Abstract 1376: Exercise alters breast cancer phenotype through distinct reductions in host-derived proinflammatory growth factor ligands.

Abstract

Abstract It is becoming increasingly recognized that host (systemic) and tumor cell release of proinflammatory growth factors are critical determinants of cancer progression and therapeutic response in patients with solid tumors. Thus, strategies that can attenuate systemic and/or tumor production of proinflammatory growth factors may offer an effective approach to improve therapeutic outcomes following a cancer diagnosis. The present study tests the central hypothesis that exercise modulates systemic levels of key growth factor ligands that, in turn, inhibit the activity of critical downstream cell signaling pathways to effectively inhibit tumor progression. To address this question, we took advantage of sera collected from a clinical trial examining the efficacy of supervised exercise training, relative to sedentary control, in patients with early or advanced solid tumors. Multiplex ELISA analysis showed that exercising patients (N=23) had significant reductions in circulating concentrations of interleukin (IL)-4, MIP1-β (macrophage inflammatory protein-1β), vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-α), and hepatocyte growth factor (HGF) in comparison with patients randomized to sedentary control (N=21). Exposure of estrogen receptor positive (ER+) and Triple-Negative (ER-/PR-/HER2-) distinct human breast cancer cell lines (MCF-7 and MDA-MB-231) to serum from exercised breast cancer patients led to marked alterations in cellular phenotype as shown by increases in proliferation, migration, and apoptosis, compared with exposure to serum from control patients. In vitro ‘add-back’ experiments using recombinant growth factors in concentrations consistent with that observed in the clinical trial, revealed that HGF produced similar alterations in tumor proliferation and apoptosis as that observed with serum from exercising patients. Co-culturing of human breast cancer cells with exercise serum and a neutralizing antibody against HGF, led to increases in proliferation and decreases in apoptosis in comparison to exercise serum alone. These results suggest that growth factor ligand deprivation may play a critical role in mediating the effects of exercise on tumor cellular phenotype. As such, our findings may provide initial insight into the potential mechanisms underlying recent observations showing higher levels of exercise correlate with more favorable disease outcomes in early breast cancer patients. More generally, this study indicates the widespread potential of exercise to modulate growth factor-driven signaling and by extension, tumor progression and possibly innate or acquired resistance to therapy. Citation Format: Oliver Glass, Brant A. Inman, Kerry S. Courneya, John R. Mackey, Erik Nelson, Zachary Hartman, Lee W. Jones. Exercise alters breast cancer phenotype through distinct reductions in host-derived proinflammatory growth factor ligands. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1376. doi:10.1158/1538-7445.AM2013-1376