Is fat to blame for metastasis in aggressive prostate cancer?

New research demonstrated that a diet high in fat combined with genetic factors may cause prostate cancer to metastasize. The findings were published in Nature Genetics.

The study, led by Ming Chen, PhD, from the Beth Israel Deaconess Medical Center at Harvard Medical School in Boston, MA, sheds new light on how obesity caused by a high-fat diet (HFD) may promote an aggressive type of metastatic prostate cancer in a subset of patients.

“Understanding the molecular events that underlie progression to metastasis, at both the genetic and environmental levels, has the potential to substantially improve therapeutic options and facilitate preventive interventions.” the authors wrote.

Two important tumor-suppressor genes, PTEN and PML, protect against prostate cancer, but the loss of both often occurs in aggressive forms of prostate cancer. The investigators found that prostate cancer metastasized to lymph nodes in 30% of mice lacking both genes.

In addition, molecular profiling of the mouse tumors revealed high levels of key lipids in the cells. Among the top genes and biological pathways affected were those involved in lipid production.

The researchers suspected that increased lipid production may be triggered by activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which is frequently deregulated in prostate cancer. The mice were fed a lard-based HFD to determine whether prostate cancer was more prevalent or more aggressive.

The HFD in mice induced lipid accumulation in prostate tumors that were more likely to develop metastases in the lymph nodes and in soft tissues such as the lung.

Finally, the investigators treated the mice with fatostatin, a small molecule inhibitor targeting a key regulator of fat production, to determine if metastasis could be prevented. Mice treated with fatostatin had less tumor growth and a lower incidence of metastasis compared with untreated mice.

In an article published in The New England Journal of Medicine, Cory Abate?Shen, PhD, Columbia University Medical Center in New York, NY, outlined the clinical implications of the study and relevance in humans.¹

It appears that lipids promote aggressive prostate cancer through mechanisms that are intrinsic to tumor cells, and reducing levels of fat in prostate cells may improve outcomes of prostate cancer, Dr. Abate-Shen wrote.

Other considerations are that a HFD and obesity have many physiological consequences in the whole organism; furthermore, high intake of sugars may also alter cellular metabolism.

In addition, bone metastasis is a major cause of death in men with prostate cancer, so it is unclear if the lymph-node and lung metastases reported in the mice models are true surrogates for lethal prostate cancer in men. It is also unknown whether increased levels of fat either affect or are affected by androgen-receptor signaling in the mouse model.

Dr. Abate-Shen feels that, if validated in humans, the results of this study may be highly relevant for understanding the risk of developing fatal subtypes of prostate cancer.

To read more about this study, click here. 

Reference:

1. Abate-Shen C. N Engl J Med. 2018 Apr 26;378(17):1643-1645.