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
Few studies have investigated the effects of exercise on modulation of host factors in cancer patients. We investigated the efficacy of chronic aerobic training on multiple host-related effector pathways in patients with solid tumours. Paired peripheral blood samples were obtained from 44 patients with solid tumours receiving cytotoxic therapy and synthetic erythropoietin (usual care; n=21) or usual care plus supervised aerobic training (n=23) for 12 weeks. Samples were characterised for changes in immune, cytokine and angiogenic factors, and metabolic intermediates. Aerobic training consisted of three supervised cycle ergometry sessions per week at 60% to 100% of peak oxygen consumption (VO2peak), 30–45 min per session, for 12 weeks following a nonlinear prescription. The between-group delta change in cardiopulmonary function was +4.1 ml kg −1 min−1, favouring aerobic training (P<0.05). Significant pre–post between-group differences for five cytokine and angiogenic factors (HGF, IL-4, macrophage inflammatory protein-1β (MIP-1β), vascular endothelial growth factor (VEGF), and TNF-α) also favour the aerobic training group (P's<0.05). These reductions occurred in conjunction with nonsignificant group differences for T lymphocytes CD4+, CD8+, and CD8+/CD45RA (P<0.10). For these factors, circulating concentrations generally increased from baseline to week 12 in the aerobic training group compared with decreases or no change in the usual care group. No significant changes in any metabolic intermediates were observed. Aerobic training alters host availability of select immune–inflammatory effectors in patients with solid tumours; larger confirmatory studies in more homogenous samples are warranted.
Purpose: Novel combinations of heat with chemotherapeutic agents are often studied in murine tumour models. Currently, no device exists to selectively heat small tumours at depth in mice. In this project we modelled, built and tested a miniature microwave heat applicator, the physical dimensions of which can be scaled to adjust the volume and depth of heating to focus on the tumour volume. Of particular interest is a device that can selectively heat murine bladder.Materials and methods: Using Avizo® segmentation software, we created a numerical mouse model based on micro-MRI scan data. The model was imported into HFSS™ (Ansys) simulation software and parametric studies were performed to optimise the dimensions of a water-loaded circular waveguide for selective power deposition inside a 0.15 mL bladder. A working prototype was constructed operating at 2.45 GHz. Heating performance was characterised by mapping fibre-optic temperature sensors along catheters inserted at depths of 0–1 mm (subcutaneous), 2–3 mm (vaginal), and 4–5 mm (rectal) below the abdominal wall, with the mid depth catheter adjacent to the bladder. Core temperature was monitored orally.Results: Thermal measurements confirm the simulations which demonstrate that this applicator can provide local heating at depth in small animals. Measured temperatures in murine pelvis show well-localised bladder heating to 42–43°C while maintaining normothermic skin and core temperatures.Conclusions: Simulation techniques facilitate the design optimisation of microwave antennas for use in pre-clinical applications such as localised tumour heating in small animals. Laboratory measurements demonstrate the effectiveness of a new miniature water-coupled microwave applicator for localised heating of murine bladder.
Purpose: This paper aims to evaluate the safety and heating efficiency of external deep pelvic hyperthermia combined with intravesical mitomycin C (MMC) as a novel therapy for non-muscle-invasive bladder cancer (NMIBC). Materials and methods: We enrolled subjects with bacillus Calmette-Guérin (BCG) refractory NMIBC to an early phase clinical trial of external deep pelvic hyperthermia (using a BSD-2000 device) combined with MMC. Bladders were heated to 42 °C for 1 h during intravesical MMC treatment. Treatments were given weekly for 6 weeks, then monthly for 4 months. Heating parameters, treatment toxicity, and clinical outcomes were systematically measured. Results: Fifteen patients were enrolled on the clinical trial. Median age was 66 years and 87% were male. Median European Organisation for Research and Treatment of Cancer (EORTC) recurrence and progression scores were 6 and 8, respectively. The full treatment course was attained in 73% of subjects. Effective bladder heating was possible in all but one patient who could not tolerate the supine position due to lung disease. Adverse events were all minor (grade 2 or less) and no systemic toxicity was observed. The most common adverse effects were Foley catheter pain (40%), abdominal discomfort (33%), chemical cystitis symptoms (27%), and abdominal skin swelling (27%). With a median follow-up of 3.18 years, 67% experienced another bladder cancer recurrence (none were muscle invasive) and 13% experienced an upper tract recurrence. Conclusions: External deep pelvic hyperthermia using the BSD-2000 device is a safe and reproducible method of heating the bladder in patients undergoing intravesical MMC. The efficacy of this treatment modality should be explored further in clinical trials.
