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Endotrophin

Peptide That Links Obesity and Cancer

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Link between Obesity and Cancer

Around one-fifth of cancer deaths in the United States are associated with obesity. But how is fat fueling the growth of tumors?

Ample evidence exists that fat animals are more likely to develop cancer than lean animals. Cancers in fat animals also grow faster and larger, spread more quickly, and are more resistant to treatment. Furthermore, although experiments explaining the molecular basis for the phenomenon have focused on rodents and monkeys, human cancer statistics suggest that the same holds true for us: overweight and obese people get more cancer, worse , and die more often from  than people with less body fat. In a landmark 2003 study, American Cancer Society researchers analyzed data on cancer and obesity from a group of 900,000 American adults that they had monitored for 16 years (1). The researchers found that the most obese women had a 62% increase in their risk of dying from cancer than women of normal weight; for obese men, the increase was 52%. The wide range of tumor types included colorectal, liver, gallbladder, pancreas, esophageal, kidney, prostate, breast, uterine, endometrial, and ovarian cancers. The researchers concluded that above-normal weight was associated with almost 20% of all cancer deaths in the United States. “There’s an incredibly powerful link between obesity and cancer,” says oncologist Joyce Slingerland of the University of Miami, Florida. “Everyone’s heard of obesity’s effect on heart disease and diabetes, and we’re now beginning to understand that the cancer risk is just as great,” she says.

“What we’re learning is that fat cells provide a microenvironment that tumor cells really enjoy,”says biologist Philipp Scherer of the University of Texas Southwestern Medical Center.  During the past few years, Scherer has focused on a different molecule produced by fat cells. Endotrophin is a small protein cleaved from collagen VI, which adipocytes produce for structural support and to recruit vital growth factors. Obese individuals, with more adipocytes, tend to have high levels of collagen VI.

Scherer’s team homed in on Endotrophin as the root cause of that effect. When they increased levels of Endotrophin in a line of mice prone to developing severe breast cancer, tumors grew even more quickly than usual and spread to the lungs faster. When Scherer administered a drug that blocked endotrophin, the mice’s tumors were smaller and less likely to spread.  It is believed that Endotrophin is an one of the major factor that connect the obesity and cancer.

Sarah C. P. Williams, PNAS May 28, 2013 vol. 110 no. 22 8753-8754; doi: 10.1073/pnas.1308182110

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COL6A3 Protein Deficiency in Mice Leads to Muscle and Tendon Defects Similar to Human Collagen VI Congenital Muscular Dystrophy.

Pan TC, Zhang RZ, Markova D et al, J Biol Chem. 2013 May 17;288(20):14320-31. doi: 10.1074/jbc.M112.433078. Epub 2013 Apr 5.

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Inhibition of endotrophin, a cleavage product of collagen VI, confers cisplatin sensitivity to tumours.

Park J, Morley TS, Scherer PE, EMBO Mol Med. 2013 Apr 30. doi: 10.1002/emmm.201202006. [Epub ahead of print]

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Endotrophin - a Novel Factor Linking Obesity with Aggressive Tumor Growth.

Park J, Scherer PE, Oncotarget. 2012 ;3(12):1487-8

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Adipocyte-derived endotrophin promotes malignant tumor progression.

Park J, Scherer PE, J Clin Invest. 2012 Nov 1;122(11):4243-56. doi: 10.1172/JCI63930. Epub 2012 Oct 8

Figure from Park J, Scherer PE. J Clin Invest. 2012 Nov 1;122(11):4243-56.

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