Senescence caused by telomerase inactivation in myeloid, mesenchymal, and endothelial cells has distinct effects on cancer progression.

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.