Liver metastasis of cancer facilitated by chemokine receptor CCR6.
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+ 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.
Dellacasagrande
J
J
Institute of Immunology; and Department of Oral Biology, University of Oslo, The National Hospital, Oslo, Norway.
Schreurs
O J F
OJ
Hofgaard
P O
PO
Omholt
H
H
Steinsvoll
S
S
Schenck
K
K
Bogen
B
B
Dembic
Z
Z
D000818:Animals; D001483:Base Sequence; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology / Q000556:secondary; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010954:Plasmacytoma / Q000235:genetics / Q000276:immunology / Q000556:secondary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D054399:Receptors, CCR6; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013045:Species Specificity; D014407:Tumor Cells, Cultured
C106311:CCR6 protein, human; C515370:CCR7 protein, human; C515371:Ccr7 protein, mouse; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D054399:Receptors, CCR6; D054400:Receptors, CCR7; D019707:Receptors, Chemokine