Serum Protein Profiling to Identify High-Risk Neuroblastoma: Preclinical Relevance of Blood-Based Biomarkers

John A. Sandoval, Katharyn E. Turner, Derek J. Hoelz, Frederick Rescorla, Robert J. Hickey, Linda H. Malkas

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Introduction: Development of early detection assays for advanced stage neuroblastoma (NB) remains elusive. We have previously shown that serum protein profiling technologies can differentiate healthy from NB children. As various sources of patient related bias exist in serum proteins, we hypothesized a well controlled animal model may provide a better method to identify tumor blood-based markers during NB progression. Methods: Tumors were induced in the left kidneys of nude mice by the injection of cultured human NB cells (106). Sera were collected from control and tumor-bearing mice at 2, 4, and 6 wk. Albumin-depleted sera were subjected to comparative proteomic profiling using 2D gel electrophoresis. Paired samples at each time point were analyzed and differentially expressed serum proteins were identified by mass spectrometry. Additionally, sera proteomic analysis from children with Stage IV NB and healthy controls were performed. Results: Overexpression of five mouse serum proteins [α1-acid glycoprotein, α1-antitrypsin, α2-macroglobulin, serum amyloid P-component, and serum amyloid A) were found only in NB-bearing mice. Changes in protein abundance were found to increase 2.5-fold (P ≤ 0.05) between 2-, 4-, and 6-wk old mice. Underexpression of immunoglobulin κ chain constant region was observed in the sera of tumor bearing mice compared with controls (2.5-fold, P ≤ 0.05). Among NB patients, α1-acid glycoprotein, apolipoprotein A-IV, haptoglobin, and serum amyloid A were found to be up-regulated. Conclusions: We identified distinct acute phase proteins that show up-regulation in both an animal tumor model and high-risk NB patients. As these serum proteins have been recognized as markers of tumor progression and prognosis in human malignancies, the validation of these polypeptides may enable serum proteomic profiling to become a valuable tool for identifying high-risk NB.

Original languageEnglish
Pages (from-to)268-274
Number of pages7
JournalJournal of Surgical Research
Volume142
Issue number2
DOIs
StatePublished - Oct 2007

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Neuroblastoma
Blood Proteins
Biomarkers
Proteomics
Serum Amyloid A Protein
Neoplasms
Serum
Immunoglobulin Constant Regions
Glycoproteins
Animal Models
Immunoglobulin Subunits
Serum Amyloid P-Component
Macroglobulins
Acids
Haptoglobins
Acute-Phase Proteins
Electrophoresis, Gel, Two-Dimensional
Tumor Biomarkers
Nude Mice
Serum Albumin

Keywords

  • acute phase proteins/response
  • animal model
  • high-risk pediatric malignancy
  • neuroblastoma
  • serum proteomics

ASJC Scopus subject areas

  • Surgery

Cite this

Serum Protein Profiling to Identify High-Risk Neuroblastoma : Preclinical Relevance of Blood-Based Biomarkers. / Sandoval, John A.; Turner, Katharyn E.; Hoelz, Derek J.; Rescorla, Frederick; Hickey, Robert J.; Malkas, Linda H.

In: Journal of Surgical Research, Vol. 142, No. 2, 10.2007, p. 268-274.

Research output: Contribution to journalArticle

Sandoval, John A. ; Turner, Katharyn E. ; Hoelz, Derek J. ; Rescorla, Frederick ; Hickey, Robert J. ; Malkas, Linda H. / Serum Protein Profiling to Identify High-Risk Neuroblastoma : Preclinical Relevance of Blood-Based Biomarkers. In: Journal of Surgical Research. 2007 ; Vol. 142, No. 2. pp. 268-274.
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AU - Hoelz, Derek J.

AU - Rescorla, Frederick

AU - Hickey, Robert J.

AU - Malkas, Linda H.

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N2 - Introduction: Development of early detection assays for advanced stage neuroblastoma (NB) remains elusive. We have previously shown that serum protein profiling technologies can differentiate healthy from NB children. As various sources of patient related bias exist in serum proteins, we hypothesized a well controlled animal model may provide a better method to identify tumor blood-based markers during NB progression. Methods: Tumors were induced in the left kidneys of nude mice by the injection of cultured human NB cells (106). Sera were collected from control and tumor-bearing mice at 2, 4, and 6 wk. Albumin-depleted sera were subjected to comparative proteomic profiling using 2D gel electrophoresis. Paired samples at each time point were analyzed and differentially expressed serum proteins were identified by mass spectrometry. Additionally, sera proteomic analysis from children with Stage IV NB and healthy controls were performed. Results: Overexpression of five mouse serum proteins [α1-acid glycoprotein, α1-antitrypsin, α2-macroglobulin, serum amyloid P-component, and serum amyloid A) were found only in NB-bearing mice. Changes in protein abundance were found to increase 2.5-fold (P ≤ 0.05) between 2-, 4-, and 6-wk old mice. Underexpression of immunoglobulin κ chain constant region was observed in the sera of tumor bearing mice compared with controls (2.5-fold, P ≤ 0.05). Among NB patients, α1-acid glycoprotein, apolipoprotein A-IV, haptoglobin, and serum amyloid A were found to be up-regulated. Conclusions: We identified distinct acute phase proteins that show up-regulation in both an animal tumor model and high-risk NB patients. As these serum proteins have been recognized as markers of tumor progression and prognosis in human malignancies, the validation of these polypeptides may enable serum proteomic profiling to become a valuable tool for identifying high-risk NB.

AB - Introduction: Development of early detection assays for advanced stage neuroblastoma (NB) remains elusive. We have previously shown that serum protein profiling technologies can differentiate healthy from NB children. As various sources of patient related bias exist in serum proteins, we hypothesized a well controlled animal model may provide a better method to identify tumor blood-based markers during NB progression. Methods: Tumors were induced in the left kidneys of nude mice by the injection of cultured human NB cells (106). Sera were collected from control and tumor-bearing mice at 2, 4, and 6 wk. Albumin-depleted sera were subjected to comparative proteomic profiling using 2D gel electrophoresis. Paired samples at each time point were analyzed and differentially expressed serum proteins were identified by mass spectrometry. Additionally, sera proteomic analysis from children with Stage IV NB and healthy controls were performed. Results: Overexpression of five mouse serum proteins [α1-acid glycoprotein, α1-antitrypsin, α2-macroglobulin, serum amyloid P-component, and serum amyloid A) were found only in NB-bearing mice. Changes in protein abundance were found to increase 2.5-fold (P ≤ 0.05) between 2-, 4-, and 6-wk old mice. Underexpression of immunoglobulin κ chain constant region was observed in the sera of tumor bearing mice compared with controls (2.5-fold, P ≤ 0.05). Among NB patients, α1-acid glycoprotein, apolipoprotein A-IV, haptoglobin, and serum amyloid A were found to be up-regulated. Conclusions: We identified distinct acute phase proteins that show up-regulation in both an animal tumor model and high-risk NB patients. As these serum proteins have been recognized as markers of tumor progression and prognosis in human malignancies, the validation of these polypeptides may enable serum proteomic profiling to become a valuable tool for identifying high-risk NB.

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