Loss of inducible nitric oxide synthase promotes Kras/Pten-driven lung tumorigenesis.

The inducible Nitric Oxide Synthase (iNOS) enzyme has been implicated in both pro- and anti-tumorigenic processes, depending on the cancer context. In oncogenic Kras-driven mouse models of lung adenocarcinoma, the loss of iNOS reduces tumorigenesis. To explore the additional loss of the tumor suppressor Pten in this setting, we compared lung tumorigenesis in mice induced by activation of oncogenic Kras in conjunction with inactivation of Pten in the absence and presence of iNOS. We report that the loss of iNOS did not affect the number or type of lung lesions compared to control iNOS wild-type mice, but was associated with shortened overall survival that was accompanired by increased tumor burden and intratumoral macrophage infiltration. These findings suggest that the antineoplastic effect of iNOS deficiency in Kras-driven lung tumorigenesis is reversed upon the loss of Pten. Thus, even within the identical cancer model, the loss of iNOS can have opposite effects depending on the genetic context.