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PURPOSE: To identify a 15-KDa novel hypoxia-induced secreted protein in head and neck squamous cell carcinomas (HNSCC) and to determine its role in malignant progression. METHODS: We used surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS) and tandem MS to identify a novel hypoxia-induced secreted protein in FaDu cells. We used immunoblots, real-time polymerase chain reaction (PCR), and enzyme-linked immunoabsorbent assay to confirm the hypoxic induction of this secreted protein as galectin-1 in cell lines and xenografts. We stained tumor tissues from 101 HNSCC patients for galectin-1, CA IX (carbonic anhydrase IX, a hypoxia marker) and CD3 (a T-cell marker). Expression of these markers was correlated to each other and to treatment outcomes. RESULTS: SELDI-TOF studies yielded a hypoxia-induced peak at 15 kDa that proved to be galectin-1 by MS analysis. Immunoblots and PCR studies confirmed increased galectin-1 expression by hypoxia in several cancer cell lines. Plasma levels of galectin-1 were higher in tumor-bearing severe combined immunodeficiency (SCID) mice breathing 10% O2 compared with mice breathing room air. In HNSCC patients, there was a significant correlation between galectin-1 and CA IX staining (P = .01) and a strong inverse correlation between galectin-1 and CD3 staining (P = .01). Expression of galectin-1 and CD3 were significant predictors for overall survival on multivariate analysis. CONCLUSION: Galectin-1 is a novel hypoxia-regulated protein and a prognostic marker in HNSCC. This study presents a new mechanism on how hypoxia can affect the malignant progression and therapeutic response of solid tumors by regulating the secretion of proteins that modulate immune privilege.

Original publication

DOI

10.1200/JCO.2005.02.0206

Type

Journal article

Journal

J Clin Oncol

Publication Date

10/12/2005

Volume

23

Pages

8932 - 8941

Keywords

Analysis of Variance, Animals, Blotting, Western, Carcinoma, Squamous Cell, Cell Hypoxia, Cell Line, Tumor, Disease Progression, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Galectin 1, Head and Neck Neoplasms, Humans, Immunoenzyme Techniques, Mice, Mice, SCID, Polymerase Chain Reaction, Prognosis, Proportional Hazards Models, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Staining and Labeling, Survival Analysis, T-Lymphocytes