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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

Effects of initial conditions on LN229 simulations.(A) IGFBP2 concentrations over time. (B) HIF1α concentrations over time. (C) LN229 glioblastoma diameter over time. Low oxygen conditions had the greatest increase in the growth of glioblastoma as compared to control.
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pcbi.1004169.g007: Effects of initial conditions on LN229 simulations.(A) IGFBP2 concentrations over time. (B) HIF1α concentrations over time. (C) LN229 glioblastoma diameter over time. Low oxygen conditions had the greatest increase in the growth of glioblastoma as compared to control.

Mentions: Results of the sensitivity analysis on the initial model conditions showed that HIF1α and IGFBP2 levels in the insulin signaling system were most sensitive to reduced oxygen (2%) and also elevated IGFItotal levels (Fig 7). At higher concentrations of IGFItotal, elevated steady state concentrations of IGFI and IGFBP2 were observed. In hypoxic conditions (2% oxygen), HIF1α and IGFBP2 concentrations were increased initially and reached a steady-state of 7× and 1.25× baseline values, respectively.


Simulation predicts IGFBP2-HIF1α interaction drives glioblastoma growth.

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

Effects of initial conditions on LN229 simulations.(A) IGFBP2 concentrations over time. (B) HIF1α concentrations over time. (C) LN229 glioblastoma diameter over time. Low oxygen conditions had the greatest increase in the growth of glioblastoma as compared to control.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004169.g007: Effects of initial conditions on LN229 simulations.(A) IGFBP2 concentrations over time. (B) HIF1α concentrations over time. (C) LN229 glioblastoma diameter over time. Low oxygen conditions had the greatest increase in the growth of glioblastoma as compared to control.
Mentions: Results of the sensitivity analysis on the initial model conditions showed that HIF1α and IGFBP2 levels in the insulin signaling system were most sensitive to reduced oxygen (2%) and also elevated IGFItotal levels (Fig 7). At higher concentrations of IGFItotal, elevated steady state concentrations of IGFI and IGFBP2 were observed. In hypoxic conditions (2% oxygen), HIF1α and IGFBP2 concentrations were increased initially and reached a steady-state of 7× and 1.25× baseline values, respectively.

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