Proteomic analysis of cerebrospinal fluid from children with central nervous system tumors identifies candidate proteins relating to tumor metastatic spread

F. Spreafico, I. Bongarzone, S. Pizzamiglio, R. Magni, E. Taverna, M. De Bortoli, C.M. Ciniselli, E. Barzanò, V. Biassoni, A. Luchini, L.A. Liotta, W. Zhou, M. Signore, P. Verderio, M. Massimino

Research output: Contribution to journalArticle

Abstract

Central nervous system (CNS) tumors are the most common solid tumors in childhood. Since the sensitivity of combined cerebrospinal fluid (CSF) cytology and radiological neuroimaging in detecting meningeal metastases remains relatively low, we sought to characterize the CSF proteome of patients with CSF tumors to identify biomarkers predictive of metastatic spread. CSF samples from 27 children with brain tumors and 13 controls (extra-CNS non-Hodgkin lymphoma) were processed using core-shell hydrogel nanoparticles, and analyzed with reverse-phase liquid chromatography/electrospray tandem mass spectrometry (LC-MS/MS). Candidate proteins were identified with Fisher's exact test and/or a univariate logistic regression model. Reverse phase protein array (RPPA), Western blot (WB), and ELISA were used in the training set and in an independent set of CFS samples (60 cases, 14 controls) to validate our discovery findings. Among the 558 non-redundant proteins identified by LC-MS/MS, 147 were missing from the CSF database at http://www.biosino.org. Fourteen of the 26 final top-candidate proteins were chosen for validation with WB, RPPA and ELISA methods. Six proteins (type 1 collagen, insulin-like growth factor binding protein 4, procollagen C-endopeptidase enhancer 1, glial cell-line derived neurotrophic factor receptor α2, inter-alpha-trypsin inhibitor heavy chain 4, neural proliferation and differentiation control protein-1) revealed the ability to discriminate metastatic cases from controls. Combining a unique dataset of CSFs from pediatric CNS tumors with a novel enabling nanotechnology led us to identify CSF proteins potentially related to metastatic status. © Spreafico et al.
Original languageEnglish
Pages (from-to)46177-46190
Number of pages14
JournalOncotarget
Volume8
Issue number28
Publication statusPublished - 2017

Fingerprint

Central Nervous System Neoplasms
Proteomics
Cerebrospinal Fluid
Protein Array Analysis
Neoplasms
Tandem Mass Spectrometry
Proteins
Bone Morphogenetic Protein 1
Glial Cell Line-Derived Neurotrophic Factor Receptors
Logistic Models
Western Blotting
Enzyme-Linked Immunosorbent Assay
Insulin-Like Growth Factor Binding Protein 4
Cerebrospinal Fluid Proteins
Nanotechnology
Hydrogel
Reverse-Phase Chromatography
Proteome
Collagen Type I
Neuroimaging

Keywords

  • Cerebrospinal fluid
  • Liquid chromatography/electrospray tandem mass spectrometry
  • Pediatric central nervous system tumors
  • Protein-based biomarker
  • Proteomic analysis
  • collagen type 1
  • core shell hydrogel nanoparticle
  • glial cell line derived neurotrophic factor receptor
  • glial cell line derived neurotrophic factor receptor alpha2
  • inter alpha trypsin inhibitor
  • inter alpha trypsin inhibitor heavy chain 4
  • membrane protein
  • nanoparticle
  • neural proliferation and differentiation control protein 1
  • procollagen C endopeptidase enhancer 1
  • proteome
  • somatomedin binding protein 4
  • unclassified drug
  • adolescent
  • adult
  • Article
  • case control study
  • central nervous system cancer
  • cerebrospinal fluid analysis
  • child
  • controlled study
  • disease association
  • enzyme linked immunosorbent assay
  • female
  • human
  • liquid chromatography-mass spectrometry
  • major clinical study
  • male
  • metastasis
  • nanotechnology
  • nonhodgkin lymphoma
  • prospective study
  • protein analysis
  • protein microarray
  • proteomics
  • reverse phase protein array
  • reversed phase liquid chromatography
  • Western blotting

Cite this

Spreafico, F., Bongarzone, I., Pizzamiglio, S., Magni, R., Taverna, E., De Bortoli, M., ... Massimino, M. (2017). Proteomic analysis of cerebrospinal fluid from children with central nervous system tumors identifies candidate proteins relating to tumor metastatic spread. Oncotarget, 8(28), 46177-46190.

Proteomic analysis of cerebrospinal fluid from children with central nervous system tumors identifies candidate proteins relating to tumor metastatic spread. / Spreafico, F.; Bongarzone, I.; Pizzamiglio, S.; Magni, R.; Taverna, E.; De Bortoli, M.; Ciniselli, C.M.; Barzanò, E.; Biassoni, V.; Luchini, A.; Liotta, L.A.; Zhou, W.; Signore, M.; Verderio, P.; Massimino, M.

In: Oncotarget, Vol. 8, No. 28, 2017, p. 46177-46190.

Research output: Contribution to journalArticle

Spreafico, F, Bongarzone, I, Pizzamiglio, S, Magni, R, Taverna, E, De Bortoli, M, Ciniselli, CM, Barzanò, E, Biassoni, V, Luchini, A, Liotta, LA, Zhou, W, Signore, M, Verderio, P & Massimino, M 2017, 'Proteomic analysis of cerebrospinal fluid from children with central nervous system tumors identifies candidate proteins relating to tumor metastatic spread', Oncotarget, vol. 8, no. 28, pp. 46177-46190.
Spreafico, F. ; Bongarzone, I. ; Pizzamiglio, S. ; Magni, R. ; Taverna, E. ; De Bortoli, M. ; Ciniselli, C.M. ; Barzanò, E. ; Biassoni, V. ; Luchini, A. ; Liotta, L.A. ; Zhou, W. ; Signore, M. ; Verderio, P. ; Massimino, M. / Proteomic analysis of cerebrospinal fluid from children with central nervous system tumors identifies candidate proteins relating to tumor metastatic spread. In: Oncotarget. 2017 ; Vol. 8, No. 28. pp. 46177-46190.
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title = "Proteomic analysis of cerebrospinal fluid from children with central nervous system tumors identifies candidate proteins relating to tumor metastatic spread",
abstract = "Central nervous system (CNS) tumors are the most common solid tumors in childhood. Since the sensitivity of combined cerebrospinal fluid (CSF) cytology and radiological neuroimaging in detecting meningeal metastases remains relatively low, we sought to characterize the CSF proteome of patients with CSF tumors to identify biomarkers predictive of metastatic spread. CSF samples from 27 children with brain tumors and 13 controls (extra-CNS non-Hodgkin lymphoma) were processed using core-shell hydrogel nanoparticles, and analyzed with reverse-phase liquid chromatography/electrospray tandem mass spectrometry (LC-MS/MS). Candidate proteins were identified with Fisher's exact test and/or a univariate logistic regression model. Reverse phase protein array (RPPA), Western blot (WB), and ELISA were used in the training set and in an independent set of CFS samples (60 cases, 14 controls) to validate our discovery findings. Among the 558 non-redundant proteins identified by LC-MS/MS, 147 were missing from the CSF database at http://www.biosino.org. Fourteen of the 26 final top-candidate proteins were chosen for validation with WB, RPPA and ELISA methods. Six proteins (type 1 collagen, insulin-like growth factor binding protein 4, procollagen C-endopeptidase enhancer 1, glial cell-line derived neurotrophic factor receptor α2, inter-alpha-trypsin inhibitor heavy chain 4, neural proliferation and differentiation control protein-1) revealed the ability to discriminate metastatic cases from controls. Combining a unique dataset of CSFs from pediatric CNS tumors with a novel enabling nanotechnology led us to identify CSF proteins potentially related to metastatic status. {\circledC} Spreafico et al.",
keywords = "Cerebrospinal fluid, Liquid chromatography/electrospray tandem mass spectrometry, Pediatric central nervous system tumors, Protein-based biomarker, Proteomic analysis, collagen type 1, core shell hydrogel nanoparticle, glial cell line derived neurotrophic factor receptor, glial cell line derived neurotrophic factor receptor alpha2, inter alpha trypsin inhibitor, inter alpha trypsin inhibitor heavy chain 4, membrane protein, nanoparticle, neural proliferation and differentiation control protein 1, procollagen C endopeptidase enhancer 1, proteome, somatomedin binding protein 4, unclassified drug, adolescent, adult, Article, case control study, central nervous system cancer, cerebrospinal fluid analysis, child, controlled study, disease association, enzyme linked immunosorbent assay, female, human, liquid chromatography-mass spectrometry, major clinical study, male, metastasis, nanotechnology, nonhodgkin lymphoma, prospective study, protein analysis, protein microarray, proteomics, reverse phase protein array, reversed phase liquid chromatography, Western blotting",
author = "F. Spreafico and I. Bongarzone and S. Pizzamiglio and R. Magni and E. Taverna and {De Bortoli}, M. and C.M. Ciniselli and E. Barzan{\`o} and V. Biassoni and A. Luchini and L.A. Liotta and W. Zhou and M. Signore and P. Verderio and M. Massimino",
note = "Cited By :2 Export Date: 5 April 2018 Correspondence Address: Pizzamiglio, S.; Unit of Medical Statistics, Biometry and Bioinformatics, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei TumoriItaly; email: sara.pizzamiglio@istitutotumori.mi.it Chemicals/CAS: inter alpha trypsin inhibitor, 39346-44-6; somatomedin binding protein 4, 136653-35-5 References: Ichimura, K., Nishikawa, R., Matsutani, M., Molecular markers in pediatric Neuro Oncol (2012) Neuro-oncology, 14, pp. iv90-iv99; Northcott, P.A., Jones, D.T., Kool, M., Robinson, G.W., Gilbertson, R.J., Cho, Y.J., Pomeroy, S.L., Pfister, S.M., Medulloblastomics: the end of the beginning (2012) Nat Rev Cancer, 12, pp. 818-834; Massimino, M., Spreafico, F., Riva, D., Biassoni, V., Poggi, G., Solero, C., Gandola, L., Meazza, C., A lower-dose, lower-toxicity cisplatin-etoposide regimen for childhood progressive low-grade glioma (2010) J Neurooncol, 100, pp. 65-71; Dhall, G., Medulloblastoma (2009) J Child Neurol, 24, pp. 1418-1430; Fangusaro, J., Massimino, M., Rutkowski, S., Gururangan, S., Non-cerebellar primitive neuroectodermal tumors (PNET): summary of the Milan consensus and state of the art workshop on marrow ablative chemotherapy with hematopoietic cell rescue for malignant brain tumors of childhood and adolescents (2010) Pediatr Blood Cancer, 54, pp. 638-640; Wootton-Gorges, S.L., Foreman, N.K., Albano, E.A., Dertina, D.M., Nein, P.K., Shukert, B., Cesario, K.B., Strain, J.D., Pattern of recurrence in children with midline posterior fossa malignant neoplasms (2000) Pediatr Radiol, 30, pp. 90-93; Walbert, T., Groves, M.D., Known and emerging biomarkers of leptomeningeal metastasis and its response to treatment (2010) Future Oncol, 6, pp. 287-297; Maksoud, Y.A., Hahn, Y.S., Engelhard, H.H., Intracranial ependymoma (2002) Neurosurg Focus, 13; Packer, R.J., Siegel, K.R., Sutton, L.N., Litmann, P., Bruce, D.A., Schut, L., Leptomeningeal dissemination of primary central nervous system tumors of childhood (1985) Ann Neurol, 18, pp. 217-221; Wagner, S., Benesch, M., Berthold, F., Gnekow, A.K., Rutkowski, S., Strater, R., Warmuth-Metz, M., Wolff, J.E., Secondary dissemination in children with highgrade malignant gliomas and diffuse intrinsic pontine gliomas (2006) Br J Cancer, 95, pp. 991-997; Shen, F., Zhang, Y., Yao, Y., Hua, W., Zhang, H.S., Wu, J.S., Zhong, P., Zhou, L.F., Proteomic analysis of cerebrospinal fluid: toward the identification of biomarkers for gliomas (2014) Neurosurg Rev, 37, pp. 367-380. , discussion 380; Holtta, M., Zetterberg, H., Mirgorodskaya, E., Mattsson, N., Blennow, K., Gobom, J., Peptidome analysis of cerebrospinal fluid by LC-MALDI MS (2012) PLoS One, 7; Samuel, N., Remke, M., Rutka, J.T., Raught, B., Malkin, D., Proteomic analyses of CSF aimed at biomarker development for pediatric brain tumors (2014) J Neurooncol, 118, pp. 225-238; Whitin, J.C., Jang, T., Merchant, M., Yu, T.T., Lau, K., Recht, B., Cohen, H.J., Recht, L., Alterations in cerebrospinal fluid proteins in a presymptomatic primary glioma model (2012) PLoS One, 7; 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year = "2017",
language = "English",
volume = "8",
pages = "46177--46190",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "28",

}

TY - JOUR

T1 - Proteomic analysis of cerebrospinal fluid from children with central nervous system tumors identifies candidate proteins relating to tumor metastatic spread

AU - Spreafico, F.

AU - Bongarzone, I.

AU - Pizzamiglio, S.

AU - Magni, R.

AU - Taverna, E.

AU - De Bortoli, M.

AU - Ciniselli, C.M.

AU - Barzanò, E.

AU - Biassoni, V.

AU - Luchini, A.

AU - Liotta, L.A.

AU - Zhou, W.

AU - Signore, M.

AU - Verderio, P.

AU - Massimino, M.

N1 - Cited By :2 Export Date: 5 April 2018 Correspondence Address: Pizzamiglio, S.; Unit of Medical Statistics, Biometry and Bioinformatics, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei TumoriItaly; email: sara.pizzamiglio@istitutotumori.mi.it Chemicals/CAS: inter alpha trypsin inhibitor, 39346-44-6; somatomedin binding protein 4, 136653-35-5 References: Ichimura, K., Nishikawa, R., Matsutani, M., Molecular markers in pediatric Neuro Oncol (2012) Neuro-oncology, 14, pp. iv90-iv99; Northcott, P.A., Jones, D.T., Kool, M., Robinson, G.W., Gilbertson, R.J., Cho, Y.J., Pomeroy, S.L., Pfister, S.M., Medulloblastomics: the end of the beginning (2012) Nat Rev Cancer, 12, pp. 818-834; Massimino, M., Spreafico, F., Riva, D., Biassoni, V., Poggi, G., Solero, C., Gandola, L., Meazza, C., A lower-dose, lower-toxicity cisplatin-etoposide regimen for childhood progressive low-grade glioma (2010) J Neurooncol, 100, pp. 65-71; Dhall, G., Medulloblastoma (2009) J Child Neurol, 24, pp. 1418-1430; Fangusaro, J., Massimino, M., Rutkowski, S., Gururangan, S., Non-cerebellar primitive neuroectodermal tumors (PNET): summary of the Milan consensus and state of the art workshop on marrow ablative chemotherapy with hematopoietic cell rescue for malignant brain tumors of childhood and adolescents (2010) Pediatr Blood Cancer, 54, pp. 638-640; Wootton-Gorges, S.L., Foreman, N.K., Albano, E.A., Dertina, D.M., Nein, P.K., Shukert, B., Cesario, K.B., Strain, J.D., Pattern of recurrence in children with midline posterior fossa malignant neoplasms (2000) Pediatr Radiol, 30, pp. 90-93; Walbert, T., Groves, M.D., Known and emerging biomarkers of leptomeningeal metastasis and its response to treatment (2010) Future Oncol, 6, pp. 287-297; Maksoud, Y.A., Hahn, Y.S., Engelhard, H.H., Intracranial ependymoma (2002) Neurosurg Focus, 13; Packer, R.J., Siegel, K.R., Sutton, L.N., Litmann, P., Bruce, D.A., Schut, L., Leptomeningeal dissemination of primary central nervous system tumors of childhood (1985) Ann Neurol, 18, pp. 217-221; Wagner, S., Benesch, M., Berthold, F., Gnekow, A.K., Rutkowski, S., Strater, R., Warmuth-Metz, M., Wolff, J.E., Secondary dissemination in children with highgrade malignant gliomas and diffuse intrinsic pontine gliomas (2006) Br J Cancer, 95, pp. 991-997; Shen, F., Zhang, Y., Yao, Y., Hua, W., Zhang, H.S., Wu, J.S., Zhong, P., Zhou, L.F., Proteomic analysis of cerebrospinal fluid: toward the identification of biomarkers for gliomas (2014) Neurosurg Rev, 37, pp. 367-380. , discussion 380; Holtta, M., Zetterberg, H., Mirgorodskaya, E., Mattsson, N., Blennow, K., Gobom, J., Peptidome analysis of cerebrospinal fluid by LC-MALDI MS (2012) PLoS One, 7; Samuel, N., Remke, M., Rutka, J.T., Raught, B., Malkin, D., Proteomic analyses of CSF aimed at biomarker development for pediatric brain tumors (2014) J Neurooncol, 118, pp. 225-238; Whitin, J.C., Jang, T., Merchant, M., Yu, T.T., Lau, K., Recht, B., Cohen, H.J., Recht, L., Alterations in cerebrospinal fluid proteins in a presymptomatic primary glioma model (2012) PLoS One, 7; 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PY - 2017

Y1 - 2017

N2 - Central nervous system (CNS) tumors are the most common solid tumors in childhood. Since the sensitivity of combined cerebrospinal fluid (CSF) cytology and radiological neuroimaging in detecting meningeal metastases remains relatively low, we sought to characterize the CSF proteome of patients with CSF tumors to identify biomarkers predictive of metastatic spread. CSF samples from 27 children with brain tumors and 13 controls (extra-CNS non-Hodgkin lymphoma) were processed using core-shell hydrogel nanoparticles, and analyzed with reverse-phase liquid chromatography/electrospray tandem mass spectrometry (LC-MS/MS). Candidate proteins were identified with Fisher's exact test and/or a univariate logistic regression model. Reverse phase protein array (RPPA), Western blot (WB), and ELISA were used in the training set and in an independent set of CFS samples (60 cases, 14 controls) to validate our discovery findings. Among the 558 non-redundant proteins identified by LC-MS/MS, 147 were missing from the CSF database at http://www.biosino.org. Fourteen of the 26 final top-candidate proteins were chosen for validation with WB, RPPA and ELISA methods. Six proteins (type 1 collagen, insulin-like growth factor binding protein 4, procollagen C-endopeptidase enhancer 1, glial cell-line derived neurotrophic factor receptor α2, inter-alpha-trypsin inhibitor heavy chain 4, neural proliferation and differentiation control protein-1) revealed the ability to discriminate metastatic cases from controls. Combining a unique dataset of CSFs from pediatric CNS tumors with a novel enabling nanotechnology led us to identify CSF proteins potentially related to metastatic status. © Spreafico et al.

AB - Central nervous system (CNS) tumors are the most common solid tumors in childhood. Since the sensitivity of combined cerebrospinal fluid (CSF) cytology and radiological neuroimaging in detecting meningeal metastases remains relatively low, we sought to characterize the CSF proteome of patients with CSF tumors to identify biomarkers predictive of metastatic spread. CSF samples from 27 children with brain tumors and 13 controls (extra-CNS non-Hodgkin lymphoma) were processed using core-shell hydrogel nanoparticles, and analyzed with reverse-phase liquid chromatography/electrospray tandem mass spectrometry (LC-MS/MS). Candidate proteins were identified with Fisher's exact test and/or a univariate logistic regression model. Reverse phase protein array (RPPA), Western blot (WB), and ELISA were used in the training set and in an independent set of CFS samples (60 cases, 14 controls) to validate our discovery findings. Among the 558 non-redundant proteins identified by LC-MS/MS, 147 were missing from the CSF database at http://www.biosino.org. Fourteen of the 26 final top-candidate proteins were chosen for validation with WB, RPPA and ELISA methods. Six proteins (type 1 collagen, insulin-like growth factor binding protein 4, procollagen C-endopeptidase enhancer 1, glial cell-line derived neurotrophic factor receptor α2, inter-alpha-trypsin inhibitor heavy chain 4, neural proliferation and differentiation control protein-1) revealed the ability to discriminate metastatic cases from controls. Combining a unique dataset of CSFs from pediatric CNS tumors with a novel enabling nanotechnology led us to identify CSF proteins potentially related to metastatic status. © Spreafico et al.

KW - Cerebrospinal fluid

KW - Liquid chromatography/electrospray tandem mass spectrometry

KW - Pediatric central nervous system tumors

KW - Protein-based biomarker

KW - Proteomic analysis

KW - collagen type 1

KW - core shell hydrogel nanoparticle

KW - glial cell line derived neurotrophic factor receptor

KW - glial cell line derived neurotrophic factor receptor alpha2

KW - inter alpha trypsin inhibitor

KW - inter alpha trypsin inhibitor heavy chain 4

KW - membrane protein

KW - nanoparticle

KW - neural proliferation and differentiation control protein 1

KW - procollagen C endopeptidase enhancer 1

KW - proteome

KW - somatomedin binding protein 4

KW - unclassified drug

KW - adolescent

KW - adult

KW - Article

KW - case control study

KW - central nervous system cancer

KW - cerebrospinal fluid analysis

KW - child

KW - controlled study

KW - disease association

KW - enzyme linked immunosorbent assay

KW - female

KW - human

KW - liquid chromatography-mass spectrometry

KW - major clinical study

KW - male

KW - metastasis

KW - nanotechnology

KW - nonhodgkin lymphoma

KW - prospective study

KW - protein analysis

KW - protein microarray

KW - proteomics

KW - reverse phase protein array

KW - reversed phase liquid chromatography

KW - Western blotting

M3 - Article

VL - 8

SP - 46177

EP - 46190

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 28

ER -