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Research explains diabetics’ increased metastatic cancer risk

As if people living with diabetes didn’t have enough health concerns, here’s another: increased risk of metastatic cancer. New Cornell research points to a possible explanation for this health double whammy.

“Cancer and diabetes are two of the worst health problems in developed countries, and there’s a link between the two,” said Mingming Wu, professor of biological and environmental engineering. “For cancer, half of the story is still in genetics. It’s only recently we realized there is another half that we missed, which is the microenvironment.”

Wu’s findings are reported in “Glycation of Collagen Matrices Promotes Breast Tumor Cell Invasion,” published May 1 in Investigative Biology. Minglin Ma, assistant professor of biological and environmental engineering, Larry Bonassar, the Daljit S. and Elaine Sarkaria Professor in Biomedical Engineering, and Jeffrey Segall, a cancer biologist at Albert Einstein College of Medicine, are co-authors.

In order for cancer to metastasize, the malfunctioning cells must travel through a slurry of minerals, carbohydrates, water and connective tissue to get into the bloodstream, through which it travels to a different part of the body. That slurry – known as extracellular matrix, or ECM – is a complex and dynamic environment. A main component is collagen, a protein that supports cell structural integrity.

Collagen fibers are composed of nanometer-sized strands, called fibrils. These fibrils combine to form fibers of varying length and thickness. In diabetics, elevated blood sugar levels influence the architecture of collagen fibers in ways that promote cancer cell movements throughout the body, according to the Cornell researchers.

Through a chemical process called glycation, sugar molecules bond to protein without an enzyme. Glycation forces fibrils to cross-link and form a compact collagen fiber. Doing so, according to Wu and her team, stiffens and alters the fibers and creates larger pore sizes between the collagen, opening up avenues for cell migration.

“Cross-linking makes more fibrils come together and a form a stronger fiber,” Wu said. “This mesh structure provides an easy path for cancer cells to adhere to and navigate across.”

Wu compared the structure to a playground rope climber. Getting across is tricky if the ropes are droopy but when the ropes are taut, movement is much easier. It’s similar for cancer cells.

“Diabetics have higher blood sugar levels which lead to glycation and changes the structure of the collagen in their tissue,” said Young Joon Suh ’17, a graduate student in biological engineering and lead author. “If they happen to have cancer, we believe this glycation process promotes the rate of metastasizing.”

Using breast cancer cells in their study, the scientists experimented with varying glycation concentrations and used software to track the trajectory of the cells as they moved through the three-dimensional space. The researchers found the cells moved farther and faster in highly glycated environments than in non-glycated ones.

The research started as an undergraduate research project led by Suh, whose academic goals include medical school. He contacted Wu about research opportunities as an undergraduate; they decided to explore the link between diabetes and cancer. Wu allocated grant money to help him start.

Later they applied for a grant from the National Institutes of Health, which now funds Suh’s research as a graduate student, along with support from the Cornell NanoScale Science and Technology Facility.

“It was really exciting to have an undergraduate initiate the project,” Wu said. “Bioengineering needs to integrate biomaterial expertise, cell biology research and an engineering perspective. Having all those elements at Cornell helps promote new ways to think about complex problems.”

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Lindsey Hadlock