Expression of the chemokine decoy receptor D6 is decreased in colon adenocarcinomas

Abstract

Recruitment of immune cells to tumors is a complex process crucial for both inflammation-driven tumor progression and specific anti-tumor cytotoxicity. Chemokines control the directed migration of immune cells, and their actions are partly controlled by nonsignaling chemokine decoy receptors. The role of the receptors such as D6, Duffy antigen receptor for chemokines and ChemoCentryx chemokine receptor in immunity to tumors is still unclear. Using real-time PCR, we detected significantly decreased expression of D6 mRNA in colon tumors compared to unaffected mucosa. D6 protein was expressed by lymphatic endothelium and mononuclear cells in the colon lamina propria and detected by immunohistochemistry in two out of six tissue samples containing high D6 mRNA levels, whereas no staining was observed in any tissue samples expressing low mRNA levels. When examining the density of lymphatic vessels in colon tumors, we detected a marked increase in vessels identified by the lymphatic endothelial marker Lyve-1, excluding passive regulation of D6 due to decreased lymphatic vessel density. In parallel, the Treg-recruiting chemokine CCL22, which is sequestered by D6, was threefold increased in tumor tissue. Furthermore, we could show that low D6 expression correlated to more invasive tumors and that tumor location influences D6 expression, which is lower in the more distal parts of the colon. The data support that regulation of D6 by colon tumors results in altered levels of proinflammatory CC chemokines, thereby shaping the local chemokine network to favor tumor survival. This may have implications for the design of future immunotherapy for colon cancer.

Inhibition of tumor formation and metastasis by a monoclonal antibody against lymphatic vessel endothelial hyaluronan receptor 1

“…11,14 In clinical studies, LYVE-1 proteins were significantly increased in colon tumors compared with in unaffected colon tissues. 15 LYVE-1 gene expression was upregulated in muscle-invasive bladder cancers exhibiting positive lympho-vascular invasion and LN metastasis compared with in non-muscle invasive bladder cancers. 16 In a xenograft mouse model, intratumoral and peritumoral LYVE-1-positive vessels increased in vascular endothelial growth factor (VEGF)-C-overexpressing breast cancer cells.…”

“…Furthermore, LYVE‐1 promotes hyaluronan‐induced lymphangiogenesis . In clinical studies, LYVE‐1 proteins were significantly increased in colon tumors compared with in unaffected colon tissues . LYVE‐1 gene expression was upregulated in muscle‐invasive bladder cancers exhibiting positive lympho‐vascular invasion and LN metastasis compared with in non‐muscle invasive bladder cancers .…”

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands

“…CCL5 is also a ligand for G-protein-coupled receptor 75 (GPR75), whose expression occurs on brain nerve cells [ 42 , 43 ]. The effect of CCL5 is mitigated by the atypical chemokine receptor 2 (ACKR2)/D6, which reduces the level of this chemokine [ 44 , 45 , 46 ].…”

Atypical chemokine receptors in cancer: friends or foes?

“…On the contrary, there is no evidence of a protective role of ACKR2 in DEN-induced hepatocellular carcinoma model, although liver of ACKR2 2/2 mice had greater macrophage infiltrates [51]. Referring to colon cancer, Langenes et al [52] found that ACKR2 expression by lymphatic endothelial and mononuclear cells was decreased in human colon adenocarcinoma samples compared with healthy tissues, and this decrease correlated with greater lymphatic vessel density and increased CCL22 levels.…”