Analysis of the quantitative balance between insulin-like growth factor (IGF)-1 ligand, receptor, and binding protein levels to predict cell sensitivity and therapeutic efficacy

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.

[1]  D. Accili,et al.  Targeted Gene Mutations Define the Roles of Insulin and IGF-I Receptors in Mouse Embryonic Development , 1999, Journal of pediatric endocrinology & metabolism : JPEM.

[2]  R. Jirtle,et al.  Altered ligand binding by insulin-like growth factor II/mannose 6-phosphate receptors bearing missense mutations in human cancers. , 1999, Cancer research.

[3]  F. Garrouste,et al.  Differential secretory polarity of IGFBP-6 vs. IGFBP-2 and IGFBP-4 in human intestinal epithelial cells: is it a way of modulating IGF-II bioavailability towards the IGF-responsive basolateral surface? , 1995, Progress in growth factor research.

[4]  R. Furlanetto.  Receptor-mediated endocytosis and lysosomal processing of insulin-like growth factor I by mitogenically responsive cells. , 1988, Endocrinology.

[5]  L. Powell-Braxton,et al.  IGF-I is required for normal embryonic growth in mice. , 1993, Genes & development.

[6]  D. Yee,et al.  The therapeutic potential of agents targeting the type I insulin-like growth factor receptor , 2004, Expert opinion on investigational drugs.

[7]  F. Berrino,et al.  Circulating levels of insulin‐like growth factor‐I and risk of ovarian cancer , 2002, International journal of cancer.

[8]  P. Sabbatini,et al.  Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase , 2009, Clinical Cancer Research.

[9]  H. Wiley,et al.  Relationship between epidermal growth factor receptor occupancy and mitogenic response. Quantitative analysis using a steady state model system. , 1984, The Journal of biological chemistry.

[10]  Jamie B. Spangler,et al.  Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling , 2010, Proceedings of the National Academy of Sciences.

[11]  R. Lefkowitz,et al.  β-Arrestins Regulate Mitogenic Signaling and Clathrin-mediated Endocytosis of the Insulin-like Growth Factor I Receptor* , 1998, The Journal of Biological Chemistry.

[12]  J. Baker,et al.  Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r) , 1993, Cell.

[13]  S. Kornfeld,et al.  Mannose 6-phosphate receptors: new twists in the tale , 2003, Nature Reviews Molecular Cell Biology.

[14]  M. Abercrombie,et al.  Observations on the social behaviour of cells in tissue culture. I. Speed of movement of chick heart fibroblasts in relation to their mutual contacts. , 1953, Experimental cell research.

[15]  Laura Sciacca,et al.  Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. , 2009, Endocrine reviews.

[16]  T. Rohan,et al.  Role of the insulin-like growth factor family in cancer development and progression. , 2000, Journal of the National Cancer Institute.

[17]  N. Ling,et al.  Identification and molecular characterization of insulin-like growth factor binding proteins (IGFBP-1, -2, -3, -4, -5 and -6). , 1991, Progress in growth factor research.

[18]  R. Radinsky,et al.  Epitope-Specific Mechanisms of IGF1R Inhibition by Ganitumab , 2013, PloS one.

[19]  D. Lauffenburger,et al.  Receptor‐mediated effects on ligand availability influence relative mitogenic potencies of epidermal growth factor and transforming growth factor α , 1996, Journal of cellular physiology.

[20]  S. Jhanwar,et al.  Tumorigenesis and Neoplastic Progression Tumor-Associated Retinal Astrocytes Promote Retinoblastoma Cell Proliferation Through Production of IGFBP-5 , 2010 .

[21]  C. Kahn,et al.  Insulin and Insulin-like Growth Factor-1 Receptors Act as Ligand-specific Amplitude Modulators of a Common Pathway Regulating Gene Transcription* , 2010, The Journal of Biological Chemistry.

[22]  D. Lauffenburger,et al.  Input–output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data , 2009, Molecular systems biology.

[23]  J. Chang-Claude,et al.  Serum IGF-I, its major binding protein (IGFBP-3) and epithelial ovarian cancer risk: the European Prospective Investigation into Cancer and Nutrition (EPIC). , 2007, Endocrine-related cancer.

[24]  J. Burdette,et al.  Insulin and insulin-like growth factor signaling increases proliferation and hyperplasia of the ovarian surface epithelium and decreases follicular integrity through upregulation of the PI3-kinase pathway , 2013, Journal of Ovarian Research.

[25]  R. Baxter,et al.  Cellular actions of the insulin-like growth factor binding proteins. , 2002, Endocrine reviews.

[26]  D. Clemmons,et al.  Phosphorylation of insulin-like growth factor (IGF)-binding protein 1 in cell culture and in vivo: effects on affinity for IGF-I. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[27]  S. Schmid,et al.  Control of EGF Receptor Signaling by Clathrin-Mediated Endocytosis , 1996, Science.

[28]  D. Leroith,et al.  Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. , 2010, Cancer research.

[29]  V. Hwa,et al.  The Insulin-like Growth Factor-binding Protein (igfbp) Superfamily* , 2022 .

[30]  J. Cerhan,et al.  Expression of insulin-like growth factor I receptor and survival in patients with clear cell renal cell carcinoma. , 2003, The Journal of urology.

[31]  M. Ohtani,et al.  Mechanisms of antibody-mediated insulin-like growth factor I receptor (IGF-IR) down-regulation in MCF-7 breast cancer cells. , 2009, Bioscience trends.

[32]  L. Powell-Braxton,et al.  Inactivation of the IGF‐I Gene in Mice Results in Perinatal Lethality , 1993, Annals of the New York Academy of Sciences.

[33]  S. Mohan,et al.  Evidence that human bone cells in culture produce insulin-like growth factor-binding protein-4 and -5 proteases. , 1994, Endocrinology.

[34]  J. Beattie,et al.  Insulin-like growth factor-binding protein-5 (IGFBP-5): a critical member of the IGF axis. , 2006, The Biochemical journal.

[35]  E. Gilles,et al.  Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors , 2002, Nature Biotechnology.

[36]  Rexxi D. Prasasya,et al.  A multivariate model of ErbB network composition predicts ovarian cancer cell response to canertinib , 2012, Biotechnology and bioengineering.

[37]  S. Monti,et al.  Insulin-like growth factor (IGF)-I, IGF-II and IGF type I receptor (IGFR-I) expression in prostatic cancer. , 2003, Anticancer research.

[38]  W. Ruan,et al.  Printed in U.S.A. Copyright © 1999 by The Endocrine Society Insulin-Like Growth Factor I Is Essential for Terminal End Bud Formation and Ductal Morphogenesis during , 1999 .

[39]  A. McClatchey,et al.  Contact inhibition (of proliferation) redux. , 2012, Current opinion in cell biology.

[40]  H. Klocker,et al.  Insulin‐Like Growth Factor‐Binding Protein‐5 Enters Vesicular Structures but Not the Nucleus , 2007, Traffic.

[41]  A. Ullrich,et al.  Expression of a type I insulin-like growth factor receptor with low affinity for insulin-like growth factor II. , 1992, The Biochemical journal.

[42]  Adrian V. Lee,et al.  Targeting the insulin-like growth factor receptor: developing biomarkers from gene expression profiling. , 2012, Critical reviews in oncogenesis.

[43]  A. Ullrich,et al.  Receptors for insulin and insulin-like growth factor-I can form hybrid dimers. Characterisation of hybrid receptors in transfected cells. , 1990, The Biochemical journal.

[44]  J. McCubrey,et al.  Growth-promoting effects of insulin-like growth factor-1 (IGF-1) on hematopoietic cells: overexpression of introduced IGF-1 receptor abrogates interleukin-3 dependency of murine factor-dependent cells by a ligand-dependent mechanism. , 1991, Blood.

[45]  I. Puzanov,et al.  Phase I dose-escalation study of continuous oral dosing of OSI-906, a dual tyrosine kinase inhibitor of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR), in patients with advanced solid tumors. , 2010 .

[46]  Elizabeth J. Robertson,et al.  Role of insulin-like growth factors in embryonic and postnatal growth , 1993, Cell.

[47]  Xuedong Liu,et al.  Transforming Growth Factor (cid:2) Depletion Is the Primary Determinant of Smad Signaling Kinetics (cid:1) , 2022 .

[48]  Yiling Lu,et al.  Identification of optimal drug combinations targeting cellular networks: integrating phospho-proteomics and computational network analysis. , 2010, Cancer research.

[49]  M. Gleave,et al.  Overexpression of insulin-like growth factor binding protein-5 helps accelerate progression to androgen-independence in the human prostate LNCaP tumor model through activation of phosphatidylinositol 3'-kinase pathway. , 2000, Endocrinology.

[50]  D A Lauffenburger,et al.  Mathematical Model for the Effects of Epidermal Growth Factor Receptor Trafficking Dynamics on Fibroblast Proliferation Responses , 1992, Biotechnology progress.

[51]  K. Siddle,et al.  Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: evidence for a second mechanism of IGF-I signaling. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[52]  C. Roberts,et al.  The insulin-like growth factor system and cancer. , 2003, Cancer letters.

[53]  H. Arnqvist,et al.  Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2. , 2009, Journal of molecular endocrinology.

[54]  T. Wood,et al.  Insulin-like Growth Factor Type-I Receptor Internalization and Recycling Mediate the Sustained Phosphorylation of Akt* , 2007, Journal of Biological Chemistry.

[55]  P. Torng,et al.  Insulin-like growth factor binding protein-3 (IGFBP-3) acts as an invasion-metastasis suppressor in ovarian endometrioid carcinoma , 2008, Oncogene.

[56]  C. Begley,et al.  Drug development: Raise standards for preclinical cancer research , 2012, Nature.

[57]  Daling Zhu,et al.  Local Expression of Insulin-Like Growth Factor-I, Insulin-Like Growth Factor-I Receptor, and Estrogen Receptor Alpha in Ovarian Cancer , 2009, Oncology Research and Treatment.

[58]  L. Paz-Ares,et al.  Safety, Pharmacokinetics, and Pharmacodynamics of the Insulin-Like Growth Factor Type 1 Receptor Inhibitor Figitumumab (CP-751,871) in Combination with Paclitaxel and Carboplatin , 2009, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[59]  M. Abercrombie,et al.  Observations on the social behaviour of cells in tissue culture. II. Monolayering of fibroblasts. , 1954, Experimental cell research.

[60]  B. Groner,et al.  The insulin like growth factor-1 receptor (IGF-1R) as a drug target: novel approaches to cancer therapy. , 2004, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[61]  A. Seifalian,et al.  The role of the insulin-like growth factor system in colorectal cancer: review of current knowledge , 2005, International Journal of Colorectal Disease.

[62]  E. K. Maloney,et al.  An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation. , 2003, Cancer research.

[63]  S. Gammeltoft,et al.  Chromaffin cells express two types of insulin-like growth factor receptors , 1990, Brain Research.

[64]  A. Berchuck,et al.  High insulin-like growth factor-2 (IGF-2) gene expression is an independent predictor of poor survival for patients with advanced stage serous epithelial ovarian cancer. , 2005, Gynecologic oncology.

[65]  G. Cavet,et al.  Molecular predictors of response to a humanized anti–insulin-like growth factor-I receptor monoclonal antibody in breast and colorectal cancer , 2009, Molecular Cancer Therapeutics.

[66]  S. Weroha,et al.  The insulin-like growth factor system in cancer. , 2012, Endocrinology and metabolism clinics of North America.

[67]  D. Coppola,et al.  Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts , 1994, Molecular and cellular biology.

[68]  M. Holzenberger,et al.  Knockout of Insulin-Like Growth Factor-1 Receptor Impairs Distal Lung Morphogenesis , 2012, PloS one.

[69]  David W. Smith,et al.  Modeling the Insulin-Like Growth Factor System in Articular Cartilage , 2013, PloS one.

[70]  L. Powell-Braxton,et al.  Insulin-like growth factor I regulates renal development in rodents. , 1999, Developmental genetics.

[71]  B. Kholodenko,et al.  Quantification of Short Term Signaling by the Epidermal Growth Factor Receptor* , 1999, The Journal of Biological Chemistry.

[72]  M. Pollak,et al.  IGF1/insulin receptor kinase inhibition by BMS-536924 is better tolerated than alloxan-induced hypoinsulinemia and more effective than metformin in the treatment of experimental insulin-responsive breast cancer. , 2011, Endocrine-related cancer.

[73]  V. Duronio,et al.  Insulin-like growth factor I receptor beta-subunit heterogeneity. Evidence for hybrid tetramers composed of insulin-like growth factor I and insulin receptor heterodimers. , 1989, The Journal of biological chemistry.

[74]  D. Katsaros,et al.  IGFBP-3 in epithelial ovarian carcinoma and its association with clinico-pathological features and patient survival. , 2001, European journal of cancer.

[75]  D. Katsaros,et al.  IGF-I in epithelial ovarian cancer and its role in disease progression , 2007, Growth factors.

[76]  J. Kopchick,et al.  Evidence that insulin-like growth factor I and growth hormone are required for prostate gland development. , 1999, Endocrinology.

[77]  J. Bonneterre,et al.  Presence and characterization of insulin-like growth factor 1 receptors in human benign breast disease. , 1988, European journal of cancer & clinical oncology.

[78]  R. Fonseca,et al.  IGF-1R is overexpressed in poor-prognostic subtypes of multiple myeloma , 2006, Leukemia.

[79]  B. Kholodenko,et al.  Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses , 2007, Molecular systems biology.

[80]  F. Peruzzi,et al.  The IGF‐1 receptor in cancer biology , 2003, International journal of cancer.

[81]  K. Siddle.  Signalling by insulin and IGF receptors: supporting acts and new players. , 2011, Journal of molecular endocrinology.

[82]  D. Leroith,et al.  Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology. , 1998, Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology.

[83]  D. Le Roith.  Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. , 1997, The New England journal of medicine.

[84]  L. Walsh,et al.  IGF-1 increases invasive potential of MCF 7 breast cancer cells and induces activation of latent TGF-β1 resulting in epithelial to mesenchymal transition , 2011, Cell Communication and Signaling.

[85]  S. Rosenzweig,et al.  Synthesis and characterization of biotinylated forms of insulin-like growth factor-1: topographical evaluation of the IGF-1/IGFBP-2 AND IGFBP-3 interface. , 2004, Biochemistry.

[86]  J. Kajstura,et al.  The insulin-like growth factor I receptor protects tumor cells from apoptosis in vivo. , 1995, Cancer research.

[87]  D. Yee.  Insulin-like growth factor receptor inhibitors: baby or the bathwater? , 2012, Journal of the National Cancer Institute.

[88]  A. Sorkin,et al.  Endocytosis of receptor tyrosine kinases. , 2013, Cold Spring Harbor perspectives in biology.

[89]  O. Larsson,et al.  Identification of c-Cbl as a new ligase for insulin-like growth factor-I receptor with distinct roles from Mdm2 in receptor ubiquitination and endocytosis. , 2008, Cancer research.

[90]  R. Weindruch,et al.  Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging. , 1997, The New England journal of medicine.

[91]  M. Foti,et al.  Insulin and IGF-1 receptor trafficking and signalling. , 2008, Novartis Foundation symposium.

[92]  R. Radinsky,et al.  AMG 479, a fully human anti–insulin-like growth factor receptor type I monoclonal antibody, inhibits the growth and survival of pancreatic carcinoma cells , 2009, Molecular Cancer Therapeutics Molecular Cancer Therapeutics.

[93]  R. Baxter,et al.  Insulin-like Growth Factor-binding Protein-5 Inhibits the Growth of Human Breast Cancer Cells in Vitro and in Vivo* , 2003, Journal of Biological Chemistry.

[94]  A. Ullrich,et al.  Differential signalling potential of insulin‐ and IGF‐1‐receptor cytoplasmic domains. , 1989, The EMBO journal.

[95]  D. Clemmons,et al.  Insulin-like growth factors and their binding proteins: biological actions. , 1995, Endocrine reviews.