Pharmacological targeting of CXCL12/CXCR4 signaling in prostate cancer bone metastasis.
The 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 Gαi2in Src and HER2 phosphorylation in lipid raft membrane microdomains and the significance of CXCR4 in prostate cancer bone tumor growth.



We 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.



We 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.



These data suggest that lipid raft membrane microdomains are key sites for CXCL12/CXCR4 transactivation of HER2 via small GTP binding protein Gαi2and 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.
Department of Urology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA.
M Katie
MK
Conley-LaComb
Department of Urology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA.
Louie
L
Semaan
Department of Urology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA.
Rajareddy
R
Singareddy
Department of Urology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA.
Yanfeng
Y
Li
Department of Oncology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA.
Elisabeth I
EI
Heath
Department of Oncology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA.|Biostatics Core, Karmanos Cancer Institute, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA.
Seongho
S
Kim
Department of Urology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA.|Department of Pathology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA.|Department of Oncology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA.
Michael L
ML
Cher
Department of Urology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA. schinni@med.wayne.edu.|Department of Pathology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA. schinni@med.wayne.edu.|Department of Oncology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA. schinni@med.wayne.edu.
Sreenivasa R
SR
Chinni
D000818:Animals; D001596:Benzylamines; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary*; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D000080027:Cyclams; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000819:agonists / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000378:metabolism
D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D066246:ErbB Receptors; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D006571:Heterocyclic Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases; D019718:Receptors, CXCR4; D019061:src-Family Kinases; C088327:plerixafor
Bone metastasis; CXCR4; CXL12; EGFR; Gefitinib; HER2; Plerixafor; Src