Abstract

Ovarian cancer (OC) is a devastating disease due to its high incidence of relapse and chemoresistance. The tumor microenvironment, especially the tumor stroma compartment, was proven to contribute tremendously to the unsatisfactory chemotherapeutic efficacy in OC. Cytotoxic agents not only effect tumor cells, but also modulate the phenotype and characteristics of the vast stromal cell population, which can in turn alter the tumor cell response to chemointervention. In this study, we focused on the tumor stroma response to cytotoxic agents and the subsequent effect on the OC tumor cells. First, we found a significant stromal overexpression of IL6 in patient samples that received cisplatin-based treatment, which was further validated in purified fibroblasts challenged with cisplatin. Stromal fibroblast derived IL6 was proven to mediate OC tumor cell chemoresistance. For the first time we found that the tumor stroma of patients with routine metformin administration exhibited lower IL6 expression. Thus, we presumed that metformin was a potent alleviator of stromal inflammation in OC. We found that metformin partly reversed cisplatin-stimulated IL6 secretion in the stromal fibroblasts and attenuated fibroblast-facilitated tumor growth in 3D organotypic co-cultures and murine xenograft models. Mechanistically, we found that metformin inhibited IL6 secretion via suppressing NF-κB signaling, an upstream controller of stromal inflammation. Collectively, our findings introduced a novel mechanism of metformin in suppressing OC progression through diminishing chemotherapy-induced stromal activation. Therefore, we provide an alternative therapeutic option in targeting stromal inflammation and a potential scheme of combination therapy to improve the chemosensitivity in OC. 

Authors

Xu S, Yang ZY, Jin P, Yang X, Li X, Wei X, Wang Y, Long S, Zhang T, Chen G, Sun C, Ma D, Gao Q

Source

Mol. Cancer Ther. 2018 Mar 15.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29545331

Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation. 

Abstract

Metformin, a hypoglycemic drug used for treatment of type 2 diabetes, regulates also inflammatory pathways. By using several models of intestinal inflammation, we examined whether metformin exerts anti-inflammatory effects and investigated the basic mechanism by which metformin blocks pathologic signals. Colitic mice given metformin exhibited less colonic inflammation and increased expression of active AMP-activated protein kinase, a mediator of the metabolic effects of metformin, in both epithelial and lamina propria compartments. Pharmacological inhibition of AMP-activated protein kinase reduced but did not prevent metformin-induced therapeutic effect as well as treatment of colitic mice with a pharmacological activator of AMP-activated protein kinase attenuated but did not resolve colitis. These data suggest that the anti-inflammatory effect of metformin relies on the control of additional pathways other than AMP-activated protein kinase. Indeed, metformin down-regulated p38 MAP kinase activation in colitic mice through an AMP-activated protein kinase-independent mechanism. Expression of active form of AMP-activated protein kinase was reduced in inflammatory bowel disease patients and treatment of mucosal cells of such patients with metformin enhanced AMP-activated protein kinase activation and reduced p38 MAP kinase activation, thereby inhibiting interleukin-6 expression.

Our findings indicate that metformin is a good candidate for inhibiting pathological inflammation in the gut. 

Authors

Di Fusco D, Dinallo V, Monteleone I, Laudisi F, Marafini I, Franzè E, Di Grazia A, Dwairi R, Colantoni A, Ortenzi A, Stolfi C, Monteleone G

Source

Clin. Sci. 2018 Mar 14.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29540537