Anti-Tumor Effects of CysLT2R in Epithelial Cancer

Sammanfattning: The pro-inflammatory cysteinyl leukotrienes (cysLTs) are implicated in several pathological disorders, such as asthma and inflammatory diseases. The well-established connection between chronic inflammation and cancer implicates inflammatory mediators in cancer progression. It is therefore of interest to examine the effects of the CysLTs in cancer. The biological effects of CysLTs are mediated through two G-protein coupled receptors (GPCRs) denoted CysLT1R, which is the high affinity receptor for LTD4 and CysLT2R, which has lower but equal affinities for LTD4 and LTC4. Signaling through CysLT1R has been associated with increased cell proliferation, migration and survival. In this context we wanted to elucidate the role of CysLT2R in regard to cancer. In this thesis I show that the cellular localization patterns of CysLT1R and CysLT2R differ. Even though CysLT1R can be found at the nuclear membrane, CysLT2R is more pronouncedly expressed here in both colon and breast tumor cells, which is quite unusual for GPCRs. Moreover, we observed that CysLT2R was down-regulated in colon cancer and that more aggressive tumors expressed less of the receptor. In addition, LTC4, the major ligand for CysLT2R, mediated increased differentiation of the colon cancer cell line Caco-2. Interestingly, CysLT2R expression is induced by the anti-tumorigenic interferon a, whereas the mitogen inducer epidermal growth factor, suppresses the expression of CysLT2R. Furthermore, in breast cancer patients, high expression of CysLT2R predicts good five-year-survival, whereas high expression of CysLT1R mediates a poor prognosis. In addition, over-expression of CysLT2R suppressed the migratory capability of both breast epithelial and breast cancer cells in vitro. A selective CysLT2R inhibitor could block this effect. These results combined indicate that CysLT2R has a protective role against tumor progression.