Reduced IL-6 levels and tumor-associated phospho-STAT3 are associated with reduced tumor development in a mouse model of lung cancer chemoprevention with myo-inositol

Several promising chemopreventive agents have for lung cancer emerged in preclinical models and in retrospective trials. These agents have been shown to modulate pathways altered in carcinogenesisand reduce markers of carcinogenesisin animal and cell culture models. Cancer-prone transgenic mice with oncogenic Kras expressed in the airway epithelium (CcspCre/+; KrasLSL-G12D/+) were raised on diets compounded with myo- inositol. These animals form lung premalignant lesionsin a stereotypical fashion over the ten weeks following weaning. Mice raised on myo- inositolcontaining diets showed potent reduction in the number, size, and stage of lesions as compared to those raised on control diets. myo- inositolhas previously been reported to inhibit phosphoinositide 3-kinase(PI3K) signaling. However, in mice raised on myo- inositol, total PI3K signaling was largely unaffected. Proteomic and cytokine analyses revealed large reduction in IL-6 related pathways, including STAT3 phosphorylation. This effect was not due to direct inhibition of IL-6 production and autocrine signalingwithin the tumor cell, but rather through alteration in macrophage recruitment and in phenotype switching, with an increase in antitumoral M1 macrophages. This article is protected by copyright. All rights reserved.