title: Simulation predicts IGFBP2-HIF1α interaction drives glioblastoma growth.
abstract: Tremendous strides have been made in improving patients' survival from cancer with one glaring exception: brain cancer. Glioblastoma is the most common, aggressive and highly malignant type of primary brain tumor. The average overall survival remains less than 1 year. Notably, cancer patients with obesity and diabetes have worse outcomes and accelerated progression of glioblastoma. The root cause of this accelerated progression has been hypothesized to involve the insulin signaling pathway. However, while the process of invasive glioblastoma progression has been extensively studied macroscopically, it has not yet been well characterized with regards to intracellular insulin signaling. In this study we connect for the first time microscale insulin signaling activity with macroscale glioblastoma growth through the use of computational modeling. Results of the model suggest a novel observation: feedback from IGFBP2 to HIF1α is integral to the sustained growth of glioblastoma. Our study suggests that downstream signaling from IGFI to HIF1α, which has been the target of many insulin signaling drugs in clinical trials, plays a smaller role in overall tumor growth. These predictions strongly suggest redirecting the focus of glioma drug candidates on controlling the feedback between IGFBP2 and HIF1α.
authors.affiliation: Department of Bioengineering, Rice University, Houston, Texas, United States of America.
authors.forename: Ka Wai
authors.initials: KW
authors.lastname: Lin
authors.affiliation: Department of Bioengineering, Rice University, Houston, Texas, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Liao
authors.affiliation: Department of Bioengineering, Rice University, Houston, Texas, United States of America.
authors.forename: Amina A
authors.initials: AA
authors.lastname: Qutub
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D003198:Computer Simulation; D025461:Feedback, Physiological; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000378:metabolism*; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism*; D008875:Middle Aged; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D015398:Signal Transduction; D055815:Young Adult
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D018971:Insulin-Like Growth Factor Binding Protein 2; D010100:Oxygen