Common ground
By Roberta Nichols
At City of Hope, where cancer and diabetes form the framework of the institution’s disease- fighting mission, researchers in both areas are beginning to see their investigations intersect.
The connections could not come at a more critical time. According to the World Health Organization (WHO), cancer will become the world’s top killer by 2010, outranking heart disease. About 7 million people will die from cancer this year, and by 2030, cancer deaths may rise to as many as 17 million.
At the same time, about 180 million people worldwide now have some form of diabetes, according to the WHO. That figure may double by 2030. The disease is believed to claim the lives of at least 3 million people each year.
From public health experts to laboratory scientists, the mandate is clear: Tackle these two major threats to health. City of Hope scientists are seeing that some of the same mechanisms are at play in cancer and diabetes — and they bring their expertise in both fields to bear as they seek answers.
Their tale begins at the dinner table.
YOU ARE WHAT YOU OVEREAT
Type 2 diabetes used to be called “adult onset diabetes” because it was diagnosed mostly in people in their 40s or 50s. Those were slimmer times.
Today, doctors see more cases of type 2 diabetes in young adults and even children just entering puberty, and they blame obesity. About 75 percent of Americans are overweight, said Barry Forman, M.D., Ph.D., the Ruth B. and Robert K. Lanman Chair in Gene Regulation and Drug Discovery Research.
And he expects the scales to tip ever higher. “By 2050, virtually everyone is going to be overweight,” predicted Forman, who is also a professor and director of the Division of Gene Regulation and Drug Discovery.
Forman and his colleagues aim to battle metabolic syndrome — a set of disorders linked to diabetes and some forms of cancer — which is spurred by obesity.
Scientists cannot say for sure how obesity encourages diabetes, but one area of research revolves around inflammation.
Anyone with a bug bite has seen it: Skin becomes red, puffy and inflamed. Under the skin, legions of white blood cells mobilize at the damaged site in a show of force called an immune response.
Obesity seems to heighten inflammation inside the body. As diabetes expert Samuel Rahbar, M.D., Ph.D., explained, “White blood cells are attacking the tissue of obese people in the same manner in which they would a disease.”
Said Forman: “The thought is that fat cells enlarge to the point where some of them burst.” White blood cells then become attracted to the dead fat cells and more immune reinforcements join the fight, causing more inflammation.
Inflammation stresses the body’s nuclear receptors, special proteins inside cells that regulate metabolism and the expression of certain genes. Forman is an expert on these receptors. He and his Division of Gene Regulation and Drug Discovery team are designing custom drugs to try to prevent these receptors from activating undesirable genes, heading off metabolic syndrome.
Inflammation also unleashes “free radicals,” oxygen molecules that can damage cells, researchers noted. They suspect these factors combine to make cells resistant to insulin and contribute to diabetes and its complications.
They also may produce other disturbing changes related to cancer. By producing free radicals, fat cells create an environment that may cause other cells to mutate, said Arthur D. Riggs, Ph.D., director emeritus of Beckman Research Institute and chair of the Department of Diabetes and Metabolic Diseases Research. And hormones may stimulate these precancerous cells, spurring cancer.
“Cancer is a long-term process. You generally have to have a mutation or epimutation — something that gets it started,” said Riggs, whose research into epigenetics helped lay the groundwork for understanding how cancer begins. “Going from precancerous mutation to a full, metastatic, life-threatening cancer takes a long time, and many events. It’s certainly possible that being overweight hastens the transition from precancer to metastatic cancer; that’s where the hormones might have an effect.” Forman agrees.
“Strictly speaking, it’s probably not going to turn out that obesity causes cancer by itself,” Forman said. “There’s no evidence that obesity does that, although it’s probably changing the environment, making tumor cells or pretumor cells grow faster.”
When cells’ DNA gets slightly damaged — if they are hit with chemicals or radiation, for example — the body can repair that damage. But if cells are hit in two or more ways, it just may be too overwhelming to fix.
“Scientists call it the ‘two-hit hypothesis,’” said Rama Natarajan, Ph.D., professor in the divisions of Diabetes, Endocrinology & Metabolism and Gene Regulation and Drug Discovery, who studies pathways regulating the breakdown of fatty acids, inflammation and other mechanisms that influence both diabetes and breast cancer. “When the second hit comes in, the cell cannot handle it anymore.
“Inflammation produces all this kindling: spark to the fire. For the fire to burn, you have to have the second spark, another source of damage. It ignites the fire.”
THE INSULIN CONNECTION
Scientists also are finding links between cancer and growth hormones including insulin, the hormone central to diabetes.
Special cells in the pancreas produce and release insulin, a hormone controlling the amount of glucose, a form of sugar, in the blood. (See “What is diabetes?” in the sidebar.)
In type 2 diabetes, the body fully or partially ignores the effects of insulin, and glucose levels rise in the blood. As a result, the pancreas works overtime to produce even more insulin.
“It’s believed that people with type 2 diabetes are prone to getting cancer because they have a lot of circulating insulin,” Natarajan said. Insulin can accelerate the growth of cells in the body, which may explain why diabetes is linked to higher risk for colon, liver and other cancers. Between diet and weight, the stage is set for disease.
“We know that people are eating too much of the wrong things and exercising less,” she said. “These bad metabolites, fatty acids and too much inflammation not only give you diabetes but also make your cells more susceptible to getting cancer.”
Researchers also have learned lessons from the effects of diabetes drugs on cancer. For example, the diabetes drug metformin actually lowers risk of cancer diagnosis and death, although no one knows exactly why.
Janice Huss, Ph.D., assistant professor in the Division of Gene Regulation and Drug Discovery, is studying how metformin helps muscle cells get energy from blood sugar. She and her colleagues know metformin acts by influencing a protein called AMP- activated protein kinase, or AMPK, but now they want to discover whether activating AMPK might stifle breast, colon, prostate and other cancers.
Sometimes just bringing diabetes and cancer specialists together in one place — City of Hope — encourages creative ideas with great potential.
Take Rahbar and brain cancer specialist Behnam Badie, M.D., for example. Rahbar told Badie about his research into advanced glycation endproducts, toxic byproducts that result from excess sugar in the blood of those with diabetes. These chemicals can cause inflammation and lead to many diabetes complications, and Rahbar is studying a compound that fights that inflammatory response.
The conversation gave Badie an idea, because a chemical related to the byproducts is active around glioma, the most common brain cancer. Now Badie has partnered with Natarajan to study how glioma might use the chemical to protect itself from the immune system.
That kind of creativity is yielding important scientific connections that will make a difference. As Natarajan put it, “City of Hope’s commitment to sharing ideas and collaboration across different medical practices opens doors to different perspectives and new avenues of research one might not have considered before.”
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