Results of work published in the journal Molecular Oncology. Colon cancer is the third most common cancer among all cancers. Often it does not manifest itself at all, is detected only in late stages and is difficult to treat. The decisive factor determining the survival of patients with colorectal cancer is the presence of metastases in other organs. In 90 percent of cases, it is metastases that cause death in patients with colon cancer.
Tumor cells that detach from the primary tumor can subsequently form metastases only if they include tumor stem cells. The presence of such cells is indicated by an increased level of expression of the CD44 protein: with the development of cancer, its number often increases significantly. At the same time, CD44 is distinguished by a variety of isoforms – different forms of the same protein, originating from the same gene. Previous studies showedthat the third and fourth isoforms are present in colorectal cancer tumors, but their role in the development of cancer remained controversial.
An international team of researchers, with the participation of scientists from the Faculty of Biology and Biotechnology of the National Research University Higher School of Economics, analyzed data from patients with intestinal cancer and compared the expression level of total CD44 protein and its individual isoforms. It turned out that people with higher expression of the third isoform had better disease progression and survival. Moreover, in patients with high expression of the fourth isoform, the tumor behaved more aggressively and metastasized.
Through analysis of patient data, the study authors were able to reveal that these two isoforms of the same protein regulate the same processes in the body, but in opposite directions: isoform 3 helps the cell “breathe” and behave calmly, while isoform 4 provokes hypoxia, which contributes to more aggressive behavior of tumor cells.
“If tumor cells do not have enough oxygen, they begin to send signals so that blood vessels grow inside the tumor. When the vessels are close, it is easier for malignant cells to enter the bloodstream, spread throughout the body and re-enter tissue at a location distant from the primary tumor. If the primary tumor contained stem cells that managed to separate, they can form a new tumor, a metastasis. In addition, hypoxia leads to transformation of the tumor cells themselves, making them more aggressive, which appears to play a key role in the case of colorectal cancer with high expression of CD44 receptor isoform 4,” explains Diana Maltsevaone of the authors of the study, head of the International laboratory microphysiological systems of the National Research University Higher School of Economics.
Scientists also experimentally confirmed their hypothesis about the fatal role of CD44. During the experiment, human colorectal cancer cells, in which the expression of the CD44 protein was suppressed, were injected into mice. Even though the cells formed a primary tumor, the survival rate of the mice improved. Animals with the gene encoding the CD44 protein turned off had significantly fewer metastases in the lungs, liver, and bone marrow compared to a control group of mice that received cancer cells with active CD44.
“For the first time, we have received answers to very important questions: which isoform of CD44 is the most dangerous for a person with colon cancer, how the third and fourth isoforms are related to each other, what will happen if the expression of this protein is suppressed. But we still have a lot to learn,” says Diana Maltseva. “For example, during the transformation of normal tissue into tumor tissue, the expression of isoform 3 increases, but the ability of the tumor to further spread is apparently determined by isoform 4. Perhaps the course and aggressiveness of colorectal cancer depends precisely on the ratio of these two isoforms.”
The results of the study could be the first step towards creating a new method of treating colorectal cancer: inhibition of the fourth isoform of the CD44 protein would reduce the likelihood of metastases in patients and significantly reduce mortality from colorectal cancer. The research was carried out within the framework of the Basic Research Program of the National Research University Higher School of Economics.
2023-12-20 11:03:32
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