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Cell Rep ; 28(8): 2156-2168.e5, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31433989

RESUMO

Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment supporting tumorigenesis. TAMs re-education has been proposed as a strategy to promote tumor inhibition. However, whether this approach may work in prostate cancer is unknown. Here we find that Pten-null prostate tumors are strongly infiltrated by TAMs expressing C-X-C chemokine receptor type 2 (CXCR2), and activation of this receptor through CXCL2 polarizes macrophages toward an anti-inflammatory phenotype. Notably, pharmacological blockade of CXCR2 receptor by a selective antagonist promoted the re-education of TAMs toward a pro-inflammatory phenotype. Strikingly, CXCR2 knockout monocytes infused in Ptenpc-/-; Trp53pc-/- mice differentiated in tumor necrosis factor alpha (TNF-α)-releasing pro-inflammatory macrophages, leading to senescence and tumor inhibition. Mechanistically, PTEN-deficient tumor cells are vulnerable to TNF-α-induced senescence, because of an increase of TNFR1. Our results identify TAMs as targets in prostate cancer and describe a therapeutic strategy based on CXCR2 blockade to harness anti-tumorigenic potential of macrophages against this disease.


Assuntos
Senescência Celular , Macrófagos/patologia , Neoplasias da Próstata/patologia , Receptores de Interleucina-8B/antagonistas & inibidores , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Polaridade Celular , Quimiocina CXCL2/administração & dosagem , Quimiocina CXCL2/farmacologia , Humanos , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estadiamento de Neoplasias , Testes de Neutralização , PTEN Fosfo-Hidrolase/metabolismo , Receptores de Interleucina-8B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor p53/metabolismo
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