Changes in fat metabolism increases the risk of prostate cancer metastasis

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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Using paracetamol during pregnancy can reduce the fertility of offsprings

Taking paracetamol during pregnancy may impair the future fertility of female offspring, according to a review published in Endocrine Connections. The article reviews three separate rodent studies that all report altered development in the reproductive systems of female offspring from mothers given paracetamol during pregnancy, which may impair their fertility in adulthood. Paracetamol, or acetaminophen, is an over-the-counter treatment for pain relief that is commonly taken by pregnant women worldwide.

 Recent studies have linked paracetamol use during pregnancy with disruptions in the development of the male reproductive system but the effects on female offspring had not yet been investigated. In this article, Dr David Kristensen and colleagues from Copenhagen University Hospital, review the findings from three individual rodent studies that evaluated the effects of paracetamol taken during pregnancy on the development of the reproductive system in female offspring. It is well known that exposure to some chemicals during pregnancy can cause developmental effects that may not manifest until much later in life.

In rodents and humans, females are born with a finite number of eggs for reproduction in the future. In these reviewed studies, rodents given paracetamol during pregnancy, at doses equivalent to those that a pregnant woman may take for pain relief, produced female offspring with fewer eggs. This means that in adulthood, they have fewer eggs available for fertilisation, which may reduce their chances of successful reproduction, particularly as they get older.

This may not be a severe impairment to fertility, it is still of real concern since data from three different labs all independently found that paracetamol may disrupt female reproductive development in this way, which indicates further investigation is needed to establish how this affects human fertility. Although there are parallels between rodent and human reproductive development, these findings have yet to be firmly established in humans.

 However, establishing a link between paracetamol taken by mothers during pregnancy and fertility problems much later in the adult life of the child will be difficult. Combining epidemiological data from human studies with more experimental research on models, such as rodents, it may be possible to firmly establish this link and determine how it happens, so that pregnant women in pain can be successfully treated, without risk to their unborn children.
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