Rupert Joseph, Gao Zhanguo, Yu Yongmei, Kolonin Mikhail G
The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, McGovern Medical School, The University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA.
Aging (Albany NY). 2025 Jun 5;17(6):1452-1465. doi: 10.18632/aging.206268.
The effects of cell senescence in individual cell populations of the tumor microenvironment (TME) on cancer progression remain unclear. Here, we investigated the effects of cell senescence caused by inactivation of the catalytic subunit of telomerase (Tert) in distinct TME components. We generated genetic knockout (KO) mice driven by the promoter in myeloid cells, by the promoter in mesenchymal cells, and by the promoter in endothelial cells. We compared the effect of the KOs in syngeneic models of orthotopically grafted E0771 breast adenocarcinoma, RM1 prostate adenocarcinoma, and KPC pancreatic adenocarcinoma. Tumors in -KO, -KO, and -KO mice displayed increased myofibrogenesis and desmoplasia. Tumors in -KO mice displayed endothelial abnormality and the strongest reduction in tumor vascularization. This was linked with increased HIF1a protein nuclear localization, indicative of hypoxia, and the highest protein expression of the glycolytic marker GLUT1 in cancer cells. KPC tumors displayed reduced epithelial cytokeratin-19 protein expression and reduced tumor growth in all KO models. However, liver metastases of KPC cells were only observed for -KO mice. We conclude that senescence of distinct cells in the TME has different effects on cancer progression and that endothelial cell function preservation is important in metastasis suppression.
肿瘤微环境（TME）中单个细胞群的细胞衰老对癌症进展的影响仍不清楚。在此，我们研究了端粒酶催化亚基（Tert）失活在不同TME组分中所引起的细胞衰老的影响。我们构建了由髓系细胞中的启动子、间充质细胞中的启动子以及内皮细胞中的启动子驱动的基因敲除（KO）小鼠。我们比较了这些KO在原位移植的E0771乳腺腺癌、RM1前列腺腺癌和KPC胰腺腺癌同基因模型中的作用。Tert-KO、Tert-KO和Tert-KO小鼠的肿瘤显示出肌成纤维细胞增生和促结缔组织增生增加。Tert-KO小鼠的肿瘤表现出内皮异常以及肿瘤血管生成的最强程度降低。这与HIF1a蛋白核定位增加（表明缺氧）以及癌细胞中糖酵解标志物GLUT1的最高蛋白表达相关。KPC肿瘤在所有KO模型中均显示上皮细胞角蛋白-19蛋白表达降低以及肿瘤生长减缓。然而，仅在Tert-KO小鼠中观察到KPC细胞的肝转移。我们得出结论，TME中不同细胞的衰老对癌症进展具有不同影响，并且内皮细胞功能的维持在转移抑制中很重要。
