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

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.

[1]  J. Piot,et al.  Brain processing of hemorphin-7 peptides in various subcellular fractions from rats , 2006, Peptides.

[2]  J. Conlon,et al.  Isolation of the opioid peptide Leu-Val-Val-hemorphin-7 from bronchoalveolar lavage fluid of a patient with non-small cell lung cancer , 2000, Peptides.

[3]  V. Ivanov,et al.  Family of hemorphins: co-relations between amino acid sequences and effects in cell cultures , 2002, Peptides.

[4]  T. Luider,et al.  Proteomics in primary brain tumors. , 2003, Frontiers in bioscience : a journal and virtual library.

[5]  E. Maronde,et al.  Identification and functional characterization of hemorphins VV‐H‐7 and LVV‐H‐7 as low‐affinity agonists for the orphan bombesin receptor subtype 3 , 2003, British journal of pharmacology.

[6]  A. A. Zamyatnin Hemoglobin as a potential source of natural regulatory oligopeptides , 2009, Biochemistry (Moscow).

[7]  J. Sironi,et al.  Hemopressins and other hemoglobin‐derived peptides in mouse brain: comparison between brain, blood, and heart peptidome and regulation in Cpefat/fat mice , 2010, Journal of neurochemistry.

[8]  Howard Schulman,et al.  Protein biomarker identification in the CSF of patients with CNS lymphoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  I. Messana,et al.  The multiple functions of hemoglobin. , 1995, Critical reviews in biochemistry and molecular biology.

[10]  V. Pletnev,et al.  Hemoglobin as a source of endogenous bioactive peptides: the concept of tissue-specific peptide pool. , 1997, Biopolymers.

[11]  Jie Yuan,et al.  Proteomic analysis of cerebrospinal fluid from patients with idiopathic temporal lobe epilepsy , 2009, Brain Research.

[12]  Lloyd D. Fricker,et al.  Hemopressin and Other Bioactive Peptides from Cytosolic Proteins: Are These Non-Classical Neuropeptides? , 2010, The AAPS Journal.

[13]  R. Lew,et al.  A Globin Fragment, LVV‐Hemorphin‐7, Induces [3H]Thymidine Incorporation in a Neuronal Cell Line via the AT4 Receptor , 1999, Journal of neurochemistry.

[14]  F. Lottspeich,et al.  Novel opioid peptides derived from hemoglobin: hemorphins. , 1986, European journal of pharmacology.

[15]  J. Rutka,et al.  Genetics of medulloblastoma: clues for novel therapies , 2010, Expert review of neurotherapeutics.

[16]  F. Nyberg,et al.  The hemorphins: a new class of opioid peptides derived from the blood protein hemoglobin. , 1997, Biopolymers.

[17]  W. Forssmann,et al.  Human hemoglobin-derived peptides exhibit antimicrobial activity: a class of host defense peptides. , 2003, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[18]  Erwin G. Van Meir,et al.  Proteomic analysis of cerebrospinal fluid discriminates malignant and nonmalignant disease of the central nervous system and identifies specific protein markers , 2006, Proteomics.

[19]  Franklyn A Howe,et al.  OMICS and brain tumour biomarkers , 2006, British journal of neurosurgery.

[20]  Erwin G. Van Meir,et al.  Proteomic identification of biomarkers in the cerebrospinal fluid (CSF) of astrocytoma patients. , 2007, Journal of proteome research.

[21]  A. Dale,et al.  CSF Biomarkers in Prediction of Cerebral and Clinical Change in Mild Cognitive Impairment and Alzheimer's Disease , 2010, The Journal of Neuroscience.

[22]  J. Bergquist,et al.  Clinical perspectives of high-resolution mass spectrometry-based proteomics in neuroscience: exemplified in amyotrophic lateral sclerosis biomarker discovery research. , 2008, Journal of mass spectrometry : JMS.

[23]  C. Fanali,et al.  The Surprising Composition of the Salivary Proteome of Preterm Human Newborn , 2010, Molecular & Cellular Proteomics.

[24]  Isidro Ferrer,et al.  Unexpected expression of α- and β-globin in mesencephalic dopaminergic neurons and glial cells , 2009, Proceedings of the National Academy of Sciences.

[25]  D. Birnbaum,et al.  Serum levels of Hemorphin-7 peptides in patients with breast cancer. , 2003, Clinica chimica acta; international journal of clinical chemistry.

[26]  J. Piot,et al.  Cathepsin D is a good candidate for the specific release of a stable hemorphin from hemoglobin in vivo: VV-hemorphin-7. , 1998, Biochemical and biophysical research communications.

[27]  T. MacDonald,et al.  Proteomic profiling of cerebrospinal fluid identifies prostaglandin D2 synthase as a putative biomarker for pediatric medulloblastoma: A pediatric brain tumor consortium study , 2011, Proteomics.

[28]  M. Chesselet,et al.  Neurons express hemoglobin α‐ and β‐chains in rat and human brains , 2009, The Journal of comparative neurology.

[29]  Y. Ohyagi,et al.  Hemoglobin as a novel protein developmentally regulated in neurons , 1994, Brain Research.

[30]  G. Smythe,et al.  Mass Spectrometric Identification and Quantification of Hemorphins Extracted from Human Adrenal and Pheochromocytoma Tissue , 1997, Journal of neurochemistry.