Journal article
Insights into the Proteome of Gastrointestinal Stromal Tumors-Derived Exosomes Reveals New Potential Diagnostic Biomarkers
Molecular & cellular proteomics, Vol.17(3), pp.495-515
03/01/2018
DOI: 10.1074/mcp.RA117.000267
PMCID: PMC5836374
PMID: 29242380
Abstract
Developing tumors continuously release nano-sized vesicles that represent circulating "fingerprints" of the tumor's identity. In gastrointestinal stromal tumor (GIST), we have previously reported that these tumors release "oncosomes" carrying the constitutively activated tyrosine kinase (TK) receptor KIT. Despite the clinical utility of TK inhibitors, such as imatinib mesylate (IM), recurrence and metastasis are clinical problems that urge the need to identify new tumor-derived molecules. To this aim, we performed the first high quality proteomic study of GIST-derived exosomes (GDEs) and identified 1,060 proteins composing the core GDE proteome (cGDEp). The cGDEp was enriched in diagnostic markers (e.g. KIT, CD34, ANO1, PROM1, PRKCQ, and ENG), as well as proteins encoded by genes previously reported expressed in GIST (e.g. DPP4, FHL1, CDH11, and KCTD12). Many of these proteins were validated using cell lines, patient-derived KIT+ exosomes, and GIST tissues. We further show that in vitro and in vivo-derived GDE, carry proteins associated with IM response, such as Sprouty homolog 4 (SPRY4), surfeit 4 (SURF4), ALIX, and the cGMP-dependent 3', 5'-cyclic phosphodiesterase 2A (PDE2A). Additionally, we report that the total exosome levels and exosome-associated KIT and SPRY4 protein levels have therapeutic values. In fact, molecular characterization of in vivo-derived KIT+ exosomes indicate significant sorting of p-KITTyr719, total KIT, and SPRY4 after IM-treatment of metastatic patients as compared with the pre-IM levels. Our data suggest that analysis of circulating exosomes levels and molecular markers of IM response in GIST patients with primary and metastatic disease is suitable to develop liquid based biopsies for the diagnosis, prognosis, and monitoring of response to treatment of these tumors. In summary, these findings provide the first insight into the proteome of GIST-derived oncosomes and offers a unique opportunity to further understand their oncogenic elements which contribute to tumorigenesis and drug resistance. Data are available via ProteomeXchange with identifier PXD007997.
Details
- Title: Subtitle
- Insights into the Proteome of Gastrointestinal Stromal Tumors-Derived Exosomes Reveals New Potential Diagnostic Biomarkers
- Creators
- Safinur Atay - University of Kansas Medical CenterDaniel W. Wilkey - University of LouisvilleMohammed Milhem - Iowa Lutheran HospitalMichael Merchant - University of LouisvilleAndrew K. Godwin - The University of Kansas Cancer Center
- Resource Type
- Journal article
- Publication Details
- Molecular & cellular proteomics, Vol.17(3), pp.495-515
- DOI
- 10.1074/mcp.RA117.000267
- PMID
- 29242380
- PMCID
- PMC5836374
- NLM abbreviation
- Mol Cell Proteomics
- ISSN
- 1535-9476
- eISSN
- 1535-9484
- Publisher
- Amer Soc Biochemistry Molecular Biology Inc
- Number of pages
- 21
- Grant note
- KU Biomedical Research Training Program P30 CA168524 / KU Cancer Center's Cancer Center Support Grant P20GM113226 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) P30CA168524; P30CA086862; R01CA106588 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) UL1 TR000001-02S1 / National Institute of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01 CA106588 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Kansas Bioscience Authority Eminent Scholar Program UL1TR000001 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS)
- Language
- English
- Date published
- 03/01/2018
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359767002771
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