Dietary fat may promote prostate cancer metastasis
Prostate tumours tend to be what scientists call “indolent” – so slow-growing and self-contained that many affected men die with prostate cancer, not of it.
But for the percentage of men whose prostate tumours metastasise, the disease is invariably fatal.
In a set of papers published 15 January 2018 in the journals Nature Genetics and Nature Communications, researchers at the Cancer Center at Beth Israel Deaconess Medical Center (BIDMC) shed new light on the genetic mechanisms that promote metastasis in the mouse model and also implicated the typical Western high-fat diet as a key environmental factor driving 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 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 tumours. Its complete loss is linked to metastatic prostate disease, but animal studies suggest the loss of PTEN alone is not enough to trigger progression. Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center and Cancer Research Institute at BIDMC, first author Ming Chen and colleagues sought to identify an additional tumor suppressing gene or pathway that may work in concert with PTEN to drive metastasis.
Looking at recent genomic data, Pandolfi and colleagues noticed that another tumour suppressor gene, called PML, tended to be present in localised (non-metastatic) prostate tumours, but was absent in about a third of metastatic prostate tumours. Moreover, about 20 percent of metastatic prostate tumours lack both PML and PTEN.
When they compared the two types of tumour – the localised ones lacking only the PTEN gene versus the metastatic tumours lacking both genes – the researchers found that the metastatic tumours produced huge amounts of lipids, or fats. In tumours that lacked both PTEN and PML tumour suppressing genes, the cells’ fat-production machinery was running amok.
“It was as though we’d found the tumours’ 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 mice studies, mice ate a vegetable-based chow – essentially a low-fat vegan diet that bore little resemblance to that of the average American male. When Pandolfi and colleagues increased the levels of saturated fats – the kind found in fast food cheeseburgers and fries – in the animals’ diet, the mice developed aggressive, metastatic tumours.
Physicians could soon be able to screen their early-stage prostate cancer patients for those whose tumours lack both PTEN and PML tumour suppressing genes, putting them at increased risk for progressing to metastatic disease. These patients may be helped by starving these tumours 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.
Reference: “An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer”; Journal: Nature Genetics; doi:10.1038/s41588-017-0027-2 and “Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism”; Journal: Nature Communications; doi:10.1038/s41467-017-02272-y
21 January 2019.