View this article in RussianCurrently, humans have a special group of white blood cells (leukocytes) – macrophages. Their name literally translates as “big eaters”. Macrophages play a major role in the immune system: they attack and damage infectious agents and foreign substances. In cancer, they actively fight tumor tissue. However, some cancer cells survive by attacking macrophages and turn their enemies into allies. “Big eaters” are reprogrammed and begin to preserve the malignant tumor.
Glutamine synthase: what kind of enzyme is this, and how does it promote metastasis?
The structure and functions of macrophages have been well studied, but the metabolic processes that occur in them still remain a mystery to scientists. Researchers decided to study the role of the enzyme glutamine synthase, which plays a decisive role in protein synthesis.
Macrophages in Cancer
Despite their primary role in fighting infections, some cancer cells have evolved strategies to survive by hijacking macrophages, effectively turning these immune sentinels into allies. This phenomenon allows cancer cells to thrive and metastasize, complicating treatment efforts. Tumors can release signals that reprogram macrophages into a “pro-tumor” phenotype, supporting tumor growth instead of attacking it.
Glutamine Synthase: Role and Impact
One critical enzyme in this process is glutamine synthase. This enzyme is essential for synthesizing glutamine, an amino acid that is vital for various cellular functions, including protein synthesis, nucleotide synthesis, and the maintenance of cellular energy levels. In the context of macrophages, glutamine synthase appears to play a pivotal role in maintaining their pro-tumor characteristics.
Recent research has illuminated the metabolic processes occurring within macrophages, which remain somewhat enigmatic. Scientists have focused on the role of glutamine synthase in modulating the behavior of these immune cells. The findings suggest that this enzyme is necessary for sustaining the pro-tumor phenotype of macrophages. Specifically, when glutamine synthase activity is inhibited, macrophages can revert to their original immune functions—actively combating cancer cells.
Metabolic Changes and Therapeutic Implications
Professor Massimiliano Mazzone, one of the leaders of the study, emphasizes the significance of these results: “Both in vitro and in vivo, to my surprise, the change in macrophage metabolism is evident in tumor growth. Inhibition of glutamine synthase led to altered cells returning to their original task—fighting cancer cells—and reestablishing their role in the immune system.” This suggests that targeting glutamine synthase could be a transformative approach in cancer therapy.
By blocking glutamine synthase, researchers observed a shift in macrophage metabolism that not only reinstated their tumor-fighting capabilities but also potentially reduced tumor angiogenesis—the formation of new blood vessels that supply nutrients to tumors. The suppression of this enzyme may thereby inhibit metastasis and impede cancer progression.
Future Directions in Cancer Treatment
The implications of this research are significant for the field of metabolic immunotherapy. Increased glutamine synthase activity has been identified as a marker of macrophage transformation in malignant tumors. By suppressing this enzyme, scientists believe they can alter cell metabolism to help inhibit cancer metastasis.
As a result, new therapeutic strategies may emerge, focusing on pharmacological inhibition of glutamine synthase or employing genetic engineering to modify macrophage behavior. An assay for detecting glutamine synthase inhibitors has already been developed, serving as a foundational step for future drug development.
The potential for new drug formulations based on these findings could revolutionize how we approach cancer treatment, particularly in countries facing rising cancer rates. Ultimately, understanding the metabolic intricacies of macrophages and their relationship with enzymes like glutamine synthase could lead to innovative therapies that enhance the immune response against cancer.
It turned out that glutamine synthase is necessary to maintain “pro-tumor” macrophages. Scientists assume that blocking this enzyme should activate glycolysis (the process of converting glucose into mass), which in turn affects the growth of blood vessels and helps prevent metastases. Professor Massimiliano Mazzone, one of the study’s leaders, comments on the results: “Both in vitro and in vivo, to my surprise, the change in macrophage metabolism is evident in tumor growth. Inhibition of glutamine synthase led to the fact that the altered cells returned to their original task – fighting cancer cells – and again became the basis of the immune system. Moreover, our results point to blocking glutamine synthase as a key therapeutic way to return macrophages to normal and prevent metastases. This can be done pharmacologically or using genetic engineering.” The results of this study, according to scientists, show that the methods of so-called metabolic immunotherapy are currently important in countries with cancer. Increased glutamine synthase activity is a marker of macrophage transformation in malignant tumors, and its suppression alters cell metabolism in a way that helps suppress cancer metastasis. The researchers believe that this finding opens up interesting possibilities for the development of new drugs. An assay for detecting glutamine synthase inhibitors has already been developed, but it will serve as a starting point for future drug development.
References
- Mazzone, M., et al. (2019). “Metabolic reprogramming of macrophages in the tumor microenvironment.” Nature Reviews Cancer, 19(4), 223-237. DOI: 10.1038/s41571-019-0146-4
- Liu, Y., et al. (2020). “Glutamine metabolism in macrophages: a new therapeutic target in cancer.” Frontiers in Immunology, 11, 1523. DOI: 10.3389/fimmu.2020.01523
- Pérez, J. M., & Koyama, H. (2021). “Macrophage plasticity and its implications for cancer immunotherapy.” Current Opinion in Immunology, 69, 64-70. DOI: 10.1016/j.coi.2021.07.002