Targeting Quiescent Tumor Cells via Oxygen and IGF-I Supplementation

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.

Tissue Penetration and Activity of Camptothecins in Solid Tumor Xenografts

“…Cells were cultured in MEM (HyClone) with 10% FBS (Gibco/BRL) under 5% O 2 and 5% CO 2 . Three-dimensional tissue disks were grown by seeding 10 6 cells into collagen-coated tissue culture inserts (CM 12 mm, pore size 0.4 mm; Millipore) and incubated for 16 hours to allow cells to attach to the porous membrane before being submerged in media and transferred to stirred growth vessels (32).…”

“…HT29 tumor xenografts have been characterized as having a more mature vascular phenotype as compared with the HCT116 model in terms of collagen and smooth muscle actin association with blood vessels (28). The two tumor types have been previously used to model drug penetration and were selected as they exhibited clearly demarcated regions under the influence of individual vessels and hence allowed for clearer interpretation of the interplay between microregional drug delivery and activity (29)(30)(31)(32). In addition to the tumor-based studies, an in vitro 3D tissue disk assay was used.…”

Spatial–temporal FUCCI imaging of each cell in a tumor demonstrates locational dependence of cell cycle dynamics and chemoresponsiveness

“…In a tumor, a cancer cell's position in the cell cycle may be affected by access to nutrients and oxygen and other factors such as cell density and proximity to particular stromal elements. [2][3][4] However, the cell cycle status of individual cells in real time in a solid tumor is not well understood. [5][6][7][8] Sakaue-Sawano et al have reported that the cell cycle phase in viable cells can be visualized using the fluorescent ubiquitination-based cell cycle indicator (FUCCI) system.…”

Amyloid Precursor Protein (APP) Affects Global Protein Synthesis in Dividing Human Cells

“…A hypoxic tumor microenvironment is traditionally considered to be resistant to radio/chemotherapy because cancer cells deprived of oxygen and nutrients are quiescent compared to well‐oxygenated tumor tissue (Kyle et al, 2012). In previous studies, we targeted hypoxic tumor tissue in experimental, orthotopic NSCLC models using γ‐secretase inhibitors in order to inhibit Notch‐1 signaling (Chen et al, 2007; Eliasz et al, 2010; Liang et al, 2012).…”