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| Endotrophin |
Peptide That Links Obesity and Cancer |
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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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Collagen VI is a ubiquitously expressed extracellular microfibrillar protein. Its most common molecular form is composed of the α1(VI), α2(VI), and α3(VI) collagen α chains encoded by the COL6A1, COL6A2, and COL6A3 genes, respectively. Mutations in any of the three collagen VI genes cause congenital muscular dystrophy types Bethlem and Ullrich as well as intermediate phenotypes characterized by muscle weakness and connective tissue abnormalities. The α3(VI) collagen α chain has much larger N- and C-globular domains than the other two chains. Its most C-terminal domain can be cleaved off after assembly into microfibrils, and the cleavage product has been implicated in tumor angiogenesis and progression. Here we characterize a Col6a3 mutant mouse that expresses a very low level of a non-functional α3(VI) collagen chain. The mutant mice are deficient in extracellular collagen VI microfibrils and exhibit myopathic features, including decreased muscle mass and contractile force. Ultrastructurally abnormal collagen fibrils were observed in tendon, but not cornea, of the mutant mice, indicating a distinct tissue-specific effect of collagen VI on collagen I fibrillogenesis. Overall, the mice lacking normal α3(VI) collagen chains displayed mild musculoskeletal phenotypes similar to mice deficient in the α1(VI) collagen α chain, suggesting that the cleavage product of the α3(VI) collagen does not elicit essential functions in normal growth and development. The Col6a3 mouse mutant lacking functional α3(VI) collagen chains thus serves as an animal model for COL6A3-related muscular dystrophy.
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Endotrophin is a cleavage product of collagenVIα3 (COL6A3). Here, we explore the relationship between thiazolidinediones (TZDs), endotrophin and cisplatin resistance in the context of a mammary tumour model. COL6A3 levels are increased in response to cisplatin exposure in tumours. Endotrophin, in turn, causes cisplatin resistance. The effects of endotrophin can be bypassed, either through use of COL6 null (COL6-/- ) mice or by administering TZDs in wild-type mice (leading to a downregulation of endotrophin). Both approaches sensitize tumours to cisplatin through the suppression of endotrophin-induced epithelial-mesenchymal transition. The beneficial effects of TZDs on cisplatin sensitivity are diminished in COL6-/-mice, whereas endotrophin+ tumours are sensitive to the TZD/cisplatin combination. Therefore, the chemosensitization obtained with TZDs is achieved through a downregulation of endotrophin. Treatment with an endotrophin neutralizing antibody in combination with cisplatin completely inhibits tumour growth of tumour allografts. Combined, our data suggest that endotrophin levels are a strong prognostic marker for the effectiveness of the combination therapy of TZDs with cisplatin, and neutralization of endotrophin activity dramatically improves the therapeutic response to combination therapy.
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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ETP stimulates tumor growth and metastasis via fibrosis, angiogenesis, and inflammation.
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Adipocytes represent a major cell type in the mammary tumor microenvironment and are important for tumor growth. Collagen VI (COL6) is highly expressed in adipose tissue, upregulated in the obese state, and enriched in breast cancer lesions and is a stimulator of mammary tumor growth. Here, we have described a cleavage product of the COL6α3 chain, endotrophin (ETP), which serves as the major mediator of the COL6-mediated tumor effects. ETP augmented fibrosis, angiogenesis, and inflammation through recruitment of macrophages and endothelial cells. Moreover, ETP expression was associated with aggressive mammary tumor growth and high metastatic growth. These effects were partially mediated through enhanced TGF-β signaling, which contributes to tissue fibrosis and epithelial-mesenchymal transition (EMT) of tumor cells. Our results highlight the crucial role of ETP as an obesity-associated factor that promotes tumor growth in the context of adipocyte interactions with tumor and stromal cells.
Park J, Scherer PE, J Clin Invest. 2012 Nov 1;122(11):4243-56. doi: 10.1172/JCI63930. Epub 2012 Oct 8
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Figure from Park J, Scherer PE. J Clin Invest. 2012 Nov 1;122(11):4243-56.
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