The Chemokine Receptor CXCR6 and Its Ligand CXCL16 Are Expressed in Carcinomas and Inhibit Proliferation

Abstract

The chemokine receptor CXCR6 and its ligand CXCL16 are involved in inflammation. Thus far, they were known to be expressed mainly by T cells and macrophages, respectively. However, we detected both in all of 170 human primary mammary carcinomas and at similar levels in all 8 human mammary carcinoma cell lines tested by microarray analysis. Expression was confirmed by reverse transcription-PCR and for the cell lines also by fluorescence-activated cell sorting analysis. CXCR6 and CXCL16 were also detected in several mouse and human mammary, colon, and pancreatic carcinoma cell lines. CXCL16 is a transmembrane protein from which the soluble chemokine can be cleaved off. The transmembrane form is present on the surface of the carcinoma cells. Surprisingly, suppression of either CXCR6 or CXCL16 led to greatly enhanced proliferation in vitro as well as in vivo, indicating that their interaction inhibits proliferation. This notion was verified using inhibitory antibodies and by introduction of CXCL16 into a rare CXCL16-negative cell line. The effect was mediated by the G protein-coupled receptor CXCR6 because it was blocked by the G i protein inhibitor pertussis toxin. In contrast, the soluble CXCL16 chemokine enhanced proliferation, and this was also mediated by CXCR6 but not via G i protein. It is remarkable that both CXCR6 and CXCL16 are expressed by all mammary carcinomas because cells that lose either acquire a growth advantage and should be selected during tumor progression. This suggests an unknown important role in tumor formation. Proteases, possibly macrophage derived, might convert inhibitory transmembrane CXCL16 into the stimulatory chemokine.

CXCL16 signaling mediated macrophage effects on tumor invasion of papillary thyroid carcinoma

“…CXCL16 is a ligand for CXCR6, a member of the seven transmembrane G protein-coupled receptor family, and signals through the Akt pathway (Meijer et al 2008). Independent of macrophages, the CXCL16-CXCR6 complex has been shown to promote cancer proliferation or metastasis in prostate (Lu et al 2008, Jung et al 2013, renal (Gutwein et al 2009), and pancreatic (Wente et al 2008) cancer.…”

“…One of the unidentified issues in the role of CXCL16 signaling in cancers is on the functional divergence of two different types of CXCL16 proteins: soluble and trans-membrane forms. Meijer et al (2008) showed that the two types of CXCL16 had different roles in cell proliferation and metastasis, and a certain model suggested that the soluble CXCL16 induces cancer cell proliferation and metastasis (Deng et al 2010), while the trans-membrane CXCL16 suppressed it. However, it is still unclear and needs to be redefined according to specific tissues.…”

Human Adipose Tissue Macrophages Display Activation of Cancer-related Pathways

“…Surprisingly, the only CXCL lower expressed in ATM was CXCL16, also involved in leukocyte migration and adhesion (38). Importantly, high expression levels of CXCL16 in renal cancer tissue has been correlated with a better survival rate of patients (39,40). Our study also reveals that circulating levels of Gro (CXCL1, -2, -3), CXCL9, -10, -11 (CXCR3 ligands), and sgp130, key players in the maintenance and amplification of autoimmunity-related inflammatory processes (35), are elevated in obese subjects, whereas anti-proliferative TGF␤1 concentrations are lower (41).…”

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].…”