The benefits of free radicals
Reactive oxygen species inhibit the growth of metastases in skeletal muscles
Georgy Chistov, PCR.news
Doctors and biologists have long noticed that cancer metastases prefer some tissues to others. Most rarely, metastases appear in skeletal muscles. Until now, the reason for this phenomenon has remained a mystery. Scientists from the USA and Australia, armed with a whole range of methods, investigated the process of metastasis of breast cancer. They found out that myocytes are able to suppress the growth of metastases with the help of reactive oxygen species (ROS). Experiments were carried out on cell cultures and on mice.
At first, researchers confirmed that breast cancer is able to metastasize to skeletal muscles. They demonstrated cancer cells in the muscles of both humans and mice. However, tumor cells in skeletal muscles were more often located near the basement membrane, rather than in the volume of tissue. Scientists have suggested that muscles are able to suppress the development of metastases.
Further experiments on cell cultures helped to find out the mechanism of resistance of myocytes to metastasis. It is known that secretory molecules, extracellular vesicles and the composition of the intercellular matrix can affect cancer cells. The scientists tested all three factors on myotubes and pulmonary fibroblasts. They concluded that none of them could suppress metastasis. However, the researchers noticed that the integrity of myocytes is very important for the inhibition of cancer cells. This led them to the idea that the metabolism of muscle cells plays an important role in suppressing metastases.
To test the hypothesis, the authors developed a new line of tumor cells that could effectively colonize skeletal muscles. Then they studied their metabolome and found an increased activity of purine and glutathione metabolism. Scientists associated the first fact with cell proliferation. To form metastases, tumor cells must actively divide and, consequently, synthesize new DNA. Glutathione is also a participant in the response to oxidative stress. Thus, the researchers suggested that myocytes produce ROS, which prevent colonization.
Analysis of the state of cancer cells confirmed the assumption of scientists. Tumor cells from muscle tissue experienced oxidative stress, and the addition of hydrogen peroxide — one of the most common ROS — suppressed the growth of metastases. Also, using bioengineering methods, scientists have derived tumor cells capable of synthesizing hydrogen peroxide independently. The growth of such cells was suppressed both in skeletal muscle cells and in a niche of lung tissues.
To prove that it is ROS that inhibit tumor growth, scientists have constructed cancer cells that produce catalase and placed them in cultures of pulmonary fibroblasts and myocytes. The presence of catalase had a positive effect only on the growth of tumor cells in muscle tissue. At the same time, the metastatic activity of cells in the lungs did not change. The scientists obtained the same results in mice, including immunocompetent animals. Thus, they proved the role of ROS in suppressing the formation of metastases and confirmed the tissue specificity of oxidative conditions.
Scientists have found out that active forms of oxygen from mitochondria are used to suppress muscle tumors. They used a special mouse model whose cells produce mitochondrial catalase. When cancer cells were introduced into such a model, the tumor actively metastasized and developed in skeletal muscles. Nothing like this was observed in the lungs. Scientists measured the level of mitochondrial ROS in these two organs. It turned out that the metabolic response of muscle tissues is specific — mitochondrial ROS in lung cells were not activated in response to the appearance of metastases.
Thus, scientists have demonstrated that skeletal muscle tissue is able to resist metastasis. To do this, it produces ROS in the mitochondria, which prevent metastases from developing. The response of myocytes is specific and is not observed in other tissues.
Article by Crist et al. Unchecked oxidative stress in skeletal muscle prevents outgrowth of disseminated tumour cells published in the journal Nature Cell Biology
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