| The chemokine receptor CXCR4 and its ligand, CXCL12, have been recently identified as important players in site-specific metastasis by promoting migration, invasion, and proliferation of tumour cells. CXCR4 is up-regulated in a number of cancer types, including colorectal cancer, and high CXCR4 expression is associated with poorer prognosis and increased mortality. There is evidence that CXCR4 expression may be influenced by the tumour microenvironment. The objective of this thesis was to determine how small molecules present within the tumour microenvironment may alter CXCR4 expression on colorectal carcinoma cells, and thereby alter the fate of the cancer.;Prostaglandins are present in elevated levels in tumours due to increased expression of cyclooxygenase 2 (COX-2) and other enzymes in the eicosanoid pathway. We found that several prostaglandins reduced cell-surface CXCR4 expression on HT-29 cells, particularly prostaglandin D2 and its bioactive metabolite, 15-deoxy-Delta12,14-prostaglandin J2 (15dPGJ2). 15dPGJ2 is known to activate the peroxisome proliferator activated receptor gamma (PPARgamma). A range of synthetic PPARgamma agonists in the thiazolidinedione class reduced CXCR4 expression, and 15dPGJ2-induced CXCR4 down-regulation was blocked by PPARgamma antagonists, suggestive of a PPARgamma-dependent effect. We also found evidence of involvement of NF-kappaB signaling in 15dPGJ2-mediated CXCR4 down-regulation.;In conclusion, small molecules present in the tumour microenvironment contribute to changes in CXCR4 expression on cancer cells, and thus may alter the ability of these cells to metastasize. Elucidation of the molecular pathways leading to changes in CXCR4 expression may lead to the development of novel strategies in the treatment of colorectal cancer.;In the first part of this study, it was found that adenosine, a purine nucleoside present in increased levels in tumours due to hypoxia, up-regulated CXCR4 mRNA and cell-surface protein expression on HT-29 colorectal carcinoma cells. This up-regulation was observed at concentrations of adenosine similar to those found within the tumour extracellular fluid, and resulted in increased migratory and proliferative responses of HT-29 cells to CXCL12. The combination of antagonists selective for the adenosine A2A and A2B receptors blocked the effect of adenosine on CXCR4 expression, implicating these two receptors in adenosine-mediated CXCR4 up-regulation. |
