动物造模,驱动癌细胞衰老 z-bio 2021-06-07 360

　　The human adaptive immune system plays an important role in the control of cancer and has been widely recognized. People are working to develop effective targeted cancer immunotherapy. Many of these treatments stop the growth of cancer cells, rather than eliminate them through cytotoxicity.

　　A new study by a research team led by Martin Cken from the University of Tubingen in Germany discovered specific TH1 cells that inhibit the growth of cancer cells and clarified the molecular mechanisms of these cells.

　　R? Cken et al. conducted an experimental study with a recombinant mouse model. The tumor antigen label of the mouse model is expressed under the control of the rat insulin promoter, which partially or partially affects the tumor suppressor genes p53 and Rb, and complete silencing leads to aggressive β-cell carcinoma. .

　　The researchers found that only CD4+TH1 cells that secrete TNF and IFN-g can inhibit the growth of these tumors, thereby doubling the lifespan of mice. The researchers confirmed that the tumor cells in the mice treated with TH1 cells cannot grow in vitro, but the tumor cells in the sham-treated mice can continue to grow.

　　Next, the researchers co-cultured β-cancer cells from mice in the sham treatment group with TNF and IFN-g or a control medium, and the cytokine-treated cells were in the G1/G0 phase of the cell cycle. Found it stagnated. Three days. On the contrary, 25 or more cells not treated with these cytokines enter the S phase and show a high growth rate. As we all know, tumor cell arrest in the G1/G0 phase is a characteristic of cell senescence.

　　So the researchers further studied whether the cytokines IFN-g and TNF can cause long-term tumor senescence and growth arrest. They washed the cells treated with cytokines for 5 days, and then put them in the culture medium for 2 weeks. The researchers found that although these cells remained fully aged within two weeks, the cells that were not treated with cytokines proliferated rapidly during this period. The researchers also observed changes in gene expression patterns and epigenetic changes known to be associated with cellular senescence in cytokine-treated cells.

　　Researchers observed the expression of premature aging marker genes such as pHP1c after treatment with IFN-g and TNF for 3 days. After cytokine incubation for 4 days, aging-related β-galactosidase (SA-b-)gal) and other late expressions were observed to aging genes and stable growth arrest. Treatment with IFN-g or TNF alone can cause changes related to gene expression, but is not sufficient to induce long-term growth arrest.

　　In addition, the researchers found that the transcription factor STAT1 and TNF receptor TNFR1 (also known as CD120) activate the downstream target protein p16INK4a in JUNB, indicating that cytokines induce senescence. In addition, the researchers found that IFN-g and TNF induce the expression of p16INK4a and promote the transcription of the tumor suppressor protein bSer795. This series of changes induce β-cancer cell senescence by stabilizing p16INK4a-Rb signal. Researchers have confirmed that when IFN-g and TNF are given, β-cancer cells lacking STAT1 or TNFR1 will not enter the senescence stage.

　　Researchers have also observed this cytokine-induced senescence in several other mouse and human cell lines, as well as in cells that have spontaneously regressed from human melanoma, and as a result, play a role in tumor immunology. Show that it might be. For testing

　　Whether TH1 cytokines can induce tumor senescence in vivo, R? Cken and colleagues transplanted different β cancer cell lines into immunodeficient mice. It was found that β-cancer cells cannot proliferate after transplantation in mice treated with Tag-TH1 cells, but similar cells that do not express TNFR1 proliferate actively in mice.

　　"These results indicate that IFN-g and TNF secreted by TH1 cells drive the senescence mechanism of tumor cells through the p16INK4a-Rb signaling pathway.