Involvement of Chemokine Receptor CCR6 in Colorectal Cancer Metastasis

Abstract

Various chemokine receptors, namely CXCR4, CCR6 and CCR7, have recently been shown to be involved in the regulation of metastasis in malignant tumors. However, little is known about the role of these receptors in promoting tumor metastasis of colorectal cancer (CRC) to the primary site of CRC metastasis in the liver. To investigate this issue, we analyzed the expression of the chemokine receptors CXCR4, CCR6 and CCR7 in colorectal tumors and colorectal liver metastases. In the present study, 30 human cancer samples from colorectal tissue, 30 human samples from colorectal liver metastases and the adjacent nontumorous liver tissues were screened using quantitative real-time PCR, Western blot analysis, histochemistry, microdissection and the enzyme-linked immunosorbent assay (ELISA). While an overexpression of all the chemokine receptors was found in CRC, in colorectal liver metastases only the chemokine receptors CXCR4 and CCR6 were significantly upregulated. Consequently, we investigated the expression of the corresponding ligands CXCL12/SDF1α, CCL20/MIP3α, CCL19/MIP3β and CCL21/6Ckine in various organs, such as the stomach, esophagus, pancreas, colon and rectum, in comparison with their expression in the liver as the primary site of metastatic spread in CRC. We found that only CCL20 exhibits peak levels of expression in the liver, thus indicating that an increased production of CCL20 may contribute to the selective recruitment of CCR6-expressing cancer cells in CRC. Furthermore, we could demonstrate that CRC patients who developed liver metastases express significantly more CCL20 and CCL21 in the liver in comparison with an unaffected control group. Therefore, our findings strongly suggest an association between CCL20/CCR6 expression in human CRC and the promotion of colorectal liver metastasis.

Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages

“…CCL20 and CCR6 have both been shown to be upregulated in human colorectal cancer. 4,6,22 An association between CCR6 expression and liver metastases in human colorectal cancer has also been demonstrated, [23][24][25] and high serum levels of CCL20 26 as well as tumor expression of CCR6 6 have been shown to correlate with poor prognosis in patients with this disease. A direct role of CCL20-CCR6 interactions on the epithelial component of colorectal cancers has been identified with studies showing that these interactions promote increased proliferation, 6-8 migration, 6 and invasion 7 of colorectal cancer cell lines in vitro.…”

Expression of the chemokine receptor CCR6 in the Lewis lung carcinoma (LLC) cell line reduces its metastatic potential in vivo

“…Similarly, CCL20 was found to be downregulated together with other genes in the metastatic subpopulations of a human pulmonary adenocarcinoma cell line. 17 On the other hand, CCL20 was reported to favor the metastatic spread of human colorectal cancer to the liver 18,19 and to promote hepatic metastases in a mouse plasmacytoma model. 20 To investigate the role played by CCL20 and CCR6 in antitumor immune responses, and as models for gene therapy approaches, the consequences of the expression of CCL20 in tumor models were investigated by several groups.…”

Overriding Elements in Colon Cancer Progression: Some Less Known Facts

“…On the other hand, CCL20 levels were higher in colon cancer patients with liver metastasis compared with controls without metastasis. 12 In a study by Kawada and colleagues, 13 amongst the colon cancer samples with CXCR3 expression, there was significantly high lymph node metastasis recorded. CXCR3 expression levels were directly proportional to poor prognosis which clearly indicates that CXCR3 activation was concomitant with colon cancer metastasis preferentially to the draining lymph nodes with poorer prognosis.…”