PMID- 25972601 OWN - NLM STAT- MEDLINE DCOM- 20150622 LR - 20171116 IS - 1460-2105 (Electronic) IS - 0027-8874 (Linking) VI - 107 IP - 5 DP - 2015 May TI - Effect of cellular senescence on the growth of HER2-positive breast cancers. LID - djv020 [pii] LID - 10.1093/jnci/djv020 [doi] AB - BACKGROUND: Oncogene-induced senescence (OIS) is a tumor suppressor mechanism. However, senescent cells remain viable and display a distinct secretome (also known as senescence-associated secretory phenotype [SASP] or senescence messaging secretome, [SMS]) that, paradoxically, includes protumorigenic factors. OIS can be triggered by ectopic overexpression of HER2, a receptor tyrosine kinase and the driving oncogene in a subtype of human breast cancer. However, cellular senescence has not been characterized in HER2-positive tumors. METHODS: Using an approach based on their inability to proliferate, we isolated naturally occurring senescent cells from a variety of tumor models including HER2-positive cells, transgenic mice (n = 3), and patient-derived xenografts (PDXs) (n = 6 mice per group from one PDX derived from one patient). Using different biochemical and cell biological techniques, we characterized the secretome of these senescent cells. All statistical tests were two-sided. RESULTS: We found that senescent cells arise constantly in different models of advanced breast cancers overexpressing HER2 and constitute approximately 5% of tumor cells. In these models, IL-6 and other cytokines were expressed mainly, if not exclusively, by the naturally occurring senescent cells (95.1% and 45.0% of HCC1954 cells and cells from a HER2-positive PDX expressing a senescent marker expressed IL-6, respectively). Furthermore, inhibition of IL-6 impaired the growth of the HER2-positive PDX (mean tumor volume at day 101, control vs anti-huIL-6 treated, 332.2mm(3) [95% confidence interval CI = 216.6 to 449.8] vs 114.4mm(3) [95% CI = 12.79 to 216.0], P = .005). CONCLUSIONS: Senescent cells can contribute to the growth of tumors by providing cytokines not expressed by proliferating cells, but required by these to thrive. CI - (c) The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. FAU - Zacarias-Fluck, Mariano F AU - Zacarias-Fluck MF AD - Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institucio Catalana de Recerca i Estudis Avancats, Barcelona, Spain (JA). jarribas@vhio.net. FAU - Morancho, Beatriz AU - Morancho B AD - Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institucio Catalana de Recerca i Estudis Avancats, Barcelona, Spain (JA). FAU - Vicario, Rocio AU - Vicario R AD - Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institucio Catalana de Recerca i Estudis Avancats, Barcelona, Spain (JA). FAU - Luque Garcia, Antonio AU - Luque Garcia A AD - Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institucio Catalana de Recerca i Estudis Avancats, Barcelona, Spain (JA). FAU - Escorihuela, Marta AU - Escorihuela M AD - Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institucio Catalana de Recerca i Estudis Avancats, Barcelona, Spain (JA). FAU - Villanueva, Josep AU - Villanueva J AD - Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institucio Catalana de Recerca i Estudis Avancats, Barcelona, Spain (JA). FAU - Rubio, Isabel T AU - Rubio IT AD - Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institucio Catalana de Recerca i Estudis Avancats, Barcelona, Spain (JA). FAU - Arribas, Joaquin AU - Arribas J AD - Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institucio Catalana de Recerca i Estudis Avancats, Barcelona, Spain (JA). LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150513 PL - United States TA - J Natl Cancer Inst JT - Journal of the National Cancer Institute JID - 7503089 RN - 0 (Biomarkers, Tumor) RN - 0 (Interleukin-6) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-2) SB - IM CIN - J Natl Cancer Inst. 2015 May;107(5). pii: djv091. doi: 10.1093/jnci/djv091. PMID: 25972602 MH - Animals MH - Biomarkers, Tumor/*analysis MH - Breast Neoplasms/*chemistry/*pathology MH - Cell Line, Tumor MH - Cell Proliferation MH - *Cellular Senescence MH - Female MH - Gene Expression Regulation, Neoplastic MH - Heterografts MH - Humans MH - Interleukin-6/metabolism MH - Mice MH - Mice, Transgenic MH - Microscopy, Confocal MH - Receptor, ErbB-2/*analysis MH - Up-Regulation EDAT- 2015/05/15 06:00 MHDA- 2015/06/24 06:00 CRDT- 2015/05/15 06:00 PHST- 2014/08/12 00:00 [received] PHST- 2015/01/20 00:00 [accepted] PHST- 2015/05/15 06:00 [entrez] PHST- 2015/05/15 06:00 [pubmed] PHST- 2015/06/24 06:00 [medline] AID - djv020 [pii] AID - 10.1093/jnci/djv020 [doi] PST - epublish SO - J Natl Cancer Inst. 2015 May 13;107(5):djv020. doi: 10.1093/jnci/djv020. Print 2015 May.