Finding ways to reverse obesity’s lingering, pro-cancer effects

Apr 16 2018

Like exposure to too much sun and drinking alcohol, obesity is a risk factor for cancer. Researchers at the University of North Carolina Lineberger Comprehensive Cancer Center are working to be a part of the solution -- they want to find ways to reverse obesity-linked biological changes in the body that are associated with cancer growth.

"Our work has evolved from questions of 'is obesity increasing cancer risk?' and 'what are the mechanisms linking obesity and cancer?'" said UNC Lineberger's Stephen Hursting, PhD, professor in the UNC Gillings School of Global Public Health. "We have largely answered the first question, and are still working on the second question, but our focus has really turned to: 'What are we going to do about it?'"

In preliminary findings presented at the American Association for Cancer Research Annual Meeting 2018, researchers from the Hursting lab reported on a number of studies examining possible ways to reverse obesity-linked biological changes. Hursting said that overall, they're finding the solution to the problem may a bit more complicated than "weight gain increases cancer risk, so losing some weight is the way to fix it."

"There are several mechanisms that we have identified, particularly epigenetic, metabolic and inflammatory changes within tissues, that are triggered by obesity but seem to be persistent, even after obesity is reversed," Hursting said. "That suggests we're going to have to get smarter about how to break the obesity-cancer link."

• Can weight loss reverse the pro-cancer effects of chronic obesity? A preclinical study by Laura Bowers, PhD, postdoctoral research associate in Hursting's lab, evaluated growth of a type of aggressive breast cancer, known as basal-like breast cancer, in mice that were obese most of their lives, but then lost weight through one of four reduced calorie diets, compared to mice that were never obese. They found returning to a normal weight via a low-fat diet did not fully reverse the pro-cancer effects of chronic obesity, but severe weight loss accomplished by very low calorie diets did break the obesity-breast cancer link. The findings will be presented on Monday, 1-5 p.m.

"We have shown previously that normalization of weight after chronic obesity doesn't fully reverse the pro-cancerous effects of obesity," Hursting said. "We've established that there are both inflammatory and epigenetic mechanisms underlying the persistent pro-cancer effects of obesity, even after successful weight normalization. We think the severity of the weight loss, and maybe the pace of weight loss, are important since a more severe caloric restriction, accomplished by very low calorie diets or bariatric surgery, have shown to fully reverse the inflammation, epigenetic alterations and cancer susceptibility that accompany chronic obesity."

• What effect does cutting calories have on the molecular drivers of cancer? In a study to be presented on Sunday from 1-5 p.m., graduate student Laura Smith asked whether cutting calories would lower activation of signals known to play a role in HER2-positive breast cancer. They reported that in preclinical laboratory models of HER2-positive breast cancer, calorie restriction reduced activation of PI3K/Akt signaling.

A second preclinical study will be presented by undergraduate Magdalena Rainey on Monday from 1-5 p.m. that shows that restricting calorie consumption could also reduce activity of a protein called p21 in HER2-overexpressing breast cancer cells. In certain conditions, the protein can allow breast cancer cells to avoid grow uncontrollably, and avoid cell death. Researchers believe their findings give support to the theory that restricting calories can reverse the conditions that allow the protein to have a cancer-promoting effect.

• Does disrupting how cells get energy help control pancreatic cancer growth?

"There are few established risk factors for pancreatic cancer, but obesity has emerged as an important one," Hursting said. We wanted to know if we could target energy metabolism to attack this problem."

Jane Pearce, winner of the 2018 AACR Margaret Foti Undergraduate Prize in Cancer Research, studied whether pancreatic cancer is reduced in models that lacked a key protein regulating autophagy, a metabolic process that helps cancer cells survive under stress. They found that editing out the autophagy regulator ATG5 in pancreatic cancer cells resulted in "striking" changes in the metabolism of cells, and helped to reduce pancreatic adenocarcinoma cell growth. The findings will be presented on Monday, 8 a.m.-noon.

In a second study, Xuewen Chen, an AACR Thomas Bardos Science Education for Undergraduates Award winner, looked at the impact of both restricting calories for pancreatic cancer tumors, and blocking autophagy.

"When the cancer cells are starving, they often depend on autophagy to survive," Hursting said. So by reducing calories to slow growth, and then also blocking autophagy, they hoped to cut off the cells' fuel sources. They found that the growth-suppressive effects of calorie restriction were enhanced when they also blocked autophagy using a therapeutic compound. The findings will be presented on Tuesday, 8 a.m.-noon.

"We see better effects when we combine autophagy inhibition with some calorie restriction approaches as well as drugs that inhibit insulin-like growth factor signaling," Hursting said. "This combination approach of restricting nutrients and inhibiting autophagy is promising in terms of a metabolic one-two punch for suppressing cancer cell growth and survival."