viernes, 22 de mayo de 2015

Effect of Cellular Senescence on the Growth of HER2-Positive Breast Cancers

Effect of Cellular Senescence on the Growth of HER2-Positive Breast Cancers

JNCI J Natl Cancer Inst

Effect of Cellular Senescence on the Growth of HER2-Positive Breast Cancers

  1. Joaquín Arribas
+Author Affiliations
  1. Affiliations of authors: Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d’Hebron Institute of OncologyBarcelona, SpainDepartment of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UABBellaterra, Spain (JA); Institució Catalana de Recerca i Estudis AvançatsBarcelona, Spain (JA).
  1. Correspondence to: Joaquín Arribas, PhD, Psg. Vall d’Hebron 119-129, Barcelona 08035, Spain (e-mail:
  • Received August 12, 2014.
  • Revision received December 4, 2014.
  • Accepted January 20, 2015.


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.

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