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

Abstract

Regular physical activity reduces the risk of several site-specific cancers in humans and suppresses tumour growth in animal models. The mechanisms through which exercise reduces tumour growth remain incompletely understood, but an intriguing and accumulating body of evidence suggests that the incubation of cancer cells with post-exercise serum can have powerful effects on key hallmarks of cancer cell behaviour in vitro. This suggests that exercise can impact tumour biology through direct changes in circulating proteins, RNA molecules and metabolites. Here, we provide a comprehensive narrative overview of what is known about the effects of exercise-conditioned sera on in vitro cancer cell behaviour. In doing so, we consider the key limitations of the current body of literature, both from the perspective of exercise physiology and cancer biology, and we discuss the potential in vivo physiological relevance of these findings. We propose key opportunities for future research in an area that has the potential to identify key anti-oncogenic protein targets and optimise physical activity recommendations for cancer prevention, treatment and survivorship.

Keywords: Cancer cell apoptosis; Cancer cell growth; Cancer cell proliferation; Cancer prevention; Cancer therapy; Exercise; Exercise-conditioned serum; Physical activity.

Fig. 1

Forest plot showing the pooled effect of serum collected immediately post exercise on cancer cell proliferation. Figure reproduced from Orange et al. (2021), distributed under an open access Creative Common CC BY license

Fig. 2

Acute-exercise-conditioned serum inhibits signalling pathways involved in cell proliferation. Increased proliferation in cancer cells is underpinned by mutations in highly conserved signalling networks that are involved in cell growth and division. Exposure of cancer cells to acute-exercise-conditioned serum has been shown to alter phosphorylation of proteins in these signalling pathways in a way that reduces cell proliferation. For example, exercise-conditioned serum was shown to reduce phosphorylation of Akt, mTOR, p70s6k and Erk 1/2 in human lung cancer cells (22). In addition, post-exercise serum has been suggested to support the Hippo tumour suppressor pathway (which involves activation of MST and LATS1/2) by inhibiting YAP/TAZ in human breast cancer cells (18); although, further studies are required to determine this since similar results were not observed in other cancer cell types (e.g. colon cancer cells (18)). Figure adapted from Kurgen et al. (2017) and reproduced under an open access Creative Common CC BY license

Fig. 3

Summary of the effect of acute-exercise- vs chronic-exercise-conditioned serum on human cancer cell biology. In humans, acute exercise serum (collected 0–24 h post exercise) induces serological changes that suppress cancer cell growth but that do not appear to induce apoptosis in vitro. In comparison, there appears to be no effect of exercise-training-conditioned serum (collected > 24 h post chronic exercise, when the acute effects of the last bout of exercise have subsided) on cancer cell proliferation

Fig. 4

A roadmap of key research opportunities on exercise-conditioned serum and cancer cell behaviour