Frequent overexpression of multiple ErbB receptors by head and neck squamous cell carcinoma contrasts with rare antibody immunity in patients

Roberto Bei, Alfredo Budillon, Laura Masuelli, Vittore Cereda, Domenico Vitolo, Elena Di Gennaro, Vanessa Ripavecchia, Camilla Palumbo, Franco Ionna, Simona Losito, Andrea Modesti, Matthias H. Kraus, Raffaela Muraro

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)317-325
Number of pages9
JournalJournal of Pathology
Volume204
Issue number3
DOIs
Publication statusPublished - Nov 2004

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Epidermal Growth Factor Receptor
Immunity
Antibodies
Tenascin
Epidermal Growth Factor
Neoplasms
Carcinoma
Immunosuppressive Agents
Tumor Cell Line
Proteolysis
ErbB Receptors
Carcinoma, squamous cell of head and neck
Cytoplasm
Mucous Membrane
Up-Regulation
Immunohistochemistry
Cell Membrane
Ligands
Serum

Keywords

  • Cooperative signalling
  • Head and neck
  • Immunity
  • Nuclear translocation
  • Overexpression
  • Squamous cell carcinoma
  • Type I receptor tyrosine kinases

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Frequent overexpression of multiple ErbB receptors by head and neck squamous cell carcinoma contrasts with rare antibody immunity in patients. / Bei, Roberto; Budillon, Alfredo; Masuelli, Laura; Cereda, Vittore; Vitolo, Domenico; Di Gennaro, Elena; Ripavecchia, Vanessa; Palumbo, Camilla; Ionna, Franco; Losito, Simona; Modesti, Andrea; Kraus, Matthias H.; Muraro, Raffaela.

In: Journal of Pathology, Vol. 204, No. 3, 11.2004, p. 317-325.

Research output: Contribution to journalArticle

Bei, Roberto ; Budillon, Alfredo ; Masuelli, Laura ; Cereda, Vittore ; Vitolo, Domenico ; Di Gennaro, Elena ; Ripavecchia, Vanessa ; Palumbo, Camilla ; Ionna, Franco ; Losito, Simona ; Modesti, Andrea ; Kraus, Matthias H. ; Muraro, Raffaela. / Frequent overexpression of multiple ErbB receptors by head and neck squamous cell carcinoma contrasts with rare antibody immunity in patients. In: Journal of Pathology. 2004 ; Vol. 204, No. 3. pp. 317-325.
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abstract = "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.",
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AU - Di Gennaro, Elena

AU - Ripavecchia, Vanessa

AU - Palumbo, Camilla

AU - Ionna, Franco

AU - Losito, Simona

AU - Modesti, Andrea

AU - Kraus, Matthias H.

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