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An Increased Expression of Cysteinyl Leukotriene 2 Receptor in Colorectal Adenocarcinomas Correlates with High Differentiation

Divisions of ¹ Cell and Experimental Pathology and ² Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden and ³ Department of Medical Biochemistry and Genetics, The Panum Institute, University of Copenhagen, Copenhagen, Denmark

Requests for reprints: Anita Sjölander, Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, CRC, Entrance 72, Building 91, Floor 11, SE-205 02 Malmö, Sweden. Phone: 46-40-39-11-68; Fax: 46-40-39-11-77; E-mail: anita.sjolander{at}med.lu.se.

Increased levels of inflammatory mediators such as cysteinyl leukotrienes (CysLT) have been found in and around tumors. These data, along with our previous observation that the G-protein–coupled receptor CysLT₁R, which signals survival and proliferation, is up-regulated in colon cancer, suggest an important role for CysLT₁R in tumor development. The objective of this study was to examine the expression and function of the low-affinity CysLT₂ receptor (CysLT₂R) in colon cancer. We found lower expression levels of CysLT₂R compared with CysLT₁R in cancer cell lines as well as clinical tumor material. Interestingly, CysLT₂R, like CysLT₁R, was found to be one of few G-protein–coupled receptors that are located both at the plasma membrane and the nuclear membrane. No effect of CysLT₂R signaling on cell proliferation was observed, nor was there a correlation between CysLT₂R and different proliferation markers such as Ki-67 and cyclooxygenase-2 in the tumor material. Instead, we found that activation of this receptor in colon cancer cells led to cellular differentiation similar to the effects of butyrate treatment. In accordance with this finding, we found that reduced expression of CysLT₂R in colon cancer was associated with poor prognosis. We report the novel finding that CysLT₂R signaling leads to terminal differentiation of colon carcinoma cells and growth inhibition, and that its expression is relatively high in less malignant forms of colon cancer. These data suggest that the balance between these two receptors is important for tumor progression and disease outcome. [Cancer Res 2007;67(19):9190–8]