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Leucine may control metastasis formation of aggressive tumors

This is what a study by Unicamp researchers shows in article recently published in the journal Scientific Report, from the Nature group

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Description
Researchers at the Nutrition and Cancer Laboratory

Cachexia, a syndrome that leads to the loss of muscle and adipose tissue, body mass and consequently weight, causing extreme weakening of the body, mainly affects patients with certain types of more aggressive cancers that manifest themselves particularly in the lungs, stomach, pancreas and large intestine. This syndrome, which causes intense weight loss, led the population to coin the expression “just skin and bones” when referring to very thin and extremely weak people. Its victims show great fragility and intense fatigue, which reduces their quality of life. In around 80% of patients with advanced cancer, cachexia is responsible for 30% of deaths.

Description
Advisor Professor Maria Cristina Cintra Gomes Marcondes

The Nutrition and Cancer Laboratory, coordinated by professor Maria Cristina Cintra Gomes Marcondes, from the Department of Structural and Functional Biology, from the Institute of Biology (IB) at Unicamp, focuses on studying what happens in the organism of animals (rats) that carry of tumors that develop cachexia. One of the strategies that has been widely used in humans to combat this syndrome is dietary supplementation with leucine, an essential amino acid well known by athletes who aim to develop muscle mass. It effectively acts to increase muscle mass by accelerating its protein synthesis, strengthening the muscle, helping the hypertrophic process and contributing to the reduction of muscle breakdown (atrophy). In patients, maintaining adequate muscle mass allows them to not lose their quality of life, helping their body to recover more easily from surgeries and resist the effects of treatments to control the proliferation of cancer. Likewise, in rats with tumors, dietary supplementation with leucine aims to reduce the loss of muscle mass and consequently the loss of body weight. How this action takes place is the main object of study at the Laboratory.

Description
Biologist and postdoctoral student Laís Rosa Viana

Although the Laboratory was always very focused on studying the muscle, with a view to minimizing its impairment due to cachexia, in a new work guided by the professor, the biologist and post-doctoral student Laís Rosa Viana proposed to direct research towards the tumor tissue that causes this syndrome. The question that arose was: would leucine, so efficient for the maintenance and development of muscle mass, not also contribute to the development of the tumor itself? “We then decided to focus our attention on determining what the effect of leucine would be on tumor development and metabolism. Even because, if it was already widely known that leucine can stimulate protein synthesis in skeletal muscle and recent studies showed an increase in the oxidative capacity of muscle cells related to this amino acid, on the other hand, the effects of leucine in tumor tissues needed to be improved. elucidated”, she explains. 

This work resulted in a great and auspicious discovery: the observation that rats submitted to a diet supplemented with leucine develop a smaller number of metastases, so called, as is widely known, tumor manifestations that occur in other organs or tissues, in addition to the tumor. original, although there was no reduction in its size. A reduction in glucose uptake was also detected, which is surprising, as most cancer cells preferentially use glucose as an energy source, a fundamental constituent of their metabolism. 

Description

Research

The research, which was supported by Fapesp, focused on the Walker 256 tumor, an originally mammary adenocarcinoma, a breast cancer, initially identified in a rat, in 1928, by the researcher from whom it got its name. It is commonly introduced into animals to induce cachexia because it closely reproduces what occurs in humans and also because it is already very well studied. The tumor cells are inoculated into animals that simultaneously begin to receive food supplemented with leucine. 

In fact, Wistar rats carrying the tumor were randomly distributed into two groups. Animals in one group received a standard rat diet and those in the other group were fed the same diet supplemented with 3% leucine.

This tumor, like many others, has a great affinity for glucose. To determine possible differences in its uptake by the tumor of the rats belonging to the two groups, radiolabeled glucose was injected into the anesthetized animals. It was then found that the tumors of animals that received leucine supplementation were those that took up less glucose. It turns out that the consumption of glucose by cancer cells is closely related to the aggressiveness of the tumor and the development of metastases. And, in fact, in animals in which the tumor became less aggressive, there were fewer metastasis sites. An encouraging observation.

The finding is surprising, because if leucine stimulates protein synthesis, contributing to an increase in muscle mass, why wouldn't it also contribute to tumor progression? So, how can we explain the effect of leucine in controlling tumor aggressiveness? Tumors preferentially feed on glucose in a mechanism also known as the Warburg, through which glucose molecules are broken down producing a lot of lactate which, when exported out of the tumor cells, causes acidification of the extracellular environment, which favors the formation of metastases. However, leucine alters this metabolism in the tumor and the process stops being essentially glycolytic and becomes preferentially oxidative. This new energy pathway leads to a decrease in lactate production and, as a result, reduces the acidity of the extracellular environment, concomitantly reducing the formation of metastases. The article, published in the prestigious journal scientific report, from the group Nature, under the title "Leucine-rich diet induces changes in tumor metabolism, reducing glucose consumption and metastasis in rats carrying Walker's tumor 256”, basically addresses this important modification in the tumor’s metabolic mechanism caused by leucine, which elucidates its effect.

Research on rats was also reproduced vitro directly feeding the cancer cells with leucine, in a process free from interference likely to occur in much more complex animal organisms, which allowed the results to be validated.

Alert

For Professor Maria Cristina, the work made a leap forward with the revelation that an amino acid, although beneficial for the recovery and formation of muscle mass, does not contribute to the development of the tumor, on the contrary, it reduces its aggressiveness and consequently the possibility of metastases. The tumor does not stop growing, but its aggressiveness and proliferation to other organs or tissues has reduced, minimizing the possibility of deaths from metastases. These were the most important discoveries. Despite this, she warns: “The results must be relativized, as they resulted from studies on animals and on a specific tumor. It would be very dangerous to extrapolate the results to humans and other tumors now. The monitoring of cancer patients must be advised by doctors, nutritionists and nutritionists.”

The professor recalls that, for a second stage of the study, partnerships are being established with researchers from the Hospital de Clínicas (HC) of Unicamp, with a view to the possibility of working with samples of patients with aggressive cancers and extending the experimental discoveries to verify the future results in patients.

Although a large part of the study was carried out by Laís at the Nutrition and Cancer Laboratory, the researchers emphasize that all the analyzes necessary for the development of the work could only be carried out thanks to partnerships established with several researchers at Unicamp, which highlights its multidisciplinary nature, fundamental to achieving results of greater amplitude and impact. In this particular, they highlight the collaborations of professors Celso Dario Ramos, from the Department of Radiology of the Faculty of Medical Sciences (FCM) and director of the Nuclear Medicine Service of the same unit; Anibal Eugenio Vercesi, from the Department of Clinical Pathology also at FCM; Leonardo Reis Silveira, the Department of Structural and Functional Biology, Institute of Biology (IB); and Sílvio Roberto Consonni, from the Department of Biochemistry and Tissue Biology at the same institute. They also consider it very important that the population is informed about the research carried out at a public university and that, therefore, it must have the commitment and obligation to be accountable to Brazilian society for those who lie to it. 

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Nutrition and Cancer Laboratory Bench

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