By Laura Smith
Last week the American Association of Cancer Research’s annual meeting took place at the World Congress Center in Atlanta, Georgia. As one of the largest cancer conferences in the world, thousands of physicians and researchers attended to hear leaders present cutting-edge research in the field of cancer prevention and treatment. As a graduate researcher studying the impact of nutrition on cancer risk and progression, I was very excited to attend a session focused entirely on obesity and cancer progression.
Obesity increases the risk of developing cancer (specifically 13 types of cancer including colorectal, postmenopausal breast, prostate, pancreatic, and liver cancers) as well as mortality from cancer; however, the way by which obesity enhances cancer risk and progression is not well understood. Several obesity-associated changes have been linked to increased cancer growth in animal models including disrupted metabolism (e.g. hyperglycemia and hyperinsulinemia), altered growth factor or hormone signaling, and chronic inflammation. In the session I attended, researchers Rachel Perry and Michael Pollak presented their work focused on hyperinsulinemia and colon cancer risk.
You’ve probably heard of insulin due to its connection with diabetes mellitus. Patients with diabetes either have reduced ability to make adequate amounts of insulin (Type 1) or exhibit decreased responsiveness to insulin (Type 2). One major function of insulin is the stimulation of glucose uptake by cells following consumption of a glucose-containing meal. Diabetic individuals are unable to adequately manage increased blood glucose experienced following a meal. To address this, patients must alter dietary intake of glucose-containing foods and/or take insulin or antidiabetic medications (such as metformin) to normalize blood glucose levels.
So where does insulin fit into the cancer equation? Research conducted by Drs. Perry and Pollak demonstrate that obesity increases tumor growth mediated in part by hyperinsulinemia, or elevated levels of serum insulin. To model obesity in a mouse model of colon cancer, mice were fed a high-fat diet for several weeks. This dietary regimen mimics obesity by increasing body weight and body fat mass of mice and promotes metabolic dysregulation, including hyperglycemia and hyperinsulinemia. High-fat fed mice developed larger colon tumors compared to normal chow fed mice. Further, tumors from hyperinsulinemic, high-fat fed mice had greater glucose uptake and utilization. This suggests that the hyperinsulinemia in the obese state increases access of cancer cells to this cellular fuel, which may explain enhanced tumor growth.
Next the researchers wanted to determine if reduction of insulin levels, by treatment with antidiabetic agent metformin, would reduce tumor growth in high-fat fed mice. To achieve this, high-fat fed mice were given metformin in their water supply for four weeks and then tumors were measured. Metformin treatment resulted in an 80% reduction in tumor size. Further, metformin decreased circulating insulin and glucose (as expected) and also reduced glucose uptake and utilization by the cancer cell. To elucidate the mechanism, researchers replenished insulin in metformin-treated mice so that they were equivalent to levels observed in untreated high-fat fed mice. This resulted in increased tumor size, abrogating the tumor protective effects observed with metformin treatment. Taken together, this suggests that antidiabetic agents such as metformin may be repurposed as anticancer agents in the context of obesity.
At the end of this session, a radiation oncologist asked the panel of researchers how he should advise his cancer patients in light of these findings. Since blood glucose stimulates insulin release, should he advise his patients to follow a low-carbohydrate, ketogenic diet? While these scientists can make educated guesses on dietary advice for cancer patients based on findings in preclinical models, there is a lack of clinical evidence to support the safety and efficacy of dietary interventions such as a ketogenic diet in cancer patients. This highlights the need for more clinical research focused on identifying interventions, either dietary or pharmacological, that will improve prognosis and therapeutic response in obese humans. Additionally, resources need to be made available for health professionals, especially those whose training did not include nutrition courses, to allow them to best advise their patients. It is promising that most hospitals have a dietitian on their treatment teams to aid in the navigation of nutrition in combination with medical care.
Peer-edited by Anandita Pal