Targeting CXCL12/CXCR4 Axis in Tumor Immunotherapy

Weiqiang Zhou, Shanchun Guo, Mingli Liu, Matthew E. Burow, Guangdi Wang
2017 Current Medicinal Chemistry  
Chemokines, which have chemotactic abilities, are comprised of a family of small cytokines with 8-10 kilodaltons. Chemokines work in immune cells by trafficking and regulating cell proliferation, migration, activation, differentiation, and homing. CXCR-4 is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1, also known as CXCL12), which has been found to be expressed in more than 23 different types of cancers. Recently, the SDF-1/CXCR-4 signaling pathway has emerged as a
more » ... tential therapeutic target for human tumor because of its critical role in tumor initiation and progression by activating multiple signaling pathways, such as ERK1/2, ras, p38 MAPK, PLC/ MAPK, and SAPK/ JNK, as well as regulating cancer stem cells. CXCL12/CXCR4 antagonists have been produced, which have shown encouraging results in anticancer activity. Here, we provide a brief overview of the CXCL12/CXCR4 axis as a molecular target for cancer treatment. We also review the potential utility of targeting CXCL12/CXCR4 axis in combination of immunotherapy and/or chemotherapy based on up-to-date literature and ongoing research progress. CXCR4 can be activated in different ways in tumor cells. First, hypoxia can up-regulate CXCR4 signaling [30]. Second, Wnt/beta-catenin can also positively regulate CXCR4 expression [31]. Third, NF-κB can also activate CXCR4 expression. Upon ligand induction, NF-κB subunits of p50 and p65 bind to the CXCR4 promoter, where a NF-κB binding site, transcriptionally activating CXCR4 and stimulating tumor invasion [32-37]. CXCR4 pathway has been implicated in the SHH-GLI1-NANOG network [38], Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) [39-40], phosphoinositide 3kinase (PI3K)/AKT [41-42] and NF -κB57 [37, 43]. In turn, the CXCL12/ CXCR4 signaling activates MAPKs signaling which stimulates chemotaxis and cell proliferation [41, 44], induces PLC/PKC-Ca 2+ signaling and affects PI3K/AKT, and promotes cell migration and survival [41][42]. This phenomenon suggests a feedback loop between CXCR4 and the other Zhou et al. CSCs are a small population of tumor cells that possess the stem cell property and initiate, drive carcinogenesis contributing to tumor cellular heterogeneity [93][94][95]. Many cancers Zhou et al.
doi:10.2174/0929867324666170830111531 pmid:28875842 pmcid:PMC5949083 fatcat:5ans3i6xcvcufmhekx73boi3iq