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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. 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 not been considered.
Epidemiological data links dietary fats (and obesity) to many types of cancer, and rates of cancer deaths from metastatic cancers including 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. Available data provide a strong genetic foundation for the mechanisms underlying metastatic progression, and also demonstrated how environmental factors can 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.
Looking at recent genomic data, Pandolfi and colleagues noticed that 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 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. 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 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. Mice are fed with saturated fat, the type found in food cheeseburgers and fries – in the animals’ 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 discovery of better therapies for the disease. Additionally, 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.
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