Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer.
Sci Transl Med
; 11(521)2019 12 04.
Article
em En
| MEDLINE
| ID: mdl-31801883
ABSTRACT
Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
/
Prostata
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
/
Resistencia a Medicamentos Antineoplásicos
/
Receptores de Interleucina-8B
/
Terapia de Alvo Molecular
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Sci Transl Med
Assunto da revista:
CIENCIA
/
MEDICINA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos