Research team pinpoints tumor mechanism that impairs glucose production
An Arizona State University professor was part of a team whose research may have discovered how cancer cells suppress the body’s production of insulin, leading to a higher risk of diabetes for women who have had breast cancer.
Dorothy Sears, a professor of nutrition in the College of Health Solutions, was part of a group of researchers whose study was recently published in the journal Nature Cell Biology. She researches obesity and the risk for obesity-related diseases such as insulin resistance, diabetes, cardiovascular disease and cancer.
“We know that people with cancer have an increased risk of diabetes – that’s been researched a lot,” she said.
“But what hasn’t been researched was how does cancer increase the risk for diabetes? The key finding of this study was the mechanism by which the cancer is increasing the risk for diabetes and exactly how that happens.
“It was an elegant series of experiments,” she said of the study. The team, in addition to Sears, one of the supervisors of the research, included scientists from the University of California at San Diego, City of Hope, Regulus Therapeutics and the University of California at Riverside.
The study found that the mechanism that connects breast cancer to diabetes are “extracellular vesicles.” Breast cancer cells shed these vesicles, which are hollow spheres that carry DNA, RNA, fats and proteins among cells. The breast cancer cells secrete molecules called microRNA-122 into the vesicles, which then travel to the pancreas and latch onto insulin-producing cells. There, the microRNA-122 damages the pancreatic cells’ ability to secrete insulin and maintain normal blood glucose levels.
That leads to higher blood glucose levels in breast cancer patients, elevating their risk of diabetes.
The initial research was done with mouse models.
“What was missing and where I came in was showing that elevation of these microRNAs was really existing in humans,” Sears said.
Shizhen Emily Wang, professor of pathology at UC San Diego School of Medicine, had serum samples from breast cancer patients, but not from women who were cancer-free.
“She needed serum from control women to show that these microRNAs were elevated in the cancer patients, just like in the mice,” Sears said.
Sears had many serum samples in her freezer from women who were cancer-free, and she was able to match their characteristics, such as age and body mass index, to Wang’s samples of people who had cancer.
"Then (Wang) was able to measure the concentration of microRNA in her breast cancer population versus my cancer-free population and show that the hers had more microRNA-122," Sears said.
“Then, she took the microRNA-122 from her population and put it on beta cells in culture and showed that the microRNA-122 from the patients did the same things in the culture as it did in the mouse model, which was to inhibit insulin secretion.”
The good thing is that, in theory, with this kind of information, we can say "Aha, I see you microRNA-122, and I can block you."
— Dorothy Sears, professor of nutrition in the College of Health Solutions
Researchers knew that extracellular vesicles could mediate cell-to-cell communication.
“They’re bubbling off and getting into the blood, which they have to get through barriers to do, and then they’re fusing to the recipient cells and delivering little envelopes of stuff to those target cells," Sears said.
“In each vesicle, there can be hundreds of microRNAs and they can deliver a lot of material to cells over time.
“MicroRNA-122 are powerful little guys that inhibit gene expression.”
Tumors grow quickly, using sugar as fuel, Sears said.
“So it’s in their best interest to impair insulin secretion, because if that happens, the blood glucose level rises, and now they have more fuel so they can grow faster,” she said.
“The good thing is that, in theory, with this kind of information, we can say ‘Aha, I see you microRNA-122, and I can block you.’”
Several clinical trials are underway now of anti-microRNAs.
“They’re treating microRNAs with another microRNA, so you’re velcroing it to itself,” Sears said.
She had the samples because of her current research study that is analyzing biomarkers in people to determine how their exposure to the built environment influences their risk of cancer.
“The built environment might be the walkability of a neighborhood. Can they walk to the market or do they have to get into a car? And do they live near areas where there’s lots of pollution, like near a freeway? And are they near green space or the ocean or water-treatment plants?
“Air pollution exposure impacts insulin resistance, which is a precursor for diabetes and obesity and cancer.”
Sears worked at UC San Diego when she started working on the study, which recruited more than 600 people and collected blood, urine and stool samples. The participants also answered a questionnaire and wore GPS devices for two weeks. She’s still analyzing the results.
The participants agreed to allow their samples to be banked, so that’s why they were available for the microRNA-122 study.
“We collected a ton of data, and I have students at ASU working on many aspects of the study,” she said.
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