Abstract 3481: Continuous load bearing exercise inhibits the development of prostate cancer bone metastasis

Abstract

Abstract Background: Prostate cancer (PCa) preferentially metastasizes to bone, causing considerable mortality and morbidity. Exercise is a widely accepted intervention for improving bone health and can benefit overall health in patients with PCa. However, there are no direct studies defining the impact of various exercise regimens on the development of PCa bone metastasis. Hypothesis: Exercise regimens that induce osteogenic responses inhibit the growth of PCa cells in bone. Methods: Human PCa cells (PC3, 1x105 cells per injection) were intracardiacally injected into 8-week-old male BALB/c nude mice which were then subjected to right tibial dynamic mechanical loading (mimicking load bearing exercise, 9N peak force, 40 cycles with 10 second intervals, three times a week) or treadmill exercise (12 meters/minute, 30 minutes/day, 5 days/week) for 3 weeks. Another cohort of mice were firstly subjected to one week of mechanical loading before the inoculation of PC3 cells and then withdrawn from exercise regimen. The growth of skeletal tumours was tracked by bioluminescence for 3 weeks post-injection and bone structure was examined by micro-CT ex vivo. For mechanical loading experiments, comparison was made between loaded and contra-lateral non-loaded tibias, while treadmill exercise group was compared to sedentary controls in the treadmill study. Results: In the continuous mechanical loading group, tumours were detected in non-loaded tibias in all 12 mice (100%), whilst 8 out of 12 mice showed reduced skeletal tumours in the loaded tibias (67%), with 4 having no tumour in the loaded leg (33%). Tumour burden (Flux: photon/second) in the non-loaded tibias was 134% higher than that in the loaded tibias. Micro-CT analysis suggested that loaded tibias had significantly increased trabecular (BV/TV) and cortical bone volume and trabecular thickness (Tb.Th) (p<0.001). Surprisingly, treadmill exercised mice had higher tumour burden (~91%) in the hind limbs compared to the sedentary controls (P<0.05), with no statistically significant improvement in bone mass examined by micro-CT. In the loading withdrawal group, 6 out of 8 mice (75%) showed larger tumour size in the loading withdrawal tibias than in the non-loaded tibias, while only two mice (25%) had smaller or no tumour in the loading withdrawal tibias. Tumor burden were ~90% higher in the loading withdrawal tibias (p<0.05, t-test). This is associated with fast diminishing osteogenic response within a week after ceasing the loading stimulus, confirmed using micro-CT analysis by comparing percentage changes of BV/TV and Tb.Th among baseline, 1-week loading, and loading withdrawn groups. Conclusion: The continuity of high-intensity load bearing exercise is critical to prevent PCa growth in bone, possibly via maintaining the balance of bone remodelling towards osteoblastic bone formation. Mild aerobic exercise evaluated here was unable to significantly improve bone mass or achieve the benefits in inhibiting PCa bone metastases observed with high intensity loading. Citation Format: Ning Wang, Hector M. Arredondo, Alexandria R. Sprules, Colby L. Eaton. Continuous load bearing exercise inhibits the development of prostate cancer bone metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3481.