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

TL;DR

This study shows that the absence of iNOS enzyme can either prevent or promote lung cancer, depending on the genetic background of the tumor.

Contribution

The study reveals that iNOS deficiency reverses its antitumor effect in Kras-driven lung cancer when Pten is also lost.

Findings

Loss of iNOS did not change the number or type of lung lesions in Kras/Pten-driven models.

iNOS deficiency was linked to shorter survival, increased tumor burden, and more macrophage infiltration.

The antitumor effect of iNOS absence in Kras-driven tumors is reversed when Pten is also lost.

Abstract

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.

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