Your browser doesn't support javascript.
loading
Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma.
Hu, Junhui; Tan, Ping; Ishihara, Moe; Bayley, Nicholas A; Schokrpur, Shiruyeh; Reynoso, Jeremy G; Zhang, Yangjun; Lim, Raymond J; Dumitras, Camelia; Yang, Lu; Dubinett, Steven M; Jat, Parmjit S; Van Snick, Jacques; Huang, Jiaoti; Chin, Arnold I; Prins, Robert M; Graeber, Thomas G; Xu, Hua; Wu, Lily.
Afiliação
  • Hu J; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • Tan P; Department of Urology, West China Hospital, Chengdu, China.
  • Ishihara M; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • Bayley NA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • Schokrpur S; Department of Hematology and Oncology, University of California San Diego, San Diego, CA, 92103, USA.
  • Reynoso JG; Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • Zhang Y; Department of Biological Repositories, Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • Lim RJ; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • Dumitras C; Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • Yang L; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • Dubinett SM; Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • Jat PS; Department of Urology, West China Hospital, Chengdu, China.
  • Van Snick J; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • Huang J; Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • Chin AI; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • Prins RM; MRC Prion Unit at UCL, Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK.
  • Graeber TG; Ludwig Institute for Cancer Research Ltd, Brussels, Belgium.
  • Xu H; Department of Pathology, Duke University, Durham, NC, USA.
  • Wu L; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Signal Transduct Target Ther ; 8(1): 155, 2023 04 17.
Article em En | MEDLINE | ID: mdl-37069149
ABSTRACT
Loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is a hallmark of clear cell renal cell carcinoma (ccRCC). The importance of heterogeneity in the loss of this tumor suppressor has been under reported. To study the impact of intratumoral VHL heterogeneity observed in human ccRCC, we engineered VHL gene deletion in four RCC models, including a new primary tumor cell line derived from an aggressive metastatic case. The VHL gene-deleted (VHL-KO) cells underwent epithelial-to-mesenchymal transition (EMT) and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing (VHL+) cells. Renal tumors with either VHL+ or VHL-KO cells alone exhibit minimal metastatic potential. Combined tumors displayed rampant lung metastases, highlighting a novel cooperative metastatic mechanism. The poorly proliferative VHL-KO cells stimulated the proliferation, EMT, and motility of neighboring VHL+ cells. Periostin (POSTN), a soluble protein overexpressed and secreted by VHL non-expressing (VHL-) cells, promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular escape. Genetic deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical models. This work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor.
Assuntos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Carcinoma de Células Renais / Neoplasias Renais / Neoplasias Pulmonares Limite: Humans Idioma: En Revista: Signal Transduct Target Ther Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Carcinoma de Células Renais / Neoplasias Renais / Neoplasias Pulmonares Limite: Humans Idioma: En Revista: Signal Transduct Target Ther Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos