Effect of cellular senescence on the growth of HER2-positive breast cancers

Mariano F. Zacarias-Fluck, Beatriz Morancho, Rocio Vicario, Antonio Luque Garcia, Marta Escorihuela, Josep Villanueva, Isabel T. Rubio, Joaquín Arribas

Research output: Contribution to journalArticleResearchpeer-review

23 Citations (Scopus)

Abstract

© 2015 © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. 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, 332.2mm3 [95% confidence interval {CI} = 216.6 to 449.8] vs 114.4mm3 [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.
Original languageEnglish
Article numberdjv020
JournalJournal of the National Cancer Institute
Volume107
Issue number5
DOIs
Publication statusPublished - 1 Jan 2015

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