Abstract
BackgroundThe insulin-like growth factor (IGF) system impacts cell proliferation and is highly activated in ovarian cancer. While an attractive therapeutic target, the IGF system is complex with two receptors (IGF1R, IGF2R), two ligands (IGF1, IGF2), and at least six high affinity IGF-binding proteins (IGFBPs) that regulate the bioavailability of IGF ligands. We hypothesized that a quantitative balance between these different network components regulated cell response.ResultsOVCAR5, an immortalized ovarian cancer cell line, were found to be sensitive to IGF1, with the dose of IGF1 (i.e., the total mass of IGF1 available) a more reliable predictor of cell response than ligand concentration. The applied dose of IGF1 was depleted by both cell-secreted IGFBPs and endocytic trafficking, with IGFBPs sequestering up to 90% of the available ligand. To explore how different variables (i.e., IGF1, IGFBPs, and IGF1R levels) impacted cell response, a mass-action steady-state model was developed. Examination of the model revealed that the level of IGF1-IGF1R complexes per cell was directly proportional to the extent of proliferation induced by IGF1. Model analysis suggested, and experimental results confirmed, that IGFBPs present during IGF1 treatment significantly decreased IGF1-mediated proliferation. We utilized this model to assess the efficacy of IGF1 and IGF1R antibodies against different network compositions and determined that IGF1R antibodies were more globally effective due to the receptor-limited state of the network.ConclusionsChanges that affect IGF1R occupancy have predictable effects on IGF1-induced proliferation and our model captured these effects. Analysis of this model suggests that IGF1R antibodies will be more effective than IGF1 antibodies, although the difference was minimal in conditions with low levels of IGF1 and IGFBPs. Examining how different components of the IGF system influence cell response will be critical to improve our understanding of the IGF signaling network in ovarian cancer.
Highlights
The insulin-like growth factor (IGF) system impacts cell proliferation and is highly activated in ovarian cancer
Proliferation in response to Insulin-like growth factor 1 (IGF1) was dose, and not concentration, dependent While OVCAR5 cells have previously been reported to proliferate in response to treatment with IGF1 [56], there are no reports describing how these cells respond to varying levels of IGF1 that would allow us to begin addressing the hypothesis that a quantitative balance between receptor, ligand, and binding proteins controls cell response
We determined that cell response to IGF1 treatment can be better predicted in terms of the absolute amount of IGF1 rather than the applied concentration, suggesting that experimental tests with IGF ligands should be described in units of ligand dose per cell rather than standard concentrations
Summary
The insulin-like growth factor (IGF) system impacts cell proliferation and is highly activated in ovarian cancer. While an attractive therapeutic target, the IGF system is complex with two receptors (IGF1R, IGF2R), two ligands (IGF1, IGF2), and at least six high affinity IGF-binding proteins (IGFBPs) that regulate the bioavailability of IGF ligands. IGF2R lacks an intracellular tyrosine kinase domain and only binds IGF2; as a result, it acts as a sink to regulate extracellular concentrations of IGF2 [23]. In addition to these interactions, the majority of IGF ligand circulating in the serum is bound to a family of six binding proteins (IGFBPs) [24,25]. While it is recognized that these different processes (i.e., trafficking, IGFBP sequestration, differential receptor-ligand interactions) can affect cellular behavior, they have not been subjected to systematic study to determine how they impact interpretation and application of experimental findings
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