Liver Metastasis of Cancer Facilitated by Chemokine Receptor CCR6

Abstract

When injected subcutaneously, mouse plasmacytoma (MOPC315) grew rapidly in situ, and metastatic cells became detectable first in the lymph nodes (LNs) and bone marrow, and later in the liver and lungs. We studied MOPC315 cell migration by tracking metastatic cells labelled with green fluorescent protein (GFP). We measured the levels of their chemokine receptor mRNA (by semiquantitative and real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), because chemokines can regulate organ predilection of metastasis. Freshly sorted metastatic cells and tumour cell lines derived from the liver of BALB/c mice overexpressed functional CCR6 and CCR7 molecules compared with primary tumour. Preincubation with the CCR6 ligand (CCL20) induced liver-sorted tumour cells to preferentially colonize the liver, demonstrating an association between liver metastasis and CCR6 expression in the mouse. Because the liver is a common site for metastasis, second only to draining LNs, we wished to ascertain whether this finding could be generalized, i.e. whether other cancers can use the similar mechanism of metastasis to the liver, and whether it holds true for humans. We found that CCR6 is overexpressed in small liver metastases of colon, thyroid and ovarian carcinomas compared with normal liver. Because human liver constitutively expresses CCL20, it could attract and select CCR6 þ cancer cells. We suggest that chemotaxis via CCR6 might be a common mechanism by which malignant cancers metastasize to the liver. As metastasis in patients with cancer poses the biggest peril for survival, inhibition of CCR6 signalling, either during or after medical or surgical treatment, might be useful in preventing 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.…”

CXCL10 Promotes Invasion-Related Properties in Human Colorectal Carcinoma Cells

“…1B). Whereas the expression of CCR6 and CCR7 by CRC cells was already described (28,29), the finding on the expression of CXCR3 is novel.…”

Expression Pattern of Chemokine Receptor 6 (CCR6) and CCR7 in Squamous Cell Carcinoma of the Head and Neck Identifies a Novel Metastatic Phenotype

“…The three subcloned, highly metastatic cells were randomly selected to ensure that this up-regulation was a generally observed phenomenon. Because of the homology between murine and human CCR7 ligands and cross-reactivity with human CCR7 (30,31), functionally relevant signaling can explain this significant CCR7 up-regulation.…”