ABERRANT EXPRESSION OF NITRIC-OXIDE SYNTHASE IN HUMAN POLYPS, NEOPLASTIC COLONIC MUCOSA AND SURROUNDING PERITUMORAL NORMAL MUCOSA

The expression of nitric oxide synthase (NOS) was studied by NAD(P)H d iaphorase histochemical localization method in (i) individual cells of the normal colonic mucosa (n = 13) which served as control, (ii) colo nic polyps (n = 14), (iii) colonic carcinoma (n = 20) and (iv) peritum oral mucosa (2 and 5 or 10 cm away from the tumor). Four of the tumor specimens had normal epithelium adjacent to the cancer, which thus ser ved as an internal control. The expression of NOS activity in colon ca ncer was significantly reduced as compared to the control group of ind ividuals (P < 0.004); undetectable in 25%, diminished in 45%, normal i n 30%. On comparing the expression in normal mucosa and polyps there w as a significant reduction of the expression in polyps (P < 0.027); un detectable in 14%, reduced in 35%, normal in 51%. When compared to the peritumoral mucosa at 2 and 10 cm the tumor showed a significant redu ction in expression of NOS activity (P < 0.001 and P < 0.0001 respecti vely). There was no significant difference seen in the expression at 2 and 10 cm (P = 0.329). The peritumoral mucosa at a distance of 2 cm a way from the tumor when compared to the control mucosa showed no signi ficant difference (P = 1.000), although there is a tendency to a high normal expression of NOS activity in the mucosa at a distance of 2 cm. Similarly, there was no significant difference between the control mu cosa and the peritumoral mucosa obtained at a distance of 10 cm (P = 0 .383). The expression of NOS activity in all tissues examined was abol ished by preincubation of tissue with the selective NOS inhibitor L-NM MA but not with D-NMMA. Our data showed extensive and significant redu ction as identified by the NAD(P)H diaphorase method in the expression of NOS activity, thereby reflecting the activity of nitric oxide in c olon cancer and colonic polyps. The generalized suppression of this ac tivity, which precedes the onset of overt neoplasia, may be an importa nt event in colon carcinogenesis. This aberrant expression could also be compatible with the selective advantage to either tumor promotion a nd metastatic progression or to tumoricidal activity.