Cerebrospinal fluid top-down proteomics evidenced the potential biomarker role of LVV- and VV-hemorphin-7 in posterior cranial fossa pediatric brain tumors

Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche, Rome, Italy.
Proteomics (Impact Factor: 3.97). 07/2012; 12(13):2158-66. DOI: 10.1002/pmic.201100499
Source: PubMed

ABSTRACT Posterior cranial fossa is the most frequent location of pediatric brain tumors. Its diagnosis is currently performed by postsurgery histopathology and the identification of biomarkers in cerebrospinal fluid (CSF) could provide a less invasive tool. Patient CSF was collected during surgery before the tumor removal (PRE-CSF) and 6 days after the resection (POST-CSF) and analyzed by top down LC-MS proteomics for comparison. The PRE-CSFs generally exhibited a less complex LC-MS profile than the relative POST-CSFs suggesting a suppressive role of the tumor toward proteins and peptides production or release. Particularly, a panel of peptides, identified as alpha- and beta-hemoglobin chains fragments, were generally absent in the PRE-CSF and present in the POST ones independently from contaminant blood hemoglobin. Among them, the LVV- and VV-hemorphin-7 showed the most repeatable trend and with a few remarkable exceptions: their unusual absence in POST surgery CSF was in fact interestingly correlated to the presence of tumor in the patient despite surgery due to metastases or to subtotal resection. These results ascribed a relevant biological role to LVV- and VV-h7 peptides in the disease and a strong potential as biomarkers. Their analysis in POST surgery CSF could be used to predict patient prognosis.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The combination of top-down and bottom-up platforms was utilized for the LC-MS proteomic characterization of the intracystic fluid of adamantinomatous chraniopharyngioma pediatric brain tumor disease. Proteins and peptides characterization was achieved by high resolution LC-ESI-LTQ-Orbitrap-MS analysis while low resolution LC-ESI-IT-MS was applied for the complete screening of the samples and the evaluation of the protein distribution within patients. Top-down analyses were applied to liquid/liquid extracted samples while bottom-up analyses were performed after trypsin digestion of both untreated and pretreated samples. The two proteomic approaches were complementary for the characterization of the proteome of craniopharyngioma intracystic fluid. Proteins and peptides involved in inflammation, mineralization processes and lipid transport were identified, in agreement with the calcium flecks, cholesterol granules and bone residues characteristic of this fluid. Apolipoprotein A-I, A-II, C-I and J, hemoglobin fragments, ubiquitin, α-2-HS-glycoprotein or fetuin A, α-1-antichymotrypsin, vitamin D-binding protein and α-1-acid glycoprotein were characterized. These data could be relevant for the comprehension of the processes involved in the pathogenesis of the disease and the development of the cyst and could contribute to the individuation of therapeutic targets for the reduction of the cyst volume delaying and/or avoiding invasive surgical treatments.This article is protected by copyright. All rights reserved
    Electrophoresis 06/2014; 35(15). DOI:10.1002/elps.201300578 · 3.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Liquid chromatography in coupling with high-resolution ESI-LTQ-Orbitrap mass spectrometry was applied for a proteomic study of pediatric pilocytic astrocytoma brain tumor intracystic fluid by an integrated top-down/bottom-up platform. Both of the proteomic strategies resulted complementary and support each other in contributing to a wide characterization of the protein and peptide content of the tumor fluid. Top-down approach allowed to identify several proteins and peptides involved in different biological activities together with the characterization of interesting proteoforms such as fibrinopeptide A and its truncated form, fibrinopeptide B, complement C3f fragments, β-thymosin peptides, ubiquitin, several apolipoproteins belonging to A and C families, apolipoprotein J and D, and cystatin C. Of particular interest resulted the identification of a N-terminal truncated cystatin C proteoform, likely involved in immune response mechanism modulations and the identification of oxidized and glycosylated apolipoproteins including disulfide bridge dimeric forms. The bottom-up approach confirmed some of the experimental data findings together with adding the characterization of high-molecular-mass proteins in the samples. These data could contribute to elucidate the molecular mechanisms involved in onset and progression of the disease and cyst development.
    Journal of Proteome Research 09/2014; 13(11). DOI:10.1021/pr500806k · 5.00 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Primary brain tumors cumulatively represent the most common solid tumors of childhood and are the leading cause of cancer related death in this age group. Traditionally, molecular findings and histological analyses from biopsies of resected tumor tissue have been used for diagnosis and classification of these diseases. However, there is a dearth of useful biomarkers that have been validated and clinically implemented for pediatric brain tumors. Notably, diseases of the central nervous system (CNS) can be assayed through analysis of cerebrospinal fluid (CSF) and as such, CSF represents an appropriate medium to obtain liquid biopsies that can be informative for diagnosis, disease classification and risk stratification. Proteomic profiling of pediatric CNS malignancies has identified putative protein markers of disease, yet few effective biomarkers have been clinically validated or implemented. Advances in protein quantification techniques have made it possible to conduct such investigations rapidly and accurately through proteome-wide analyses. This review summarizes the current literature on proteomics in pediatric neuro-oncology and discusses the implications for clinical applications of proteomics research. We also outline strategies for translating effective CSF proteomic studies into clinical applications to optimize the care of this patient population.
    Journal of Neuro-Oncology 04/2014; 118(2). DOI:10.1007/s11060-014-1432-3 · 2.79 Impact Factor