Abstract 3374: GM-CSF and MMP9 are key regulators of the effect of adipose progenitor cells over breast cancer onset and metastatic progression in obesity

Abstract

Abstract We recently described a human cell population with progenitor-like phenotype (CD45-CD34+), resident in the white adipose tissue (WAT) and able to promote local and metastatic breast cancer (BC) progression and angiogenesis (Orecchioni et al., 2013). The molecular mechanism involved in this interaction has been so far elusive. An extensive screening of candidate molecules related to angiogenesis, inflammation, motility and invasiveness revealed that two proteins are significantly up-regulated in WAT-derived progenitors following culture with BC cells: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and Matrix metallopeptidase 9 (MMP9). In vivo, both proteins were overexpressed in orthotopic models of human BC co-injected with human WAT progenitors. The inhibition of GM-CSF by a monoclonal antibody in diet-induced, obese BC mice led to a reduced intratumor vascularization and a strong impairment of WAT immunosuppressive microenvironment, targeting mainly myeloid cells such as macrophages and myeloid derived suppressor cells (MDSCs) in peritumoral WAT. Circulating levels of monocytes and of CD4+CD25brightCD127low/neg T-regulatory cells (T-regs) were also reduced in treated mice. Similarly, soluble immunosuppressive factors, such as IL-10 and IL-5, and CD274 (PD-L1) were reduced in tumors and WAT collected from immune competent mice neutralized for GM-CSF, confirming the crucial role of the factor in promoting tumor immune escape. This resulted in a significantly reduced local BC growth and lower metastatic progression in vivo. All these findings challenge the clinical use of GM-CSF. In the same syngeneic model, MMP9 inhibition reduced neoplastic angiogenesis and significantly decreased local and metastatic tumor growth, without altering immune cells composition in tumor microenvironment. The combined inhibition of GM-CSF and MMP9 was synergic in impairing angiogenesis, local and metastatic BC growth in diet-induced obese orthotopic BC models, indicating a potential complementary role in tumor spread. As we recently reported that Metformin targets both BC cells and the neoplastic WAT environment (Orecchioni et al., 2015), we investigated Metformin effect over GM-CSF and MMP9 expression. Metformin inhibited GM-CSF and MMP9 up-release from WAT progenitors in vitro. Circulating GM-CSF was significantly impaired in BC xenografts administered with Metformin and MMP9 expression was also affected by the treatment. Collectively these results indicate GM-CSF and MMP9 as key candidates involved in the pro-tumorigenic effect of WAT progenitors on BC in a setting of obesity. The comparison between Metformin and GM-CSF/MMP9 specific inhibition is currently under investigation. Citation Format: Francesca Reggiani, Valentina Labanca, Giovanna Talarico, Stefania Orecchioni, Patrizia Mancuso, Francesco Bertolini. GM-CSF and MMP9 are key regulators of the effect of adipose progenitor cells over breast cancer onset and metastatic progression in obesity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3374.