The serological responses to acute exercise in humans reduce cancer cell growth in vitro: A systematic review and meta‐analysis

Abstract

We systematically reviewed and meta‐analyzed the effects of acute exercise‐conditioned serum on cancer cell growth in vitro. Five literature databases were systematically searched for studies that measured cancer cell growth after exposure to human sera obtained before and immediately after an acute bout of exercise. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using a three‐level random‐effects model. Meta‐regressions were also performed with participant age and disease status, exercise type, cell line TP53 status, and serum incubation time entered as covariates. Seven studies met the inclusion criteria encompassing a total of 21 effect estimates and 98 participants. Exercise‐conditioned serum significantly reduced cancer cell growth compared with preexercise serum (SMD = −1.23, 95% CI: −1.96 to −0.50; p = .002; I2 = 75.1%). The weighted mean reduction as a percentage of preexercise values was 8.6%. The overall treatment effect and magnitude of heterogeneity were not statistically influenced by any covariate. There were concerns regarding the risk of bias within individual studies and Egger's test of the intercept showed evidence of small study effects (β = −3.6, p = .004). These findings provide in vitro evidence that the transient serological responses to acute exercises reduce cancer cell growth, although many questions remain regarding the underlying mechanistic pathways and potential effect modifiers. To strengthen this evidence‐base, future studies should seek to reduce the risk of bias by using more rigorous experimental designs, and consider using 3D cell culture models to better replicate in vivo tumor conditions. PROSPERO registration: CRD42020161333.

Anti-carcinogenic effects of exercise-conditioned human serum: evidence, relevance and opportunities

“…This finding has since been replicated using LNCaP cells and sera derived from a comparable population (young healthy men) (Baldelli et al 2020), and it has also demonstrated in human breast cancer cell lines using sera derived from young healthy women and women with breast cancer (Baldelli et al 2020;Dethlefsen et al 2016Dethlefsen et al , 2017a, human colon cancer cell lines using sera derived from colon cancer survivors (Devin et al 2019), and human lung cancer cells using sera derived from healthy men (Kurgan et al 2017). Indeed, Orange et al (2020) recently summarised studies that had examined the effect of serum collected immediately post-exercise on in vitro cancer cell viability and, in a meta-analysis, reported an 8.6% decrease in cell viability compared with serum collected pre-exercise (Fig. 1).…”

“…This is perhaps unsurprising given the diverse range of populations, cancer cell lines, and exercise characteristics that have been included across different independent studies, all of which could be hypothesised to alter the presence and/or magnitude of the effect of exerciseconditioned serum on growth/viability. Interestingly, in the meta-analysis by Orange et al (2020), covarying for different cancer types (breast vs other), disease status (healthy vs cancer survivor), or exercise mode (continuous vs interval training) did not alter the effect magnitude or heterogeneity. However, these findings should be treated with some caution given the small number of studies included and the fact that this analysis was largely based on comparisons of effect sizes between independent studies (i.e.…”

“…However, an intriguing and accumulating body of evidence also suggests that incubation of cancer cells with exerciseconditioned serum (i.e. no immune cells) can also have powerful effects on key hallmarks of cancer cell behaviour (Orange et al 2020). This suggests that exercise can have an impact on tumour biology through direct changes in the circulating transcriptome/metabolome/proteome and opens up a new and exciting area of research, with the potential to isolate key anti-oncogenic serological targets and to enhance our ability to develop optimal physical activity recommendations for cancer prevention, treatment and survivorship.…”

“…It should also be noted that there is a high level of variability in the reported effects of acute-exercise-conditioned serum on in vitro cancer cell viability in studies conducted to date (Orange et al 2020). This is perhaps unsurprising given the diverse range of populations, cancer cell lines, and exercise characteristics that have been included across different independent studies, all of which could be hypothesised to alter the presence and/or magnitude of the effect of exerciseconditioned serum on growth/viability.…”

“…However, there is also accumulating evidence that exercise and physical activity can promote physiological changes that directly alter tumour growth and behaviour (Christensen et al 2018). This includes improvements in immune function and immune surveillance (Idorn and Hojman, 2016), but emerging evidence also suggests that other serological changes elicited by exercise can also be anti-carcinogenic, as evidenced by alterations in in vitro cancer cell growth and behaviour following incubation with post-exercise serum (Hojman et al 2011;Orange et al 2020). These findings suggest that physical activity/exercise can promote the release of metabolites, proteins or RNA species with anti-tumorigenic properties.…”