Obesity is the second leading cause of cancer and is one of the biggest threats to global health. But just not clear how all the body's metabolism affects the formation of tumors. In particular, the molecular mechanisms of interaction between fat cells and tumor tissue remain poorly understood.
Researchers at the Institute Sanford Prebys Medical Discovery Institute has recently raised this issue, noting that the inactivation of the protein, called p62 in fat cells, leading to aggressive metastatic cancer of the prostate in mice. As reported in Cancer Cell, p62 deficiency causes a stop of energy-intensive processes in adipose tissue, thereby increasing the availability of nutrients to cancer cells.
"This work could lead to better treatments that will take cancer not only as a genetic or cell disease, but as a whole body process when tumors interact with metabolic authorities to maintain an unlimited appetite for nutrients," - says senior study author Maria Diaz - meco.
diversion of energy
Prostate canceris the second leading cause of cancer death among men in the United States, and obesity is a major risk factor for progression and aggressiveness of the disease. But the underlying molecular mechanisms remain unclear, partly because of the limitations of muscle obesity models, which do not allow researchers to study specific crosstalk between fat cells and tumor tissue, regardless of dietary factors.
"Most of the research on the role of obesity in cancer in mice fed a diet high in fat," - says one of the study authors Jorge Moscato, Ph.D., professor and director of the program "Cancer metabolism and signaling networks. Although it mimics some situations patients, it prevents real understanding of the signaling pathways that control the bi-directional link between tumors and adipocytes or fat cells. This is important if we want to identify therapeutic targets that can be used to prevent protuorogennyh signals originating from adipose tissue. "
To solve this problem, Diaz-Meco and Moscato appealed to obesity model, which they had previously helped to develop. These mice lacking p62 in fat cells, which leads to an increase in obesity and metabolic problems without changing food intake. In the new study, scientists have discovered the central role of p62 in adipose tissue tumor-communication, which supports cancer using metabolic fitness. In particular, they found that p62 deficiency in fat cells contribute to the progression and metastasis of prostate cancer in mice by inhibiting protein complex, called mTORC1. Tumors suppress power-consuming activity, such as the development of fat cells, the metabolic process called oxidative phosphorylation, fatty acid metabolism in white adipose tissue. As a result, available in more fatty acids and other nutrients to support tumor growth. "This metabolic reprogramming, organized by the loss of p62 in adipocytes, it seems, helps tumors to cope with the high demands of aggressive cancers," - says Diaz-Meco.
Additional experiments showed that p62 deficiency in adipose tissue promotes the synthesis of proteins called osteopontin and Cpt1a, which are critical for the proliferation of prostate cancer, migration and invasion. These results are clinically significant because the high level of osteopontin and Cpt1a associated with aggressive metastatic prostate cancer in humans. "The significance is huge, because we identify a new set of therapeutic targets to block the ability of adipose tissue to stimulate the activated cancer", - says Moscato.
In addition to genetics
According to the authors, the findings suggest that mTOR inhibitors are currently used to treat a wide range of malignant tumors may have the unintended consequences of the termination of the metabolism of adipose tissue and stimulate tumor growth, at least in certain circumstances. But this possibility needs to be assessed in future studies. For its part, the authors plan further investigate the signaling pathway and p62 in patients to identify drug targets that can be evaluated for their therapeutic potential.
"We need to consider other aspects of cancer treatment outside the better known of genetics", - says Diaz-Meco. "That is, we need to invest more in research of cancer metabolism, which is associated with the identification of metabolic factors, which should be extended to all types of cancer. This will eventually lead to better treatments, which are less susceptible to resistance that is too often a problem in the approaches to the treatment of cancer. "