Colorectal Cancers Raise Defensive Barrier In Response To Chemotherapy: Study

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Colorectal cancer occurs when tumors develop in the colon or rectum. Adenocarcinomas are the most common type of colorectal cancer, often growing out of cells that make up the mucous lining of the tissue. A new study has found that drugs commonly used as the first line of treatment for colorectal cancer cause tumor cells to secrete a protein called mucin. The study was published in the journal eLife.

Proteins alter the mucous layer, creating a physical barrier that prevents drugs from reaching their intended target.

Using a variety of techniques using genetic manipulation and chemical inhibitors, the research team was able to experimentally regulate mucin secretion in cancer cell lines and patient-derived organoids, paving the way for the development of future treatments that could be used with chemotherapy. . Drug-resistant forms of colorectal cancer. The experiments also revealed potential new biomarkers for disease prognosis.

The researchers studied mucins, a heavy, sugar-coated protein secreted by specialized cells in the lining of the digestive tract, including the eyes, nose, airways and colon. On average, humans secrete up to one liter of mucin every day. Mucins have gel-forming properties that combine with other biological substances to form mucosa, a thick liquid that acts as a lubricant, prevents tissues from becoming dehydrated and also acts as a barrier to protect cells from pathogens and other external factors.

Researchers have studied whether excessive expression of mucins can inhibit drugs reaching tumor cells. Experiments with two drugs given in combination as a first-line treatment for colorectal cancer, fluorouracil and irinotecan, have shown that cancer cells respond to treatment by secreting large amounts of mucin.

“15-20% of colorectal cancers are associated with increased production of mucin. In some of these cases, this is a problem because it will block the drugs from reaching their intended goal. We were surprised to learn that chemotherapy itself stimulates mucin secretion, potentially trapping patients in a vicious cycle that requires increasing doses.

This can be prevented if chemotherapy is combined with treatment to prevent mucin secretion, “said Vivek Malhotra, ICREA research professor at CRG, coordinator of the Cell and Developmental Biology program and author of the study.

Researchers studied various ways to block mucin secretion to make tumor cells more sensitive to drugs. They first attempted to genetically manipulate the levels of the protein KChIP3, which was previously used to control mucin secretion. Was demonstrated by Malhotra’s research group. They found that degraded colorectal cancer cells of KChIP3 were four times more drug-resistant than cells with normal levels of KChIP3. In contrast, cells with higher than normal levels of KChIP3 were ten times more susceptible to chemotherapeutic drugs.

CIBER Cancer (CIBERONC) researcher and co-author of the study, Dr. According to Luis Espinosa, “The disadvantage of using KCHIP3 as a treatment is that it requires the use of gene therapy, a technology that is still in its infancy and is very expensive to use.”

The authors of the study then evaluated the potential of KChIP3 as a biomarker for the prognosis of colorectal cancer. Studying publicly available datasets following the progression of colorectal cancer patients, they found that high levels of KChIP3 indicate a long time for disease-free survival, with the cancer surviving after primary treatment so long as the patient lives without it. Any signs or symptoms of that cancer.

Dr. According to Espinosa, more work should be done to develop the potential of KChIP3 as a prognostic biomarker. “One of the major obstacles to finding KChIP3 in clinical settings is that we do not have the antibodies needed to measure their levels. More research is needed to develop ways to measure this biomarker in the first place to incorporate it into regular practice. “

The researchers studied other methods of blocking mucin secretion without resorting to genetic manipulation, such as the use of chemical inhibitors. An earlier work by Vivek Malhotra’s research group showed that inhibitors that inhibit the function of sodium and calcium channels, known as NCX blockers, also inhibit the secretion of mucin.

The researchers chose an NCX blocker called SN-6 for their experiments, which had previously been studied for its potential in the treatment of cardiac arrhythmias. They tested SN-6 in organoids obtained from patients, which found that they made colorectal cancer cells 40 times more susceptible to chemotherapeutic drugs.

Dr. According to Gerard Cantero, who did the work at CRG and is currently serving as chief investigator at the Val d’Hebron Research Institute (VHIR), the findings shed light on potential new treatment strategies. “SN-6 is a very specific blocker, which means it is less likely to have side effects compared to other NCX blockers. We found that SN-6 specifically inhibits the secretion of mucins stimulated by chemotherapy. Clinical trials are needed to confirm our findings, but combining chemotherapy with SN-7 to eliminate the side effects of chemotherapy is of great interest. “

Although this study addresses the problem of colorectal cancer cells, this approach may generally benefit patients with mucinous cancer or adenocarcinomas. “Musin is produced in many parts of the body, not just in the digestive tract. Further research should explore whether inhibitors may affect the treatment of other types of chemotherapy-resistant cancers, including the mucosal layer, “concluded Dr. Cantero.

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