Written by nagashi
With the advancement of science and technology and the development of medicine, many diseases that have left ancient physicians at a loss have been alleviated one by one, or even cured. However, cancer -as the " king of all diseases ", it seems like a great moat that is difficult to conquer and has not yet been defeated by humans.
Deciphering the mechanism of cancer occurrence and development is crucial for cancer treatment. Mutations in tumor suppressor genes are believed to be an important cause of cancer. Scientists have long believed that gene mutations promote uncontrolled growth of cancer cells. However, a recent study shows that the actual situation is much more complicated than this.
On September 16, 2021, Harvard Medical School researchers published in the top international academic journal Science _strong17 immune system _span _strong17 The _span strong immune system The _span _strong17 immune system The research paper of driver of selection for tumor suppressor gene inactivation .
The study found thatThere are more than 100 mutated tumor suppressor genes that do not directly act on cancer cells and encourage them to grow wildly. Instead, uses a "curve to save the country"- prevents the immune system from recognizing and destroying tumor tissue . This is the real reason for the uncontrolled proliferation of tumor tissues.
It is well known that many cancer cell lines have the potential to proliferate indefinitely, which is thought to be the result of tumor suppressor gene mutations. But usually, the immune system treats cancer cells as an emerging pathogen and tries to eliminate them. Therefore, the ability of cancer cells to proliferate indefinitely is far from enough. It must also evolve the ability to escape immune system surveillance through genetic mutations.
For example, this is like the famous science fiction movie " Matrix ", the protagonist "spanspanspan13" span13 _spanspanspan13 _spanspan13 _spanspanspan12 (Human body) will be hunted down by countless people in black (immune system) after being under the control of . If Neo wants to be free, he must completely defeat or pretend to hide from the people in black. And for cancer cells,The latter is undoubtedly easier to do.
In this study, the research team used CRISPR technology to construct 7,500 tumor cell lines with single mutations in tumor suppressor genes and implanted these cells into mice. These mice were also divided into two groups. The immune system of wild-type mice in the control group was intact, and the experimental group was immunodeficient mice.
Screening of gene mutations required for tumor growth based on CRISPR technology
Researchers use genetic analysis to determine which mutant genes play a role in tumor formation. They found that in each tumor cell line tested, compared with immunodeficient mice, tumors grown in wild-type mice had a significant enrichment of tumor suppressor gene deletions. Among them, one-third of tumor suppressor genes are through immune evasion.
CRISPR-based gene screening to characterize the interaction between tumors and the immune system
The research team will also focus on a special gene-G_span _strong span13span13 strongspan13 , and clarified the mechanism of this process. Through in-depth study of this gene, the researchers found that the mutation of disguised cancer cells, making the T cells of the immune system unable to detect them .
The anti-tumor effect of GNA13 deletion is due to the increase of CCL2 expression and secretion, which leads to the increase of tumor macrophages
span13 strong span13 span13 strong_span Dr. Elledge said: " is shocking that these gene mutations teach cancer cells how to evade the immune system, rather than simply saying'grow, grow, grow! '" p2p
Themutant tumor suppressor gene and the protein it produces are common targets in cancer drug development, but some are frustratingly elusive, such as p53 . Earlier this month, a study published by a team of Vanderbilt University showed that aneuploidy chromosome abnormality is common in p53 mutant cells, and they believe this discovery can be used for Provide information on drug development for this abnormal protein.
In addition, in June of this year, Karolinska Institute 's Galina Selivanova span12 Span13 Strong Span_strong Span12 and others showed on strong Discovery_span12 span13span13span _strong_span12The normal p53 can be reactivated by MDM2 inhibitors. Therefore, MDM2 inhibitors combined with other drugs that suppress immune checkpoints can better inhibit the growth of cancer cells.
Stephen Elledge span13span strong12span Doctor believes that their research provides a better understanding of the cancer gene list. How to evade the immune system . He said: " tumors may use hundreds of ways to achieve immune evasion, and the discovery of these pathways may inspire new ways to treat cancer. ”
Paper link: _strong p17 0 span //www.science.org/doi/10.1126/science.abg5784
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