The genetic apparatus is a cellular structure that ensures the cell’s ability to reproduce itself and transmit hereditary (genetic) information to offspring.

The first descriptions of cancer can be found in Ancient Egypt. The Edwin Smith Papyrus, which dates back to approximately 1600 BC (and the information and fragments of text contained in it can be dated to the middle of the third millennium BC), already contains a description of breast cancer and a procedure for cauterizing tumors.

Currently, cancer research is one of the most actively developing areas of medicine and related biological sciences. There are 216 peer-reviewed scientific journals in the world devoted to the study of cancer. The attention of scientists around the world is focused on cancer due to the fact that it is one of the main causes of death. In 2020, according to WHO, 10 million people died from cancer.

There are many reasons for the occurrence and development of cancer. For example, poor nutrition, obesity, a sedentary lifestyle, smoking, drug and alcohol use, exposure to radiation (including solar radiation), and genetic predisposition. Cancer can also be an occupational disease if the work involves constant contact with carcinogens, or it can develop against the background of an unfavorable environmental situation.

Chemical carcinogens are responsible for the occurrence of up to 80-90% of all malignant tumors in humans. Their action is associated with biochemical processes that are triggered when carcinogens enter the body. They can enter the body through the skin, with food, by inhalation, and in the case of diagnostic procedures – into the bloodstream through an injection. These include, for example, nitrates and nitrites, some food additives (E121, E123), arsenic, nickel, chromium, cadmium compounds, and asbestos. Also, Reuters, citing sources, reported in July that the International Agency for Research on Cancer (IARC) may declare one of the world’s most common artificial sweeteners, aspartame (Aspartame E951, used in the production of diet Coca-Cola), a “possible carcinogen”.

Based on how carcinogens behave, they can be divided into initiators and promoters. Initiators directly participate in the development of cancer, and their action is virtually irreversible. Promoters, one might say, create conditions for the development of cancer, and their action is reversible up to a certain point – most of them exhibit carcinogenic properties with prolonged, frequent, and continuous contact. The most dangerous and powerful carcinogens combine both types of action.

Chemical carcinogens, like the following physical ones, can be divided into natural and anthropogenic carcinogens. So, the increase in cancer incidence in recent decades is associated not only with an increase in life expectancy and the development of diagnostics, but also with the fact that the impact of anthropogenic carcinogens on the body has increased many times over.
Physical carcinogens include various types of ionizing radiation: α-, β-, γ-radiation, X-rays, neutrons, protons, cluster radioactivity, ion flows, fission fragments. During the ionization process, an atom loses or gains an electron. This can lead to the rupture of molecular bonds and disruption of the structure of molecules.

In addition to radiation, physical carcinogens include inert fibers and particles that do not chemically interact with the body’s molecules, but provoke the development of tumors precisely due to the manifestation of physical properties.

Living organisms can also be the culprits of cancer (we will omit the discussion of whether viruses are alive). At present, 11 biological agents are considered carcinogenic to humans. This number includes seven viruses, three parasitic worms and one bacterium.

In 2012, 15.4% of cancer cases (2.2 million) were caused by viruses (9.97%), 5.5% by bacteria, and 0.06% by parasitic helminth worms. The main pathogens are the bacterium Helicobacter pylori, which infects the stomach and duodenum, the human papillomavirus (HPV), the hepatitis B and hepatitis C viruses (HCV), and the Epstein-Barr virus. To a lesser extent, carcinogenesis is caused by the Kaposi’s sarcoma herpesvirus, human T-cell lymphotropic virus type 1, human immunodeficiency virus (HIV-1), and the parasitic worms Opisthorchis viverrini, Clonorchis sinensis, and Schistosoma haematobium. To a large extent, the division of carcinogenic substances into initiators and promoters coincides with the division by the addressee of the action: carcinogens can be divided into genotoxic and non-genotoxic.

Genotoxic carcinogens disrupt the functioning of the genetic apparatus: they provoke errors in the copying of the DNA molecule, which precedes cell division, and thereby cause mutations in the genome of the daughter (new) cell. Most often, such carcinogens intercalate into DNA, that is, they are cross-linked with a nitrogenous base in DNA and thus interfere with the functioning of the genetic apparatus, preventing the information from being read. This can be imagined as if you put a small lock on a bicycle chain from the inside – as soon as the lock reaches the cogwheel, the bicycle would stop.

A protein created on the basis of a damaged code will most likely not be able to perform its construction function. There is a possibility that the mutation will not affect the structure of the protein and its active center. In addition, there may be other mutations, and they will compensate for each other or encode the correct sequence of amino acids, but in an alternative way.

Another option for the action of chemical carcinogens is various alkylating agents. They are able to “hang” small molecules on the DNA molecule, which will also interfere with the work of the genetic apparatus. Or they can regulate the work of the genetic apparatus in a way that is not planned by nature.

The cell has mechanisms for “repairing” (reparation) errors, but they are not omnipotent, and the more places accumulate where reparation is needed, the higher the probability that it will not happen. A significant part of the DNA molecule does not encode proteins, so if a breakdown occurs there, it will not lead to the fact that the “broken” protein will float around the cell aimlessly (and perhaps harmfully). That is, the effect of carcinogens is statistical: one organism will be lucky and the harmful effects will bypass it much longer than another organism.

The action described above is direct. The carcinogen independently binds to the DNA molecule. There are genotoxic carcinogens of indirect action. They require enzymatic activation during metabolism. They bind to active metabolic products (metabolites) and through them affect DNA.

Non-genotoxic carcinogens (promoter type) have an indirect effect. They accumulate in the body as they enter and cause a number of malignant processes. However, their action, as it is believed, can be stopped if the body stops being exposed to new doses of the carcinogen. Their toxic effect leads to disruption of both intracellular and intercellular processes and provokes spontaneous cell division or even a cascade of such divisions (cell proliferation), causes oxidative stress, as a result of which the number of free radicals in the body increases. In addition, particles of the harmful substance can form a bond with receptors, which stops the cell from receiving signals from the environment, or can clog intercellular channels, which prevents two neighboring cells from communicating directly with each other. Other non-genotoxic carcinogens can inhibit apoptosis (programmed cell death).

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.