RESUMO
Senescence is a tumor-suppressive mechanism induced by telomere shortening, oncogenes, or chemotherapy treatment. Although it is clear that this suppressive pathway leads to a permanent arrest in primary cells, this might not be the case in cancer cells that have inactivated their suppressive pathways. We have recently shown that subpopulations of cells can escape chemotherapy-mediated senescence and emerge as more transformed cells that induce tumor formation, resist anoikis, and are more invasive. In this study, we characterized this emergence and showed that senescent cells favor tumor growth and metastasis, in vitro and in vivo. Senescence escape was regulated by secreted proteins produced during emergence. Among these, we identified thrombospondin-1 (TSP1), a protein produced by senescent cells that prevented senescence escape. Using SWATH quantitative proteomic analysis, we found that TSP1 can be detected in the serum of patients suffering from triple-negative breast cancer and that its low expression was associated with treatment failure. The results also indicate that senescence escape is explained by the emergence of CD47low cells that express a reduced level of CD47, the TSP1 receptor. The results show that CD47 expression is regulated by p21waf1. The cell cycle inhibitor was sufficient to maintain senescence since its downregulation in senescent cells increased cell emergence. This leads to the upregulation of Myc, which then binds to the CD47 promoter to repress its expression, allowing the generation of CD47low cells that escape the suppressive arrest. Altogether, these results uncovered a new function for TSP1 and CD47 in the control of chemotherapy-mediated senescence.
Assuntos
Antígeno CD47/metabolismo , Trombospondina 1/metabolismo , Animais , Senescência Celular , Humanos , CamundongosRESUMO
PURPOSE: Prophylaxis for febrile neutropenia (FN) is recommended for the duration of myelosuppressive chemotherapy in high-risk patients; yet, granulocyte-colony-stimulating factor (G-CSF) discontinuation occurs frequently in clinical practice. The objective of this study was to investigate the incidence of FN in real-world settings and the extent and impact of early pegfilgrastim discontinuation. METHODS: This prospective, observational study enrolled patients with any-stage non-Hodgkin's lymphoma (NHL) or breast cancer initiating a new chemotherapy course with a high (> 20%) FN risk, with pegfilgrastim in cycle 1. During routine clinical visits, data were collected on FN events, discontinuation of pegfilgrastim (defined as administration of G-CSF other than pegfilgrastim for ≥ 1 cycle) and all G-CSF (and reasons), neutropenic complications and adverse drug reactions (ADRs). RESULTS: Overall, 943 patients were enrolled; 844 met the eligibility criteria (full analysis set) and 814 (86%) completed the study. Twenty-eight patients (3%) had 31 FN events (NHL, n = 17; breast cancer, n = 11). Twenty-six patients (3%) discontinued pegfilgrastim. Forty-four patients (5%) discontinued G-CSF. The most common reason for pegfilgrastim discontinuation was physician preference for daily G-CSF (n = 14 [2%]), and for discontinuation of all G-CSFs was reduced FN risk (n = 14 [2%]). Patients who continued G-CSF prophylaxis were less likely to experience neutropenic complications (odds ratio [95% confidence interval]: 0.26 [0.09-0.80]). Suspected ADRs to pegfilgrastim occurred in 43 patients (5%) and serious ADRs in 5 (1%). CONCLUSIONS: FN rates were consistent with previous reports with pegfilgrastim in clinical practice. No new ADRs were observed. G-CSF discontinuation was uncommon but appeared to increase the likelihood of neutropenic complications.