumors that lacked both PTEN and PML tumor-suppressing genes, the cells' fat-production machinery was running amok
"It was as though we'd found the tumors' lipogenic, or fat production, switch," said Pandolfi. "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," he added.
Such a drug already exists. Discovered in 2009, a molecule named "fatostatin" is currently being investigated for the treatment of obesity. Pandolfi and colleagues tested the molecule in lab mice. "The obesity drug blocked the lipogenesis fantastically, and the tumors regressed and didn't metastasize."
In addition to opening the door to new treatment for metastatic prostate cancer, these findings also helped solve a long-standing scientific puzzle. For years, researchers had difficulty modeling metastatic prostate cancer in mice, making it hard to study the disease in the lab. Some speculated that mice simply weren't a good model for this particular disease. But the lipid production finding raised a question in Pandolfi's mind.
"I asked, 'What do our mice eat?'" Pandolfi recalled. It turned out; the mice ate a vegetable-based chow - essentially a low-fat vegan diet that bore little resemblance to that of the average American male. When increased levels of saturated fats - the kind found in cheeseburgers and fries, were added in the experimental diet, the mice developed aggressive, metastatic tumors
The findings could result in more accurate and predictive mouse models for metastatic prostate cancer, which in turn could accelerate the discovery of better therapies for the disease.
Physicians could soon be able to screen their early-stage prostate cancer patients for those whose tumors lack both PTEN and PML tumor-suppressing genes, putting them at increased risk for progressing to metastatic disease. These patients may be helped by starving these tumors of fat either with the fat-blocking drug or through diet
"The data are tremendously actionable, and they surely will convince you to change your lifestyle," Pandolfi said.
- Pandolfi, Chen, Katia Sampier, John G Clohessy,et.al.An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer , Nature genetics (2018).DOI:10.1038/s41588-017-0027-2
- Ming Chen, Lixin Wan, Jiangwen Zhang, et.al . Deregulated PP1Ģ\ phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism, Nature communications (2018).DOI:10.1038/s41467-017-02272-y