A group of American scientists have found that pancreatic cancer is able to reprogram itself and alter metabolism in order to spread to other tissues and organs and become immune to chemotherapy. At the same time, researchers found his Achilles' heel: he needs glucose to metastasize. "Lenta.ru" talks about the details of the study, published in the journal Nature.
Despite significant advances in cancer treatment, some cancers remain highly lethal. For example, ductal adenocarcinoma of the pancreas, which ranks second in developed countries in the number of deaths from malignant neoplasms. Its lethality is explained by the fact that the primary tumor consists of different populations of cells that differ from each other in genetic, epigenetic and other characteristics. Finding the right drugs is very difficult: some cells may not respond to treatment.
In addition, evolutionary processes take place inside a cancerous tumor, and some subpopulations, arising, for example, as a result of mutations, gain an advantage over others. Nevertheless, it has been shown that even cancer cells differing from each other contain the same driver mutations that promote the growth of malignant neoplasms. In addition, the vast majority (if not all) of mutations unique to each subpopulation, as it turned out, are "hitchhikers." That is, they do not in any way affect the ability of cells to reproduce, but they spread due to the fact that they are near the driver mutation.
The question arises: what leads to the emergence of heterogeneous tumors and the formation of drug-resistant metastases? According to the researchers, it's not about genetic mutations, but about epigenetic regulation. As a result of the attachment of various molecules to DNA, some genes are turned off, while others increase their activity. These changes can be transmitted from the parent cell to the daughter, which ultimately forms a subpopulation. To find out how this happens, the scientists studied changes in the epigenome (the general epigenetic state of cells) during the formation of subpopulations and metastases of pancreatic adenocarcinoma.
Tissue samples were used from primary and secondary tumors of five patients. We took various subpopulations, including the one from which all the others descended (it was she who caused cancer, and her descendants acted as "seeds" for metastases). Then an immunohistochemical analysis was carried out: using labeled antibodies, proteins (histones) linked to DNA were detected, to which two or three methyl groups (CH3) were attached. Methylation is one of the methods of epigenetic regulation capable of both suppressing and enhancing gene activity. The effect depends on what type of histone and where CH3 is attached. The researchers were interested in histone H3 methylation at the K9 site, which has been shown to lead to inhibition of the protein-bound gene.
Liver with metastases from pancreatic cancer
Photo: Haymanj / Wikipedia
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Researchers have identified the degree of epigenetic changes in all histones H3, located in a compact region of chromosomes - heterochromatin. These are tightly folded sections of chromosomes where genes are inactive. However, scientists were not interested in all heterochromatin, but in its individual regions (domains) - LOCK and large hypomethylated DNA blocks. LOCKs are usually characterized by high levels of H3 methylation, while hypomethylated blocks in cancerous tumors are low. It turned out that in patients in whom the tumor metastasized to the liver and lungs, the level of histone methylation was low. In those patients whose metastases were limited only to the abdominal region, the number of modified histones remained high.
This suggests that secondary tumors are formed due to the fact that individual subpopulations of malignant cells reprogram themselves, activating those genes that should be "silent". Additional analyzes with cell lines extracted from metastases and primary tumors of eight patients confirmed that the development of cancer is associated with a global restructuring of the epigenome.
Micrograph of pancreatic ductal adenocarcinoma
Image: KGH / Wikipedia
Changes were also found in euchromatin, an active and non-compact region of the genome. Some of the genes found here are activated due to the enrichment of methyl groups at the K36 site in histones H3. Others, on the other hand, were suppressed due to a drop in K36 methylation.
Scientists analyzed which genes were affected by epigenetic changes to find out if the reprogramming is really related to the aggressiveness of the tumors. It has been established that in the LOCK region, when the methylation level falls, genes associated with the activity of oxidoreductase are activated. This enzyme is an antioxidant and detoxifies reactive oxygen species, which makes cells resistant to oxidative stress. Genes involved in DNA repair are activated in euchromatin, and tumors become resistant to chemotherapy.
How to inhibit the growth of pancreatic tumors? It has been found that metastatic cells absorb a lot of glucose, which enhances the synthesis of various substances, and also weakens the generation of reactive oxygen species that help suppress cancer growth. In addition, the pentose phosphate pathway (an alternative way of glucose oxidation) is associated with epigenetic regulation that promotes tumor growth. It may be a potential target for drugs that prevent metastases of adenocarcinoma of the pancreas.
Alexander Enikeev
