NDLI: EXTRACELLULAR REGULATORS OF GLIOBLASTOMA SIGNALING

Content Provider	PubMed Central
Author	Phillips, Joanna J. Wade, Anna Tran, Vy My Mckinney, Andrew
Copyright Year	2014
Abstract	BACKGROUND: Extracellular proteoglycans, including heparan sulfate proteoglycan (HSPG), play critical roles in the regulation of neural stem cell signaling and progenitor cell migration via their interactions with extracellular ligands, matrix, and cell receptors and may serve similar purposes in oncogenic states. In glioblastoma (GBM), our studies suggest that proteoglycans regulate critical oncogenic signaling pathways. Here we assess the function of proteoglycans and their alterations that drive GBM, and test the hypothesis that these may represent novel therapeutic targets and biomarkers of disease. METHODS: To investigate the role for proteoglycans in tumorigenesis we used a combination of primary human GBM, primary human GBM cultures, and a murine model for malignant glioma based on the genetic manipulation of neural progenitor cells. GAG structure was elucidated and quantified using liquid chromatography-mass spectrometry (LCMS), an ultra-sensitive and high-resolution technique that can overcome problems associated with low availability of biological samples. RESULTS: In GBM we identified patterns of altered expression of HSPG protein cores and their modifying enzymes relative to non-tumor brain, including the extracellular enzyme SULF2. Indeed, SULF2 is overexpressed in many human GBM and ablation of SULF2 function results in decreased activation of PDGFRα signaling and in decreased tumor growth in vivo. Consistent with a role for SULF2 in PDGFRA signaling in human GBM, SULF2 is upregulated in PDGFRA-amplified compared to non-amplified tumors (p < 0.05, n = 40 amplified, 332 non-amplified). SULF2 reduced HS sulfation, specifically the HS6S component of heparin, as determined by liquid chromatography-mass spectrometry (LCMS) and immunohistochemistry. As HS6S sulfation is an important determinant of HS-ligand binding, we investigated whether SULF2 could alter PDGF binding to HS. While ligand binding was similar, SULF2 was associated with altered expression and cell surface localization of PDGFRA. Thus, SULF2, and possibly HS6S, may regulate PDGFRA signaling via two distinct mechanisms. As HS structure is critical for normal neural stem cell proliferation and differentiation, we analyzed HS structure over tumor progression using LCMS. We demonstrate that tumor progression is associated with changes in GAG structure, and we are now using HS mimetics to try to inhibit the oncogenic role for proteoglycans in GBM. CONCLUSIONS: Our data demonstrate the functional importance of proteoglycans in GBM and suggest GAG structure may be particularly important for oncogenic signaling. While therapeutic targeting of single RTKs has been difficult in GBM, a drug targeting HS has the potential to simultaneously inhibit multiple oncogenic pathways in tumor cells and disrupt critical tumor-microenvironment interactions. SECONDARY CATEGORY: n/a.
Related Links	http://dx.doi.org/10.1093/neuonc/nou206.65
Starting Page	18
File Format	PDF
ISSN	15228517
e-ISSN	15235866
Journal	Neuro-Oncology
Issue Number	Suppl 3
Volume Number	16
Language	English
Publisher	Oxford University Press
Publisher Date	2014-07-01
Access Restriction	Open
Rights Holder	Oxford University Press
Subject Keyword	Cancer Research Oncology Clinical Neurology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Neurology (clinical) Oncology

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

PI3Kinase signaling in glioblastoma

miRNA contents of cerebrospinal fluid extracellular vesicles in glioblastoma patients

Belonging to a network—microRNAs, extracellular vesicles, and the glioblastoma microenvironment

Wnt/β-catenin signaling is a key downstream mediator of MET signaling in glioblastoma stem cells

mTOR signaling in glioblastoma: lessons learned from bench to bedside

SC-36RECIPROCAL INTERACTION OF PGE2 AND WNT SIGNALING REGULATES CANCER STEM CELLS IN GLIOBLASTOMA

P01.18AUTOCRINE VEGFC-VEGFR2 SIGNALING IS OF IMPORTANCE FOR THE GROWTH OF GLIOBLASTOMA MULTIFORME

Defective p53 antiangiogenic signaling in glioblastoma

CS-19PDGF SIGNALING DEPENDENCE IN PRONEURAL GLIOBLASTOMA, THE BEGINNING BUT NOT THE END

EXTRACELLULAR REGULATORS OF GLIOBLASTOMA SIGNALING

Similar Documents

PI3Kinase signaling in glioblastoma

miRNA contents of cerebrospinal fluid extracellular vesicles in glioblastoma patients

Belonging to a network—microRNAs, extracellular vesicles, and the glioblastoma microenvironment

Wnt/β-catenin signaling is a key downstream mediator of MET signaling in glioblastoma stem cells

mTOR signaling in glioblastoma: lessons learned from bench to bedside

SC-36RECIPROCAL INTERACTION OF PGE2 AND WNT SIGNALING REGULATES CANCER STEM CELLS IN GLIOBLASTOMA

P01.18AUTOCRINE VEGFC-VEGFR2 SIGNALING IS OF IMPORTANCE FOR THE GROWTH OF GLIOBLASTOMA MULTIFORME

Defective p53 antiangiogenic signaling in glioblastoma

CS-19PDGF SIGNALING DEPENDENCE IN PRONEURAL GLIOBLASTOMA, THE BEGINNING BUT NOT THE END

EXTRACELLULAR REGULATORS OF GLIOBLASTOMA SIGNALING