Metformin Suppresses Tumor Progression by Inactivating Stromal Fibroblasts in Ovarian Cancer

Abstract

Ovarian cancer 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 ovarian cancer. 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 ovarian cancer 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 ovarian cancer 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 ovarian cancer. We found that metformin partly reversed cisplatin-stimulated IL6 secretion in the stromal fibroblasts and attenuated fibroblast-facilitated tumor growth in 3D organotypic cocultures and murine xenograft models. Mechanistically, we found that metformin inhibited IL6 secretion via suppressing NFκB signaling, an upstream controller of stromal inflammation. Collectively, our findings introduced a novel mechanism of metformin in suppressing ovarian cancer 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 ovarian cancer. .

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

“…Another idea is to reprogram CAFs back to a quiescent phenotype by inhibiting activating pathways, e.g., nuclear factor kappa B (NFκb) signaling that is increased in activated fibroblasts. Inhibition of NFκb reversed the typical CAF phenotype and improved response to cisplatin in ovarian cancer xenografts (Xu et al, 2018). The authors also showed that NFκb inhibition strongly reduced the deposition of collagen in the tumor matrix observed after cisplatin treatment.…”

“…CAFs already contribute to chemoresistance by themselves via various mechanisms: PAI-1, a cytokine produced by CAFs, activates Erk/Akt signaling and suppresses caspase-3 activation, which is necessary for tumor apoptosis following chemotherapeutic stress (Che et al, 2018). Similarly, interleukin 6 (IL6) is also produced predominantly by CAFs and induces expression of resistance-mediating CXCR7 in tumor cells (Qiao et al, 2018;Xu et al, 2018). Especially under hypoxic conditions, CAFs produce high levels of TGFβ, which induces stem celllike properties in tumor cells including increased resistance to chemotherapy (Tang et al, 2018).…”

Exosomes promote pre-metastatic niche formation in ovarian cancer

“…Intriguingly, it was recently shown that breast cancer exosomes have enhanced pre-metastatic niche forming ability in the lung after a chemotherapy application [76]. In another study, researchers showed the first-line chemotherapeutic cisplatin to increase IL-6-producing myofibroblastic CAFs in ovarian cancer patients by activating the NFκB signaling pathway [77]. Furthermore, they demonstrated pretreatment with the well-known diabetes drug metformin arrested stromal NFκB/IL6 activation and lessened the chemoresistance response in ovarian cancer cells [77].…”

“…In another study, researchers showed the first-line chemotherapeutic cisplatin to increase IL-6-producing myofibroblastic CAFs in ovarian cancer patients by activating the NFκB signaling pathway [77]. Furthermore, they demonstrated pretreatment with the well-known diabetes drug metformin arrested stromal NFκB/IL6 activation and lessened the chemoresistance response in ovarian cancer cells [77]. Metastatic and drug-resistant, recurrent ovarian cancer produces significantly higher IL-6 compared to matched primary tumors.…”

Abilities of berberine and chemically modified berberines to interact with metformin and inhibit proliferation of pancreatic cancer cells

“…Thus, the association between metformin use and PDAC is controversial (Chaiteerakij et al, 2016). However, it should be emphasized that metformin has been proposed to have effects on cancer stem cells (CSC) and sensitivity to chemotherapy (Hirsch et al, 2009(Hirsch et al, , 2013Iliopoulos et al, 2011;Rattan et al, 2011;Bao et al, 2012Bao et al, , 2014Xu et al, 2018).…”