The Chemokine CXCL16 and Its Receptor, CXCR6, as Markers and Promoters of Inflammation-Associated Cancers

Abstract

Clinical observations and mouse models have suggested that inflammation can be pro-tumorigenic. Since chemokines are critical in leukocyte trafficking, we hypothesized that chemokines play essential roles in inflammation-associated cancers. Screening for 37 chemokines in prostate cancer cell lines and xenografts revealed CXCL16, the ligand for the receptor CXCR6, as the most consistently expressed chemokine. Immunohistochemistry and/or immunofluorescence and confocal imaging of 121 human prostate specimens showed that CXCL16 and CXCR6 were co-expressed, both on prostate cancer cells and adjacent T cells. Expression levels of CXCL16 and CXCR6 on cancer cells correlated with poor prognostic features including high-stage and high-grade, and expression also correlated with post-inflammatory changes in the cancer stroma as revealed by loss of alpha-smooth muscle actin. Moreover, CXCL16 enhanced the growth of CXCR6-expressing cancer and primary CD4 T cells. We studied expression of CXCL16 in an additional 461 specimens covering 12 tumor types, and found that CXCL16 was expressed in multiple human cancers associated with inflammation. Our study is the first to describe the expression of CXCL16/CXCR6 on both cancer cells and adjacent T cells in humans, and to demonstrate correlations between CXCL16 and CXCR6 vs. poor both prognostic features and reactive changes in cancer stoma. Taken together, our data suggest that CXCL16 and CXCR6 may mark cancers arising in an inflammatory milieu and mediate pro-tumorigenic effects of inflammation through direct effects on cancer cell growth and by inducing the migration and proliferation of tumor-associated leukocytes.

Chemokines in tumor development and progression

“…CXCL12 expression correlates well with lower apoptosis in human myelodysplastic syndrome [27]. Likewise, CCR6 and CXCR6 can promote the proliferation of colorectal cancer cells [28] and prostate cancer cells [29], respectively. Furthermore, phosphatidylinositol-3-kinase (PI3K)-mediated protection of tumor cells from apoptosis has been reported after CCR10 activation in melanoma [30] and CCR7 activation in squamous cell carcinoma of the head and neck [31] (Figure 1).…”

Chemokines in cancer related inflammation

“…In human glioma, colorectal, breast and renal cancer, tumors with high CXCL16 expression had slower progression and showed infiltration of CD4 and CD8 lymphocytes [53][54][55][56][57]. On the contrary in prostate cancer CXCL16 expression has been correlated with poor prognosis [58]. Interestingly, it has been reported that ionizing radiation therapy markedly enhanced CXCL16 secretion by mouse and human breast cancer cells, which recruited CXCR6+ effector cells [55].…”

Expression analysis and clinical significance of CXCL16/CXCR6 in patients with bladder cancer

“…Coupled with their previous cell line studies, this result appears to corroborate the results of Ha et al (17) that CXCL16 and total CXCR6 mRNA expression are higher in more aggressive cancer cases. Other recent findings from studies of prostate cancer tissue have provided further confirmation that the CXCL16/CXCR6 expression level is closely associated with high malignant features, as observed with the Gleason grade and tumor stage in prostate cancer (25). Metastatic bone marrow, but not the liver and lung tissues, expressed higher levels of CXCL16 and total CXCR6 mRNA than the primary prostate cancer tissues, implying that the metastatic process was correlated with chemokines and its receptors (17).…”