December 3, 2023

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Obesity makes tumor cells more active!

Obesity makes tumor cells more active!

Obesity makes tumor cells more active! Healthy obesity is defined as obesity without metabolic risk factors. But in fact this concept is misleading. The so-called fat and healthy does not exist.


Obesity causes diseases

Obesity is a risk factor for many diseases, including 13 cancers. According to statistics, among cancer patients over 30 years old in the United States, approximately 5% and 10% of men and women are attributed to obesity, respectively. In recent years, with the development of medical technology, the total incidence of cancer has decreased year by year, but some cancers related to obesity, such as liver cancer, pancreatic cancer, colorectal cancer, thyroid cancer and uterine cancer, are on the rise.

A study in The Lancet Oncology in 2018 showed that among 330 patients with advanced melanoma treated with PD-1 inhibitors, the overall survival of overweight patients can be as long as 13 months compared with normal weight patients. The role of obesity in the occurrence and development of tumors is confusing. The contradiction of “love and kill” between them requires further research to explore the answer behind it.


Obesity makes tumor cells more active!  

Obesity reshapes tumor microenvironment metabolism

In the past, the root cause of obesity is that calorie intake exceeds calorie consumption, which seems to be more related to diet and digestion.

However, recent studies have shown that the immune system can also regulate neuroendocrine pathways to not only control food intake, but also control the body’s energy expenditure.


On December 9, 2020, researchers from Harvard Medical School published an online study titled “Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity” in the top international journal “Cell”. The study showed

A high-fat diet can reduce the number of CD8 + T cells (an important type of immune cell) and anti-tumor activity within the tumor. This happens because cancer cells reprogram their metabolism in response to the increase in fat to better consume energy-rich fat molecules, thereby depriving T cells of fuel and accelerating tumor growth.


Marcia Haigis, professor of cell biology at the HMS Blavatnik Institute and co-author of the study, said: “Putting the same tumor in an obese and non-obese environment shows that cancer cells will re-regulate their metabolism according to a high-fat diet. “This finding suggests that a therapy that may work in one environment may not be effective in another. Given the obesity epidemic in our society, we need to better understand the variety of treatments that may appear. “


The research team found that preventing this fat-related metabolic process can significantly reduce tumor volume in mice on a high-fat diet. Since CD8 + T cells are the main weapon used in immunotherapy that activates the immune system to fight cancer, the results of the study suggest new strategies to improve such therapies.

Co-author, HMS George Fabyan Professor of Comparative Pathology and Director of the Department of Immunology at the Blavatnik Institute, Arlene Sharpe said: “Cancer immunotherapy is greatly affecting the lives of patients, but it does not benefit everyone. .”


Sharp said: “We now know that there is a metabolic tug of war between T cells and tumor cells. This change will change with obesity.” “Our research provides a road map to explore this interaction. It can Help us start thinking about cancer immunotherapy and other combination therapies in new ways.”


Haigis, Sharpe and colleagues studied the effects of obesity on mouse models of different types of cancer, including colorectal cancer, breast cancer, melanoma, and lung cancer. Led by the co-first authors Alison Ringel and Jefte Drijvers, the research team provided mice with a normal or high-fat diet, the latter causing weight gain And other changes related to obesity. Then, they studied the different cell types and molecules in and around the tumor, and called the objective environment formed by these factors the tumor microenvironment.

High-fat diet can interfere with the metabolism of CD8+ T cells

Obesity makes tumor cells more active!


Fat paradox

Obesity makes tumor cells more active!

High-fat diet inhibits the proliferation and activity of CD8+ T cells in tumors

Researchers found that tumors grew faster in animals on a high-fat diet compared to a normal diet. But this only occurs in immunogenic cancer types (ie, hot tumors). Such cancers may contain a large number of immune cells when they occur, which are more easily recognized by the immune system; and are more likely to trigger an immune response.


Experiments have shown that diet-related differences in tumor growth depend particularly on the activity of CD8 + T cells (immune cells that can target and kill cancer cells). If CD8 + T cells in mice are eliminated through experiments, diet will not affect the growth rate of tumors.


Surprisingly, a high-fat diet reduced the presence of CD8 + T cells in the tumor microenvironment. Even if the few remaining CD8 + T cells are not very active, they divide more slowly and have signs of reduced activity. However, when these cells are isolated and grown in the laboratory, they have normal activity, which indicates that certain substances in the tumor impair the function of these cells.


The team also encountered an interesting paradox. In obese animals, although the rest of the body is rich in fat, the tumor’s microenvironment lacks key free fatty acids, which are the main source of cell fuel.


These clues prompted the researchers to compile a comprehensive atlas of the metabolic profiles of different cell types in tumors under normal and high-fat diets.


Analysis shows that cancer cells have adapted to changes in fat supply. Under a high-fat diet, cancer cells can reorganize their metabolism to increase fat intake and utilization, while CD8 + T cells cannot. Eventually, the tumor microenvironment of certain fatty acids is exhausted, making T cells unable to obtain this essential fuel.


Ringel, a postdoctoral researcher in the Haigis laboratory, said: “The abnormal consumption of fatty acids is the most surprising finding of this study. It really shocked us. This is the starting point for our analysis.” Obesity and systemic metabolism can change different cells in tumors. The use of fuel is an exciting discovery. Now, our metabolic map allows us to analyze and better understand these processes. “

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