Targeting quiescent tumor cells via oxygen and IGF-1 supplementation
Menée in vitro sur un modèle tridimensionnel et à l'aide de xénogreffes, cette étude suggère qu'une supplémentation en IGF-1 permet d'augmenter la réponse des tumeurs à une chimiothérapie cytotoxique
Conventional chemotherapy targets proliferating cancer cells, but most cells in solid tumors are not in a proliferative state. Thus, strategies to enable conventional chemotherapy to target non-cycling cells may greatly increase tumor responsiveness. In this study, we employed a 3D tissue culture system to assay diffusible factors that can limit proliferation in the context of the tumor microenvironment, with the goal of identifying targets to heighten proliferative capacity in this setting. We found that supra-physiological levels of insulin or IGF-1 in combination with oxygen supplementation was sufficient to initiate proliferation of quiescence cells in this system. At maximal induction with IGF-1, net tissue proliferation increased 3- to 4-fold in the system such that chemotherapy treatment could trigger a 3- to 6-fold increase in cytotoxicity, compared to control conditions. These effects were confirmed in vivo in colon cancer xenograft models with demonstrations that IGF-1 receptor stimulation was sufficient to generate a 45% increase in tumor cell proliferation, along with a 25-50% increase in chemotherapy-induced tumor growth delay. While oxygen was a dominant factor limiting in vitro tumor cell proliferation, we found that oxygen supplementation via pure oxygen breathing at 1 or 2 atmospheres pressure (mimicking hyperbaric therapy) did not decrease hypoxia in the tumor xenograft mouse model and was insufficient to increase tumor proliferation. Thus, our findings pointed to IGF-1 receptor stimulation as a rational strategy to successfully increase tumor responsiveness to cytotoxic chemotherapy.