Impact of inducible nitric oxide synthase gene on tumor progression.

We investigated the involvement of the inducible nitric oxide synthase (iNOS) gene in tumor promotion and progression. In the first study, 1 week after subcutaneous injection of benzo(a)pyrene into iNOS-deficient (iNOS) and wild-type (iNOS) mice, a foreign body (plastic plate) was subcutaneously inserted into the carcinogen injection site to evoke chronic inflammation. In the second study, primarily cultured tumor cells (PCTc) with different iNOS gene status were prepared from tumors induced in the first study, and they were implanted into the subcutaneous space of iNOS and iNOS mice, making four different combinations of iNOS gene status. Although the mice that were subjected to plastic plate-induced inflammation [p-IN(+)] exhibited significantly shorter tumor latency than those with p-IN(-), iNOS gene status did not affect it in the p-IN(-) or p-IN(+) groups. The rate of microscopic invasion and expression levels of matrix metalloproteinase mRNA were, however, higher in iNOSp-IN(+) than iNOSp-IN(+) mice. In the second study, microscopic invasion was also observed in the subcutaneously implanted tumors only in the case of PCTc with iNOS gene into iNOS mice, although iNOS gene status in PCTc or host mice did not affect the tumor growth curve. These data suggest that the iNOS gene was associated with tumor progression, rather than tumorigenesis, in this experimental model. The iNOS gene in both the stromal and cancer cells played an important role in invasion. Inhibition of iNOS gene activity might be useful for local cancer control in inflammation-associated cancers.