Galectin-1: a link between tumor hypoxia and tumor immune privilege.
OBJECTIVE
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.


CONCLUSIONS
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.
Le
Quynh-Thu
QT
Department of Radiation Oncology, Stanford University Medical Center, 875 Blake Wilbur Drive, Stanford, CA 94305-5847, USA. qle@stanford.edu
Shi
Gongyi
G
Cao
Hongbin
H
Nelson
Daniel W
DW
Wang
Yingyun
Y
Chen
Eunice Y
EY
Zhao
Shuchun
S
Kong
Christina
C
Richardson
Donna
D
O'Byrne
Ken J
KJ
Giaccia
Amato J
AJ
Koong
Albert C
AC
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D018450:Disease Progression; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D037483:Galectin 1 / Q000096:biosynthesis*; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016513:Mice, SCID; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013194:Staining and Labeling; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology
D037483:Galectin 1