| Summary: | Previous studies on the significance of vitamin D insufficiency and chronic inflammation in colorectal cancer development clearly indicated that maintenance of cellular homeostasis in the large intestinal epithelium requires balanced interaction of 1,25-(OH)<sub>2</sub>D<sub>3</sub> and prostaglandin cellular signaling networks. The present study addresses the question how colorectal cancer pathogenesis depends on alterations of activities of vitamin D hydroxylases, <em>i.e.</em>, <em>CYP27B1</em>-encoded 25-hydroxyvitamin D-1a-hydroxylase and <em>CYP24A1</em>-encoded 25-hydroxyvitamin D-24-hydroxylase, and inflammation-induced cyclooxygenase-2 (COX-2). Data from 105 cancer patients on <em>CYP27B1</em>, <em>VDR</em>, <em>CYP24A1</em>, and <em>COX-2</em> mRNA expression in relation to tumor grade, anatomical location, gender and age were fit into a multivariate model of exploratory factor analysis. Nearly identical results were obtained by the principal factor and the maximum likelihood method, and these were confirmed by hierarchical cluster analysis: Within the eight mutually dependent variables studied four independent constellations were found that identify different features of colorectal cancer pathogenesis:<em> </em>(i) Escape of COX-2 activity from restraints by the <em>CYP27B1/VDR</em> system can initiate cancer growth anywhere in the colorectum regardless of age and gender; (ii) variations in <em>COX-2</em> expression are mainly responsible for differences in cancer incidence in relation to tumor location; (iii) advancing age has a strong gender-specific influence on cancer incidence; (iv) progression from well differentiated to undifferentiated cancer is solely associated with a rise in <em>CYP24A1</em> expression.
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