Pharmacological targeting of CXCL12/CXCR4 signaling in prostate cancer bone metastasis

Molecular Cancer

Research

Elisabeth I. Heath¹  Seongho Kim²  Yanfeng Li³  M. Katie Conley-LaComb³  Rajareddy Singareddy³  Louie Semaan³  Michael L. Cher⁴  Sreenivasa R. Chinni⁴ 

[1] Department of Oncology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, 48201, Detroit, MI, USA;Department of Oncology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, 48201, Detroit, MI, USA;Biostatics Core, Karmanos Cancer Institute, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, 48201, Detroit, MI, USA;Department of Urology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, 48201, Detroit, MI, USA;Department of Urology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, 48201, Detroit, MI, USA;Department of Pathology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, 48201, Detroit, MI, USA;Department of Oncology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, 48201, Detroit, MI, USA;

关键词: CXL12;    CXCR4;    Src;    EGFR;    HER2;    Plerixafor;    Gefitinib;    Bone metastasis;   

DOI  :  10.1186/s12943-016-0552-0

 received in 2016-07-08, accepted in 2016-10-20,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundThe CXCL12/CXCR4 axis transactivates HER2 and promotes intraosseous tumor growth. To further explore the transactivation of HER2 by CXCL12, we investigated the role of small GTP protein Gαi2 in Src and HER2 phosphorylation in lipid raft membrane microdomains and the significance of CXCR4 in prostate cancer bone tumor growth.MethodsWe used a variety of methods such as lipid raft isolation, invasion assays, an in vivo model of intratibial tumor growth, bone histomorphometry, and immunohistochemistry to determine the role of CXCR4 signaling in lipid raft membrane microdomains and effects of targeting of CXCR4 for bone tumor growth.ResultsWe determined that (a) CXCL12/CXCR4 transactivation of EGFR and HER2 is confined to lipid raft membrane microdomains, (b) CXCL12 activation of HER2 and Src is mediated by small GTP proteins in lipid rafts, (c) inhibition of the CXCL12/CXCR4 axis through plerixafor abrogates the initial establishment of tumor growth without affecting the growth of established bone tumors, and (d) inhibition of EGFR signaling through gefitinib leads to inhibition of established bone tumor growth.ConclusionsThese data suggest that lipid raft membrane microdomains are key sites for CXCL12/CXCR4 transactivation of HER2 via small GTP binding protein Gαi2 and Src kinase. The initial establishment of prostate cancer is supported by the endosteal niche, and blocking the CXCL12/CXCR4 axis of this niche along with its downstream signaling severely compromises initial establishment of tumors in the bone microenvironment, whereas expanding bone tumors are sensitive only to the members of growth factor receptor inhibition.

【 授权许可】

CC BY   
© The Author(s). 2016