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Journal of Clinical Oncology, Vol 24, No 32 (November 10), 2006: pp. 5173-5174 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.9095
Chemokine Receptor CCR6 Expression in Colorectal Liver MetastasisDepartment of General, Visceral, Vascular and Pediatric Surgery, University of the Saarland, Homburg/Saar, Germany
Institute of Pathology, University of the Saarland, Homburg/Saar, Germany To the Editor: We would like to comment on the recent article by Ghadjar et al,1 published in the April 20, 2006 issue of the Journal of Clinical Oncology. The study describes a strong association between CCR6 staining intensity in primary colorectal cancer (CRC) samples and the development of synchronous liver metastases suggesting involvement of CCR6 and its ligand CCL20 in the metastatic spread of CRC to the liver. We have published an article2 on the same topic with a different strategy and distinct methods but reaching the same conclusions. CCL20/CCR6 involvement in the neoplastic progression and metastatic spread is presently reported in several tumor types, with major focus on the amplification of local necroinflammatory response in the liver.3 While Uchida et al4 correlated CCR6 expression with intrahepatic metastases of hepatocellular carcinoma, others associate CCR6 expression with hepatic metastases in a rodent model5 and recent studies also reported an association with pancreatic cancer cell invasion.6 Based on the theory that chemokines organ specifically attract special types of cancer cells,7 we intended to assess potential chemotactic factors regulating CRC metastasis of the liver, which constitutes the primary site of metastatic CRC spread. Investigating the expression profile of the CCL20/CCR6 couple on the RNA and protein level, we have recently shown that CCR6 is significantly upregulated in CRC and colorectal liver metastases (CRLM) with respect to the corresponding tumor neighboring tissues, while CCL20 is not only constitutively expressed in the human liver, but reveals also peak levels of expression in the liver compared with other organs, which constitute rare metastatic destinations of colorectal metastases.2 Moreover, we were able to show that CRC patients who develop CRLM, express significantly more CCL20 in their liver compared with patients without CRLM. We think this is a very important finding indicating that increased CCL20 production in the liver of CRC patients may contribute to the selective recruitment of CCR6-expressing cancer cells to the liver and that the distribution of CRLM reflects the relative abundance of CCL20 in the liver of patients who develop CRLM. Even though we chose a methodically different approach using quantitative real-time polymerase chain reaction, microdissection, histochemistry, enzyme-linked immunosorbent assay, and Western blot techniques, we still came to the same conclusion as Ghadjar et al, indicating that CRLM may be influenced by the CCL20/CCR6 interaction. However, their studies do not include investigations on the CCL20 expression profile, while we have paid special attention to this aspect. On the basis of our findings we suggest that CCL20 attracts CCR6-expressing migrating cancer cells to the liver and that CCR6-expressing cancer cells might be arrested by the CCL20/CCR6 interaction. However, only a functional approach can ultimately clarify whether tumor cell-host cell CCR6/CCL20 interactions are mechanistically implicated and causally responsible for CRLM. If so, neutralization of the CCL20-CCR6 interaction may significantly impair the metastatic spread of colorectal carcinoma to the liver and the CCL20/CCR6 couple could represent a promising target for future therapeutic strategies against CRLM. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Ghadjar P, Coupland SE, Na I-K, et al: Chemokine receptor CCR6 expression level and liver metastases in colorectal cancer. J Clin Oncol 24
: 1910
-1916, 2006 2. Rubie C, Oliveira V, Kempf K, et al: Involvement of chemokine receptor CCR6 in colorectal cancer metastasis. Tumor Biol 27 : 166 -174, 2006[CrossRef] 3. Shimuzu Y, Murata H, Kashii Y, et al: CC-chemokine receptor 6 and its ligand macrophage inflammatory protein 3alpha might be involved in the amplification of local necroinflammatory response in the liver. Hepatology 34 : 311 -319, 2001[CrossRef][Medline] 4. Uchida H, Iwashita Y, Sasaki A, et al: Chemokine receptor CCR6 as a prognostic factor after hepatic resection for hepatocellular carcinoma. J Gastroen Hepatol 21 : 161 -168, 2006[CrossRef][Medline] 5. Dellacasagrande J, Schreurs OJ, Hofgaard PO, et al: Liver metastasis of cancer facilitated by chemokine receptor CCR6. Scand J Immunol 57 : 534 -544, 2003[CrossRef][Medline] 6. Kimsey TF, Campbell AS, Albo D, et al: Co-localization of macrophage inflammatory protein-3alpha (Mip-3alpha) and its receptor, CCR6, promotes pancreatic cancer cell invasion. Cancer J 10 : 374 -380, 2004[Medline] 7. Muller A, Homey B, Soto H, et al: Involvement of chemokine receptors in breast cancer metastasis. Nature 410 : 50 -56, 2001[CrossRef][Medline]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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