The intricate interplay between chemokines and their receptors within the tumor microenvironment has emerged as a critical area of research in understanding cancer biology. Among these, the CXC motif chemokine ligand 16 (CXCL16)/CXC motif chemokine receptor 6 (CXCR6) axis has been identified as a pivotal player in orchestrating various cellular processes that contribute to tumorigenesis.
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Introduction of CXCL16
CXCL16, a distinct chemokine, is encoded by a gene located on chromosome 17p13, separate from other chemokine genes, exhibiting poor homology. Through alternative splicing, two transcripts of 1.8 kb and 2.5 kb are formed, showing differences in tissue expression and 3'-noncoding regions. Post-translation, the membrane-bound form (mCXCL16) is generated, sharing structural similarities with transmembrane CX3CL1. mCXCL16 plays a crucial role in CXCR6-mediated signaling, contributing to bacterial adhesion and immune cell accumulation at inflammatory sites. Regulated by disintegrin and metalloproteinases, mCXCL16 undergoes cleavage to release the soluble form (sCXCL16). Both forms have distinct functions, with sCXCL16 acting as a cell chemotaxis factor and mCXCL16 exhibiting adhesion and signaling properties.
Fig. 1 mCXCL16 structure (Korbecki J., et al. 2021).
Various pro-inflammatory cytokines, such as TNF-α and IFN-γ, influence CXCL16 expression, regulating immune cell accumulation during inflammatory reactions. It's noteworthy that many studies do not distinguish between the two CXCL16 forms, potentially impacting the interpretation of experimental findings. Understanding the multifaceted roles of mCXCL16 and sCXCL16 is crucial in comprehending immune responses and disease processes.
The Role of CXCL16→CXCR6 Axis in Tumors
The CXCL16→CXCR6 axis exerts a profound influence on various aspects of tumor biology. Tumors such as glioblastoma multiforme, lung cancer, lymphoma, and nasopharyngeal carcinoma produce CXCL16, and its expression is regulated by factors like Notch1, ERK MAPK, and pro-inflammatory cytokines. In some tumors, mutations in CXCL16 and CXCR6 genes are observed, with stomach adenocarcinomas exhibiting a notable 8% deletion of the CXCL16 gene. Hepatitis C virus (HCV) infection in hepatocytes and osteopontin (OPN) also contribute to increased CXCL16 expression in liver cancer.
The effect of the CXCL16→CXCR6 axis on tumor cell proliferation varies across cancer types. While sCXCL16 promotes proliferation in several cancer cell lines, including colorectal, gastric, glioblastoma, hepatocellular carcinoma, melanoma, and prostate cancer cells, the underlying mechanisms are diverse. The axis influences the activity of signaling pathways such as ERK MAPK, PI3K→Akt/PKB, and NF-κB. Intriguingly, CXCL16 may also exhibit anti-proliferative effects in specific cancer cells, and its impact on cancer stem cells warrants further exploration.
In addition, CXCL16 plays a crucial role in cancer cell migration and invasion. sCXCL16 stimulates migration in various cancer cell lines through pathways like PI3K→Akt/PKB, ERK MAPK, and STAT3 activation. Additionally, the CXCL16→CXCR6 axis induces epithelial-mesenchymal transition (EMT) and upregulates matrix metalloproteinases (MMP), contributing to enhanced migration and invasion. However, in certain contexts, CXCL16 can inhibit cancer cell migration, especially when co-expressed with CXCR6.
Role of CXCL16→CXCR6 Crosstalk on the Tumor Microenvironment
The CXCL16→CXCR6 axis significantly influences the tumor microenvironment, particularly in angiogenesis. sCXCL16, activated by CXCR6, promotes capillary tube formation and endothelial cell proliferation through pathways involving PI3K→Akt/PKB, p38 MAPK, and ERK MAPK. Additionally, CXCL16 indirectly induces angiogenesis by elevating VEGF and CXCL8/IL-8 expression.
Within the tumor, CXCL16 interacts with diverse cell types, including cancer-associated fibroblasts (CAFs), endothelial cells (EC), tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), tumor-associated neutrophils (TAN), mesenchymal stem cells (MSC), astrocytes, regulatory T cells (Treg), and anti-cancer tumor-infiltrating lymphocytes. CAFs influenced by cancer cells and monocytes secrete CXCL16, as do endothelial cells. TAM polarization, MDSC survival, and MSC conversion to CAFs are also modulated by CXCL16. Moreover, CXCL16 affects TAN recruitment, MSC migration, and Treg pro-tumorigenic functions. Notably, CXCL16 attracts Anti-Cancer Tumor-Infiltrating Lymphocytes, with NKT cells playing a crucial role in anti-cancer responses, inhibiting liver cancer and metastasis.
In conclusion, the multifaceted interactions orchestrated by CXCL16→CXCR6 across various cell types underscore its pivotal role in tumor development and microenvironment modulation.
References
- Korbecki J.; et al. The role of CXCL16 in the pathogenesis of cancer and other diseases. International Journal of Molecular Sciences. 2021, 22(7): 3490.
- Han J.; et al. CXCL16 promotes gastric cancer tumorigenesis via ADAM10-dependent CXCL16/CXCR6 Axis and activates akt and MAPK signaling pathways. International Journal of Biological Sciences. 2021, 17(11): 2841.
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