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Simulation predicts IGFBP2-HIF1α interaction drives glioblastoma growth.

Lin KW, Liao A, Qutub AA - PLoS Comput. Biol. (2015)

Bottom Line: Tremendous strides have been made in improving patients' survival from cancer with one glaring exception: brain cancer.The average overall survival remains less than 1 year.The root cause of this accelerated progression has been hypothesized to involve the insulin signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, Rice University, Houston, Texas, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Insulin signaling in glioma.(A) Microscope image of glioma spheroids grown in vitro. Inset illustrates detailed intracellular insulin signaling. HIF1α = hypoxia-inducible factor 1 α, IGFBP2 = Insulin like growth factor binding protein 2, IGFI = Insulin like growth factor 1, IGFIR = Insulin like growth factor receptor 1, VHL = von Hippel-Lindau complex, PHDs = prolyl hydroxylase domain proteins and Ub = Ubiquitinated. (B) Schematic of the simplified insulin signaling pathway used in the computational model.
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pcbi.1004169.g001: Insulin signaling in glioma.(A) Microscope image of glioma spheroids grown in vitro. Inset illustrates detailed intracellular insulin signaling. HIF1α = hypoxia-inducible factor 1 α, IGFBP2 = Insulin like growth factor binding protein 2, IGFI = Insulin like growth factor 1, IGFIR = Insulin like growth factor receptor 1, VHL = von Hippel-Lindau complex, PHDs = prolyl hydroxylase domain proteins and Ub = Ubiquitinated. (B) Schematic of the simplified insulin signaling pathway used in the computational model.

Mentions: Key molecular players involved in this signaling have been identified (Fig 1), and extensively studied experimentally since the 1980s [13–18]. Insulin-like growth factor 1 (IGFI) and insulin-like growth factor 1 receptor (IGFIR) are an integral part of normal fetal and postnatal growth of the brain [19]. Brain cancer cells use the same pathways to develop into a cancerous phenotype [20]. Activation of IGFIR by IGFI and subsequent downstream signaling leads to malignant cell proliferation, motility and metastasis [21]. Consequently, researchers have targeted IGFIR to suppress glioblastoma growth. IGFIR inhibition has successfully reduced glioblastoma spheroid growth in vitro and in animal models [3, 22].


Simulation predicts IGFBP2-HIF1α interaction drives glioblastoma growth.

Lin KW, Liao A, Qutub AA - PLoS Comput. Biol. (2015)

Insulin signaling in glioma.(A) Microscope image of glioma spheroids grown in vitro. Inset illustrates detailed intracellular insulin signaling. HIF1α = hypoxia-inducible factor 1 α, IGFBP2 = Insulin like growth factor binding protein 2, IGFI = Insulin like growth factor 1, IGFIR = Insulin like growth factor receptor 1, VHL = von Hippel-Lindau complex, PHDs = prolyl hydroxylase domain proteins and Ub = Ubiquitinated. (B) Schematic of the simplified insulin signaling pathway used in the computational model.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401766&req=5

pcbi.1004169.g001: Insulin signaling in glioma.(A) Microscope image of glioma spheroids grown in vitro. Inset illustrates detailed intracellular insulin signaling. HIF1α = hypoxia-inducible factor 1 α, IGFBP2 = Insulin like growth factor binding protein 2, IGFI = Insulin like growth factor 1, IGFIR = Insulin like growth factor receptor 1, VHL = von Hippel-Lindau complex, PHDs = prolyl hydroxylase domain proteins and Ub = Ubiquitinated. (B) Schematic of the simplified insulin signaling pathway used in the computational model.
Mentions: Key molecular players involved in this signaling have been identified (Fig 1), and extensively studied experimentally since the 1980s [13–18]. Insulin-like growth factor 1 (IGFI) and insulin-like growth factor 1 receptor (IGFIR) are an integral part of normal fetal and postnatal growth of the brain [19]. Brain cancer cells use the same pathways to develop into a cancerous phenotype [20]. Activation of IGFIR by IGFI and subsequent downstream signaling leads to malignant cell proliferation, motility and metastasis [21]. Consequently, researchers have targeted IGFIR to suppress glioblastoma growth. IGFIR inhibition has successfully reduced glioblastoma spheroid growth in vitro and in animal models [3, 22].

Bottom Line: Tremendous strides have been made in improving patients' survival from cancer with one glaring exception: brain cancer.The average overall survival remains less than 1 year.The root cause of this accelerated progression has been hypothesized to involve the insulin signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, Rice University, Houston, Texas, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus