Journal article
IGFBP6 controls the expansion of chemoresistant glioblastoma through paracrine IGF2/IGF-1R signaling
Cell communication and signaling, Vol.16(1), pp.61-61
09/19/2018
DOI: 10.1186/s12964-018-0273-7
PMCID: PMC6148802
PMID: 30231881
Abstract
Background
Glioblastomas (GBMs), the most common and most lethal of the primary brain tumors, are characterized by marked intra-tumor heterogeneity. Several studies have suggested that within these tumors a restricted population of chemoresistant glioma cells is responsible for recurrence. However, the gene expression patterns underlying chemoresistance are largely unknown. Numerous efforts have been made to block IGF-1R signaling pathway in GBM. However, those therapies have been repeatedly unsuccessful. This failure may not only be due to the complexity of IGF receptor signaling, but also due to complex cell-cell interactions in the tumor mass. We hypothesized that differential expression of proteins in the insulin-like growth factor (IGF) system underlie cell-specific differences in the resistance to temozolomide (TMZ) within GBM tumors.
Methods
Expression of IGF-1R was analyzed in cell lines, patient-derived xenograft cell lines and human biopsies by cell surface proteomics, flow cytometry, immunofluorescence and quantitative real time polymerase chain reaction (qRT-PCR). Using gain-of-function and loss-of-function strategies, we dissected the molecular mechanism responsible for IGF-binding protein 6 (IGFBP6) tumor suppressor functions both in in vitro and in vivo. Site direct mutagenesis was used to study IGFBP6-IGF2 interactions.
Results
We determined that in human glioma tissue, glioma cell lines, and patient-derived xenograft cell lines, treatment with TMZ enhances the expression of IGF1 receptor (IGF-1R) and IGF2 and decreases the expression of IGFBP6, which sequesters IGF2. Using chemoresistant and chemosensitive wild-type and transgenic glioma cells, we further found that a paracrine mechanism driven by IGFBP6 secreted from TMZ-sensitive cells abrogates the proliferation of IGF-1R-expressing TMZ-resistant cells in vitro and in vivo. In mice bearing intracranial human glioma xenografts, overexpression of IGFBP6 in TMZ-resistant cells increased survival. Finally, elevated expression of IGF-1R and IGF2 in gliomas associated with poor patient survival and tumor expression levels of IGFBP6 directly correlated with overall survival time in patients with GBM.
Conclusions
Our findings support the view that proliferation of chemoresistant tumor cells is controlled within the tumor mass by IGFBP6-producing tumor cells; however, TMZ treatment eliminates this population and enriches the TMZ-resistant cell populationleading to accelerated growth of the entire tumor mass.
Details
- Title: Subtitle
- IGFBP6 controls the expansion of chemoresistant glioblastoma through paracrine IGF2/IGF-1R signaling
- Creators
- Claudia R Oliva - Birmingham, AL 35294 USABrian Halloran - Birmingham, AL 35294 USAAnita B Hjelmeland - Birmingham, AL 35294 USAAna Vazquez - East Lansing, MI 48823 USAShannon M Bailey - Birmingham, AL 35294 USAJann N Sarkaria - Rochester, MN 55902 USACorinne E Griguer - Birmingham, AL 35294 USA
- Resource Type
- Journal article
- Publication Details
- Cell communication and signaling, Vol.16(1), pp.61-61
- DOI
- 10.1186/s12964-018-0273-7
- PMID
- 30231881
- PMCID
- PMC6148802
- NLM abbreviation
- Cell Commun Signal
- ISSN
- 1478-811X
- eISSN
- 1478-811X
- Publisher
- BioMed Central; London
- Grant note
- R01CA160821 / ; 5R21NS100054 / ;
- Language
- English
- Date published
- 09/19/2018
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984047863202771
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