Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer

Abstract

The purpose of this study is to investigate the effects of exercise on cancer progression, metastasis, and underlying mechanisms in an orthotopic model of murine prostate cancer. C57BL/6 male mice (6-8 wk of age) were orthotopically injected with transgenic adenocarcinoma of mouse prostate C-1 cells (5 × 10(5)) and randomly assigned to exercise (n = 28) or a non-intervention control (n = 31) groups. The exercise group was given voluntary access to a wheel 24 h/day for the duration of the study. Four mice per group were serially killed on days 14, 31, and 36; the remaining 38 mice (exercise, n = 18; control, n = 20) were killed on day 53. Before death, MRI was performed to assess tumor blood perfusion. Primary tumor growth rate was comparable between groups, but expression of prometastatic genes was significantly modulated in exercising animals with a shift toward reduced metastasis. Exercise was associated with increased activity of protein kinases within the MEK/MAPK and PI3K/mTOR signaling cascades with subsequent increased intratumoral protein levels of HIF-1α and VEGF. This was associated with improved tumor vascularization. Multiplex ELISAs revealed distinct reductions in plasma concentrations of several angiogenic cytokines in the exercise group, which was associated with increased expression of angiogenic and metabolic genes in the skeletal muscle. Exercise-induced stabilization of HIF-1α and subsequent upregulation of VEGF was associated with "productive" tumor vascularization with a shift toward suppressed metastasis in an orthotopic model of prostate cancer.

Effects and potential mechanisms of exercise training on cancer progression: A translational perspective

“…Results indicated that primary tumor growth rate was comparable between groups but expression of prometastatic genes was significantly modulated in exercising animals with a shift towards reduced metastasis (Jones et al, in press-a,2012a). Paradoxically, exercise was associated with significant increases in tumor vascularization, as measured by magnetic resonance blood perfusion imaging, while multiplex ELISAs revealed distinct reductions in plasma concentrations of interleukin-6 and CXCL1 in the exercise group.…”

Modulation of the tumor vasculature and oxygenation to improve therapy

“…Since rodent skin and immediate subcutaneous tissue has a very low blood flow (Armstrong & Laughlin, 1985), it is possible that subcutaneously transplanted tumors may actually become hypoxic during exercise. However, studies in which tumors were grown at the site of origin (orthotopic implantation) have reported that low intensity exercise does not affect tumor growth (Jones et al, 2012) and reduces the incidence of metastasis (Cohen et al, 1992). These latter findings are consistent recent observations which showed no evidence of increased metastasis or enhanced primary tumor growth in exercised animals bearing orthotopically implanted prostate tumors (McCullough et al, 2013).…”

Efficacy and Mechanisms of Aerobic Exercise on Cancer Initiation, Progression, and Metastasis: A Critical Systematic Review ofIn VivoPreclinical Data

“…After secondary screening, 53 papers were deemed eligible and underwent full review (Figure S1). Classification of papers was as follows: (1) incidence (n=24; 45.3%) (23–46), growth (n=33; 62.3%) (24, 26, 34, 37, 39, 40, 42, 44–69), and metastasis (n=10; 18.9%) (53, 55, 63, 64, 70–75). …”

“…Details of the exercise prescriptions are summarized in Tables 1, 2 and 3. The most common modalities included voluntary running (n=22; 41.5%) (24–28, 31, 33, 35, 42, 43, 51, 52, 55, 57, 64–66, 70, 71, 73–75) forced running (n=25; 47.2%) (26, 29, 36–41, 44–46, 48, 49, 54, 56, 58–60, 63, 67–70, 72, 74) and swimming (n=10; 18.9%) (23, 30, 32, 34, 47, 50, 53, 54, 61, 62). …”