APR 09, 2018 3:00 PM PDT

Understanding how Fat Promotes Cancer Growth

WRITTEN BY: Carmen Leitch

We know that it isn’t healthy to be obese, and obesity is a major preventable cause of cancer. But exactly how metabolism in the whole body impacts tumor growth is not well understood. Researchers have been trying to learn how fat cells signal to tumors and now, work by scientists at Sanford Prebys Medical Discovery Institute (SBP) has revealed more. They found that when a protein called p62 is inactive in mice, deadly, metastatic prostate cancer formation is promoted. Reporting in Cancer Cell, they discovered that without p62, fat tissue stops consuming energy, which increases nutrient availability for cancer cells.

This is Maria-Diaz Meco, Ph.D., professor, and Jorge Moscat, Ph.D., professor and director of Metabolism Initiatives at SBP. / Credit: Sanford Burnham Prebys Medical Discovery Institute (SBP)

"This work could lead to better therapies that consider cancer not just as a genetic or cellular disease, but as a whole-body process where tumors communicate with metabolic organs to maintain their unlimited appetite for nutrients," explained co-senior study author Maria Diaz-Meco, Ph.D. She is a professor in the Cancer Metabolism and Signaling Networks Program at SBP. "This is a vulnerability that can be targeted therapeutically."

Prostate cancer killed over 26,000 men in the United States in 2017, making it a focus of research. But challenges with mouse models have prevented researchers from exploring how obesity makes prostate cancer worse.

"Most of the studies addressing the role of adiposity and obesity in cancer use mice fed a high-fat diet. Although this mimics some of the situations in patients, it prevents a real understanding of the signaling pathways that control the bidirectional communication between tumors and adipocytes, or fat cells," noted co-senior study author Jorge Moscat, Ph.D., director, and professor of the Cancer Metabolism and Signaling Networks Program at SBP. “This is essential if we want to identify therapeutic targets that can be harnessed to prevent the pro-tumorigenic signals emanating from the adipose tissue."

The investigators used a mouse model they helped create in previous work. These mice are engineered so their fat cells have no p62, which increases adiposity and metabolic dysfunction, without needing to manipulate their diet. 

The researchers showed that p62 has an essential role in the communications between fat and tumors. It inhibits a protein complex termed mTORC1. Several processes that need a lot of energy get suppressed, and that leaves nutrients and fatty acids available to promote the growth of tumors.

"This metabolic reprograming orchestrated by the loss of p62 in adipocytes appears to help tumors cope with the high-energy demands of an aggressive cancer," Diaz-Meco said.

The scientists also learned that without p62, fat cells make more of two proteins, osteopontin, and Cpt1a. Both are needed for prostate cancer to grow, move and invade. 

"The significance is huge because we identify a new set of therapeutic targets that, if modulated, should block the ability of activated adipose tissue to promote tumor malignancy," Moscat noted. In the video above, he speaks more about p62 and tumor growth.

The researchers want to continue searching for therapeutic targets, starting in the p62 pathway. "We need to consider other aspects of cancer therapeutics beyond the better-known genetics. That is, we need to invest more in the research of cancer metabolism, which deals with the identification of metabolic vulnerabilities that should be common to all types of cancers. This will ultimately lead to better therapies that are less susceptible to resistance, which is an all-too-common problem in oncogene-target approaches," Diaz-Meco concluded. 


Sources: AAAS/Eurekalert! Via SBP Medical Discovery Institute, Cancer Cell

About the Author
BS
Experienced research scientist and technical expert with authorships on over 30 peer-reviewed publications, traveler to over 70 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
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