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(American Journal of Pathology. 2003;162:793-801.)
© 2003 American Society for Investigative Pathology

Inducible Nitric Oxide Synthase Expression in Human Colorectal Cancer

Correlation with Tumor Angiogenesis

Fabio Cianchi^*, Camillo Cortesini^*, Ornella Fantappiè, Luca Messerini, Nicola Schiavone, Alfredo Vannacci^¶, Silvia Nistri^||, Iacopo Sardi^**, Gianna Baroni, Cosimo Marzocca^¶, Federico Perna^*, Roberto Mazzanti, Paolo Bechi^* and Emanuela Masini^¶

From the Departments of General Surgery,^* Internal Medicine, Human Pathology and Oncology, Experimental Pathology and Oncology, Preclinical and Clinical Pharmacology,^¶ Anatomy, Histology, and Forensic Medicine,|| and Pediatrics (Onco-Hematology Unit),^** Medical School, University of Florence, Florence, Italy

To investigate the potential involvement of the nitric oxide (NO) pathway in colorectal carcinogenesis, we correlated the expression and the activity of inducible nitric oxide synthase (iNOS) with the degree of tumor angiogenesis in human colorectal cancer. Tumor samples and adjacent normal mucosa were obtained from 46 surgical specimens. Immunohistochemical expression of iNOS, vascular endothelial growth factor (VEGF), and CD31 was analyzed on paraffin-embedded tissue sections. iNOS activity and cyclic GMP levels were assessed by specific biochemical assays. iNOS protein expression was determined by Western blot analysis. iNOS and VEGF mRNA levels were evaluated using Northern blot analysis. Both iNOS and VEGF expressions correlated significantly with intratumor microvessel density (r_s = 0.31, P = 0.02 and r_s = 0.67, P < 0.0001, respectively). A significant correlation was also found between iNOS and VEGF expression (P = 0.001). iNOS activity and cyclic GMP production were significantly higher in the cancer specimens than in the normal mucosa (P < 0.0001 and P < 0.0001, respectively), as well as in metastatic tumors than in nonmetastatic ones (P = 0.002 and P = 0.04, respectively). Western and Northern blot analyses confirmed the up-regulation of the iNOS protein and gene in the tumor specimens as compared with normal mucosa. NO seems to play a role in colorectal cancer growth by promoting tumor angiogenesis.

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