Role of inducible nitric oxide synthase expression in aberrant crypt foci-adenoma-carcinoma sequence

To investigate the expression of inducible nitric oxide synthase (iNOS) in aberrant crypt foci (ACF) -adenoma-carcinoma sequence and its relation with tumor cell apoptosis, proliferation and angiogenesis.

The expression of iNOS, proliferating cell nuclear antigen (PCNA) and microvessel density (MVD) in different stages of colorectal cancer were studied by immunohistochemical method from 30 normal tissues, 30 nonhyperplastic ACF, 30 hyperplastic ACF, 30 dysplastic ACF, 30 adenomas and 60 carcinomas. The apoptotic cells were detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method using an Apop Tag in situ detection kit.

The immunoreactivity of iNOS significantly increased in the transition from hyperplastic ACF to dysplastic ACF. This transition was associated with a significant decrease in the apoptotic index (AI) (0.73+/-0.37 vs 0.61+/-0.35, P<0.05) and significant increases in the PCNA labeling index (LI) (27.3+/-2.80 vs 40.3+/-3.11, P<0.01) and microvessel density (MVD) (55+/-11.5 vs 70+/-13.2, P<0.01). The expression of iNOS was in low levels and positively correlated with PCNA-LI (r=0.812, P<0.01) and MVD (r=0.863, P<0.01) during transition from normal mucosa to nonhyperplastic ACF and hyperplastic ACF. The expression of iNOS was in high levels and positively correlated with AI (r=0.901, P<0.01) after transition from hyperplastic ACF to dysplastic ACF, adenoma and carcinoma.

The results suggest that the transition from hyperplastic ACF to dysplastic ACF may be a crucial step in the ACF-adenoma-carcinoma sequence, in which iNOS plays an important role by regulating tumor cell apoptosis, proliferation and angiogenesis.