Abstract
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 noncycling cells may greatly increase tumor responsiveness. In this study, we used a 3-dimensional 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 supraphysiologic levels of insulin or insulin-like growth factor I (IGF-I) in combination with oxygen supplementation were sufficient to initiate proliferation of quiescence cells in this system. At maximal induction with IGF-I, net tissue proliferation increased 3- to 4-fold in the system such that chemotherapy could trigger a 3- to 6-fold increase in cytotoxicity, compared with control conditions. These effects were confirmed in vivo in colon cancer xenograft models with demonstrations that IGF-I receptor stimulation was sufficient to generate a 45% increase in tumor cell proliferation, along with a 25% to 50% increase in chemotherapy-induced tumor growth delay. Although 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-I receptor stimulation as a rational strategy to successfully increase tumor responsiveness to cytotoxic chemotherapy.
Highlights
The microenvironment of solid tumors has long been identified as a source of resistance to chemotherapy and radiotherapy
This study shows that insulin-like growth factor I (IGF-I) receptor stimulation could be successfully used to increase response to chemotherapy, though the presence of hypoxic cells within the tumors likely remains a significant barrier to full resensitization of the tissue
A key to the success shown here seemed to be the determination of the appropriate conditions from studies using the engineered 3D tissue model which replicated the gradients in diffusible factors leading to tumor-derived quiescence [13, 16, 26, 34, 35]
Summary
The microenvironment of solid tumors has long been identified as a source of resistance to chemotherapy and radiotherapy. Sustained expansion of the tumor cell population and aberrant neovascularization leads to the creation of an environment that differs from normal tissues. Tumor cells can be located up to 15 to 20 cells away from the nearest blood vessel (more in some cases), whereas in most normal tissues cells are within just a few cell layers of a vessel [12]. The diffusion gradient of molecules supplied by the blood creates subpopulations of cells within the tumor that will differ in proliferation status and response to chemotherapy. This phenomenon is well illustrated in corded HCT116 xenografts, Authors' Affiliation: BC Cancer Research Centre, Department of Integrative Oncology, Vancouver, British Columbia, Canada
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