Publication Date:
2014-08-27
Description:
Aberrant activation of oncogenes or loss of tumour suppressor genes opposes malignant transformation by triggering a stable arrest in cell growth, which is termed cellular senescence. This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence. Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours in mice are massively infiltrated by a population of CD11b(+)Gr-1(+) myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-1(+) cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype of the tumour through the secretion of interleukin-1 receptor antagonist (IL-1RA). Strikingly, Pten-loss-induced cellular senescence was enhanced in vivo when Il1ra knockout myeloid cells were adoptively transferred to PTEN null mice. Therapeutically, docetaxel-induced senescence and efficacy were higher in PTEN null tumours when the percentage of tumour-infiltrating CD11b(+)Gr-1(+) myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2). Taken together, our findings identify a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Di Mitri, Diletta -- Toso, Alberto -- Chen, Jing Jing -- Sarti, Manuela -- Pinton, Sandra -- Jost, Tanja Rezzonico -- D'Antuono, Rocco -- Montani, Erica -- Garcia-Escudero, Ramon -- Guccini, Ilaria -- Da Silva-Alvarez, Sabela -- Collado, Manuel -- Eisenberger, Mario -- Zhang, Zhe -- Catapano, Carlo -- Grassi, Fabio -- Alimonti, Andrea -- England -- Nature. 2014 Nov 6;515(7525):134-7. doi: 10.1038/nature13638. Epub 2014 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2]. ; 1] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2] Faculty of Biology and Medicine, University of Lausanne UNIL, Lausanne CH1011, Switzerland. ; Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland. ; Institute for Research in Biomedicine (IRB), Bellinzona CH6500, Switzerland. ; 1] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2] Molecular Oncology Unit, CIEMAT, 28040 Madrid, Spain. ; Laboratory of Stem Cells in Cancer and Aging, (stemCHUS) Health Research Institute of Santiago de Compostela (IDIS), Clinical University Hospital (CHUS), E15706 Santiago de Compostela, Spain. ; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231-1000, USA. ; Divisions of BioStatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231-1000, USA. ; 1] Institute for Research in Biomedicine (IRB), Bellinzona CH6500, Switzerland [2] Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan I-20100, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25156255" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
*Cell Aging/drug effects
;
*Cell Movement
;
Disease Progression
;
Drug Resistance, Neoplasm
;
Humans
;
Immunity, Innate
;
Interleukin 1 Receptor Antagonist Protein/deficiency/metabolism/secretion
;
Interleukin-1alpha/immunology/metabolism
;
Male
;
Mice
;
Myeloid Cells/*cytology/*metabolism/transplantation
;
PTEN Phosphohydrolase/deficiency/genetics/metabolism
;
Prostatic Neoplasms/drug therapy/immunology/metabolism/*pathology
;
Receptors, Chemokine/*metabolism
;
Receptors, Interleukin-8B/antagonists & inhibitors
;
Taxoids/pharmacology
;
Tumor Escape
;
Tumor Microenvironment
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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