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can cancer research lead to a "cure" for obesity?
The key to treating obesity; reversing weight loss in cancer patients [University of New South Wales]
Researchers from UNSW are part of a team which has developed a novel way to control the extreme weight loss that commonly accompanies and hastens death in late stage cancer patients.
The findings published in Nature Medicine suggest it may soon be possible to prevent this condition, giving people the strength to survive treatment and improve their chances of recovery.
The team of researchers from the Centre for Immunology at St Vincent's Hospital and UNSW, and the Garvan Institute of Medical Research have shown that most common cancers produce large amounts of a molecule known as MIC-1, which targets brain receptors that switch off appetite.
Antibodies against MIC-1, already developed by St Vincent's, make it possible to switch appetite back on.
Conversely, when normal and obese mice are treated with MIC-1, they eat less and lose a lot of weight, suggesting that MIC-1 may also form the basis of a treatment for severe obesity.
Professor Sam Breit at the Centre for Immunology originally cloned the MIC-1 gene. He discovered that blood levels of MIC-1 were high in many patients with advanced cancers, and correlated this with the extreme weight loss seen in these patients. In a collaboration with Professor Herbert Herzog, Director of the Neuroscience Research Program at Garvan, he analysed the effect of this molecule on metabolism and the brain control of appetite.
"This work has given us a better understanding of the part of the brain that regulates appetite. Our bodies send complex chemical signals to our brains, which interpret them and send back responses, in this case 'eat' or 'don't eat'. Our research indicated that MIC-1 is a previously unrecognised molecule sending a 'don't eat' signal to the brain," said Professor Herzog.
The study showed that if a human cancer making a lot of MIC-1 is grafted onto a mouse, that mouse lost weight dramatically. When the researchers injected that mouse with an antibody that 'mopped up' MIC-1, the weight loss was reversed. In effect, they rescued the mouse from the excessive influence of MIC-1.
It is hoped that in the near future, the MIC-1 findings will prevent a sizeable proportion of advanced cancer patients from literally wasting away. The team hopes to develop a human antibody and run clinical trials in the next few years.
Professor Breit who, since discovering the MIC-1 gene in the 1990s, has conducted several internationally-published studies relating to the gene's influence on coronary disease, miscarriage and cancer. He now believes the findings could also have a significant impact on a range of appetite-related disorders.
"Injecting mice with MIC-1 protein also made them stop eating, suggesting that it may be possible to use this to advantage for treating patients with severe obesity," he said.
ABSTRACT: Tumor-induced anorexia and weight loss are mediated by the TGF-bold beta superfamily cytokine MIC-1 [Nature Medicine]
Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss. In mice with xenografted prostate tumors, elevated MIC-1 levels were also associated with marked weight, fat and lean tissue loss that was mediated by decreased food intake and was reversed by administration of antibody to MIC-1. Additionally, normal mice given systemic MIC-1 and transgenic mice overexpressing MIC-1 showed hypophagia and reduced body weight. MIC-1 mediates its effects by central mechanisms that implicate the hypothalamic transforming growth factor-? receptor II, extracellular signal-regulated kinases 1 and 2, signal transducer and activator of transcription-3, neuropeptide Y and pro-opiomelanocortin. Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.
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