Peroxisome proliferator-activated receptor gamma (PPARg), a member of the nuclear receptor superfamily, is activated by several compounds, including the thiazolidinediones. In addition to being a therapeutic target for obesity, hypolipidaemia and diabetes, perturbation of PPARg signalling is now believed to be a strategy for treatment of several cancers, including breast. Although differential expression of PPARg is observed in tumours compared to normal tissues and PPARg agonists have been shown to inhibit tumour cell growth and survival, the interdependence of these observations is unclear. This study demonstrated that the potent, irreversible and selective PPARg antagonist GW9662 prevented activation of PPARg and inhibited growth of human mammary tumour cell lines. Controversially, GW9662 prevented rosiglitazone-mediated PPARg activation, but enhanced rather than reversed rosiglitazone-induced growth inhibition. As such, these data support the existence of PPARg-independent pathways and question the central belief that PPARg ligands mediate their anticancer effects via activation of PPARg.
Matrix metalloproteinase (MMP)-mediated degradation of the extracellular matrix is a major factor for tumor development and expansion. This study analysed MMP-10 protein expression and activity in human lung tumors of various grade, stage, and type to address the relationship between MMP-10 and tumor characteristics and to evaluate MMP-10 as a therapeutic target in non small cell lung carcinoma (NSCLC). Unlike the majority of MMPs, MMP-10 was located in the tumor mass as opposed to tumor stroma. MMP-10 protein was observed at low levels in normal human lung tissues and at significantly higher levels in all types of NSCLC. No correlation was observed between MMP-10 protein expression and tumor type, stage, or lymph node invasion. To discriminate between active and inactive forms of MMP-10 in samples of human NSCLC, we have developed an ex vivo fluorescent assay. Measurable MMP-10 activity was detected in 42 of 50 specimens of lung cancer and only 2 of 10 specimens of histologically normal lung tissue. No relationship was observed between MMP-10 activity levels and clinicopathologic characteristics. Our results suggest that MMP-10 is expressed and active at high levels in human NSCLC compared to normal lung tissues, and, as such, is a potential target for the development of novel therapeutics for lung cancer treatment.
'Expression of matrix metalloproteinase-10 in human bladder transitional cell carcinoma.', Urology., 65 (4).pp. 815-820.Further information on publisher's website:http://dx.doi.org/10. 1016/j.urology.2004.11.016 Publisher's copyright statement: NOTICE: this is the author's version of a work that was accepted for publication in Urology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be re ected in this document. Changes may have been made to this work since it was submitted for publication. A de nitive version was subsequently published in Urology, 65/4, 2005, 10.1016/j.urology.2004.11.016 Additional information:
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Summary. Elevated plasminogen activator inhibitor 1 (PAI-1) levels are associated with venous thromboembolism, although their significance is unclear. PAI-1 levels are influenced by a PAI-1 promoter dimorphism (4G/5G), the 4G allele being associated with increased PAI-1 activity. We investigated whether the 4G allele influenced thrombotic risk by studying 99 symptomatic factor V (FV) Leiden heterozygotes and 99 healthy subjects. The 4G allele was more prevalent among cases than among healthy subjects (x 2 8´00, P 0´005) and the odds ratio (OR) for thrombosis associated with either heterozygosity or homozygosity for the 4G allele was 2´43 (P 0´011). We conclude that carriership of the 4G allele was more prevalent in patients who already carried factor V Leiden than in control subjects without factor V Leiden.
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