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

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0552-0) contains supplementary material, which is available to authorized users.

Bone as a Preferential Site for Metastasis

“…Preventing tumor cell dissemination and colonization by disrupting the factors shown in Table may prove to be a promising strategy to prevent metastasis. In support of this notion, disruption of the CX3CR1 or CXCR4 pathway in murine models of breast and prostate cancer, respectively, reduces metastatic incidence and tumor burden in the bone . Similarly, substantial preclinical evidence suggests that pharmacological targeting of αvβ3 integrin effectively prevents metastatic colonization of the bone .…”

Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis

“…Both HSC and prostate cancer cells express the CXCL12 receptor C-X-C chemokine receptor type 4 (CXCR4) [25,26] and/or CXCR7 [27], and migrate towards CXCL12-expressing organs, including bone marrow. When the CXCL12/CXCR4 interaction is inhibited with a CXCR4 antagonist AMD3100, the initial colonization to the bone and the growth of prostate cancer are prevented [28]. However, the same treatment fails to diminish the established bone metastatic tumor [28].…”

“…When the CXCL12/CXCR4 interaction is inhibited with a CXCR4 antagonist AMD3100, the initial colonization to the bone and the growth of prostate cancer are prevented [28]. However, the same treatment fails to diminish the established bone metastatic tumor [28]. This finding suggests that CXCL12/CXCR4 axis may be involved in an early dissemination process of prostate cancer, but not later metastatic growth.…”

C‐X‐C motif chemokine receptor 4 promotes tumor angiogenesis in gastric cancer via activation of JAK2/STAT3

“…CXC chemokines exert their biological activities through interaction with specific receptors (Strieter et al, 2006). CXCR4 is aberrantly expressed on multiple types of tumor cells such as prostate cancer (Conley-LaComb et al, 2016) and lung cancer (Gangadhar et al, 2010). In gastric cancer, CXCR4 upregulation contributes to tumor growth and metastasis (Bao et al, 2011).…”