Frequent overexpression of multiple ErbB receptors by head and neck squamous cell carcinoma contrasts with rare antibody immunity in patients.
In an effort to elucidate the role of ErbB receptors in human head and neck squamous cell carcinoma (HNSCC), expression abnormalities and subcellular localization of epidermal growth factor receptor (EGFR), ErbB2, ErbB3, and ErbB4 were investigated along with EGF and tenascin by immunohistochemistry in 38 carcinomas as compared to adjacent normal mucosa of 24 cases. Although tumour-specific overexpression affected each ErbB receptor (EGFR 47%, ErbB2 29%, ErbB3 21%, ErbB4 26%), EGFR abnormalities were most prevalent. The latter, and overexpression of more than two ErbB receptors in the same tumour, which always included EGFR, correlated with metastatic disease. ErbB products were specifically detected on the cell membrane and in the cytoplasm. In contrast, ErbB4 was uniquely localized to the nucleus in 7 carcinomas and a tumour-derived cell line, indicating a role for regulated intramembrane proteolysis resulting in nuclear ErbB4 translocation in HNSCC. Expression of prototype ligand EGF or low-affinity stromal activator tenascin correlated significantly with EGFR overexpression, implying chronic EGFR activation. Simultaneous overexpression of additional ErbB receptors in most of these cases suggested recurrent involvement of receptor heterodimers. In spite of frequent ErbB receptor alterations, autologous ErbB serum antibodies were rare, with only 1 of 38 tumour patients exhibiting an ErbB2-specific immune response. Based on upregulation of several known immunosuppressive molecules, scarcity of ErbB-specific antibodies is consistent with attenuation of natural tumour-specific immune responses in HNSCC.
Department of Experimental Medicine and Biochemical Sciences, University Tor Vergata, Rome, Italy.
Roberto
R
Bei
Alfredo
A
Budillon
Laura
L
Masuelli
Vittore
V
Cereda
Domenico
D
Vitolo
Elena
E
Di Gennaro
Vanessa
V
Ripavecchia
Camilla
C
Palumbo
Franco
F
Ionna
Simona
S
Losito
Andrea
A
Modesti
Matthias H
MH
Kraus
Raffaella
R
Muraro
D000917:Antibody Formation / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics* / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D018815:Genes, erbB / Q000235:genetics* / Q000276:immunology; D018734:Genes, erbB-2 / Q000235:genetics / Q000276:immunology; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D009363:Neoplasm Proteins / Q000235:genetics* / Q000276:immunology; D066247:Receptor, ErbB-4; D015375:Receptors, Interleukin-2 / Q000276:immunology; D019063:Tenascin / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000276:immunology; D014178:Translocation, Genetic / Q000235:genetics
D009363:Neoplasm Proteins; D015375:Receptors, Interleukin-2; D019063:Tenascin; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4