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Chronic inflammation resulting from obesity and other metabolic factors can injure normal tissues and set the stage for cancer.
Illustration by Lee Whale
Unlike mutations or mistakes in a cell's DNA, metabolic factors don't appear to directly turn normal cells into cancerous ones. Rather, they create conditions more favorable to cancer development, or act like a souped-up fertilizer to spur the growth of existing tumors.
In addition, metabolic imbalances may help cancer cells survive by evading the normal "programmed death" commands that order damaged cells to self-destruct for the good of the body. More than 80 years ago, scientists discovered that cancer cells generate energy differently from normal cells. Today, this metabolic discrepancy is being dusted off and exploited as a strategy for designing new cancer therapies (see How cancer cells make energy).
A clue to metabolic influences in cancer emerged from the Spiegelman laboratory in the early 1990s. For many years, his lab has focused on how generic cells develop into specialized fat-storing cells called adipocytes. Graduate student Gokhan Hotamisligil (now MD, PhD) was studying fat cells and found that they secreted a chemical messenger called tumor necrosis factor alpha that could trigger an inflammatory reaction in the body's immune system. "His work was the beginning of an 'inflammation' model showing one way obesity can lead to diabetes, a model now widely accepted," says Spiegelman.
Inflammation, which causes the pain, swelling, and hot sensation around a wound or bite injury, is an important defensive response by the immune system. But excessive or prolonged inflammation can harm healthy cells and prod them toward a cancerous career. According to one current hypothesis, obesity and diabetes ignite a chronic, simmering state of inflammation throughout the body, like a persistent underground coal fire.
"There is a ton of evidence that chronic inflammation leads to cancer," says Matt Vander Heiden, PhD, a postdoctoral researcher affiliated with the group headed by Philip Kantoff, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber/Brigham and Women's Cancer Center. "Inflammation acts as a growth driver; it causes proliferation of cells."
Wendy Garrett, MD, PhD, of Dana-Farber recently led research in the Harvard School of Public Health (HSPH) laboratory of Laurie Glimcher, MD, which revealed an important immune mechanism that causes ulcerative colitis, a form of inflammatory bowel disease. This has potential implications for cancer, she explains, because people with ulcerative colitis have a higher risk of colon cancer.
"You have raging inflammation going on in the colon, which causes death and injury to cells of the colon's lining," says Garrett. "And this puts stress on cells that are the precursors to colon lining cells – and that can lead to mutations in those cells that make them more susceptible to cancer."
Following up his findings linking fat cells' chemical messengers to inflammation, Hotamisligil, now chair of Genetics and Complex Diseases at the HSPH, is exploring how metabolic and immune pathways influence obesity, diabetes, and other diseases. Two years ago, he reported finding in mice a "missing link" – a biochemical pathway – through which excess body fat promotes inflammation, insulin resistance (a prelude to diabetes), and diabetes itself.
Hotamisligil discovered that in obese people, fat cells are put under stress by their own sheer mass, setting off a "crisis" within them. The cells' emergency response suppresses normal insulin action and sends a wave of inflammation through the body. Over time, damage accumulates; cardiovascular disease and Type II diabetes can ensue, along with conditions favoring cancer. Hotamisligil has identified some key molecular players in the chain reaction.
- Next: Implicating insulin
- Metabolism matters: 1 | 2 | 3 | 4
