Elsevier

Oral Oncology

Volume 38, Issue 1, January 2002, Pages 73-80
Oral Oncology

C-erbB receptors in squamous cell carcinomas of the head and neck: clinical significance and correlation with matrix metalloproteinases and vascular endothelial growth factors

https://doi.org/10.1016/S1368-8375(01)00029-XGet rights and content

Abstract

We studied the profile of four c-erbB receptors in head and neck squamous cell carcinomas (HNSCC) and to determine whether their expression was associated with clinicopathological features and key molecules involved in angiogenesis and metastasis. We also assessed the impact of expression on survival. This study included 54 cases of primary HNSCC, of which 27 cases showed lymph node metastasis. The expression of c-erbB receptors, matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) family members was analysed in the same tissue homogenates by semi-quantitative RT-PCR. HNSCC frequently co-expressed multiple c-erbB receptors and showed significant correlations amongst their levels. High expression of epidermal growth factor receptor (EGFR), c-erbB-2 or c-erbB-3 was associated with an infiltrating mode of invasion, nodal metastases and advanced pathological stages. EGFR and c-erbB-2 levels were strongly correlated (P=0.0004–0.029) with the expression of MMP-2, MMP-7, MMP-9, MMP-10, MMP-11, MMP-13, VEGF-A and VEGF-C whereas the levels of c-erbB-3 and B-4 showed a weaker correlation (P=0.049–0.01) with some MMPs and VEGF-C. Only nodal metastasis and EGFR levels were significantly associated with poor outcome in uni- and multi-variate analysis. We conclude that co-operative signalling of all four c-erbB receptors may play a significant role in the pathogenesis of HNSCC. Amongst these, EGFR appears to be the dominant component controlling the invasive and angio-/lymphangiogenic phenotype in HNSCC via upregulation of multiple MMPs and VEGFs.

Introduction

Squamous cell carcinoma of the head and neck region (HNSCC) is a major problem world-wide [1]. In the United Kingdom, HNSCCs are uncommon cancers but they often present difficult problems in clinical situation [2]. Clearly, a better understanding of the molecular mechanisms and the identification of potential biological markers may provide accurate prognostic markers and useful information for effective treatment. In this context, our group has focused on the role of c-erbB receptors, the transmembrane type I receptor tyrosine kinase family. The c-erbB receptors have four homologous members in the family: the epidermal growth factor receptor (EGFR or c-erbB-1 or HER-1 for human EGF receptor-1), c-erbB-2 (neu or HER-2), c-erbB-3 (HER-3) and c-erbB-4 (HER-4) [3], [4]. Receptor activation results in phosphorylation of specific tyrosine residues located within the receptor's cytoplasmic region, which leads to the recruitment of phosphotyrosine-binding effector proteins, and subsequent simultaneous stimulation of multiple signalling pathways. Numerous studies have suggested the potential role of the c-erbB receptors and their ligands in the progression of HNSCC [5], [6], [7], [8], [9], [10], [11], [12], [13]. However, the underlying mechanisms remained unclear.

HNSCC is characterised by its capacity to invade adjacent tissues and metastasise loco-regionally. The cooperation of multiple proteolytic enzymes which are secreted by tumour cells and/or host cells and whose substrates include extracellular matrix (ECM) components is required for cancer cells to invade the ECM and penetrate the lymphatic or blood vessel wall where they may grow and metastasise to distant sites [14]. ECM proteolysis is also involved in the angiogenesis necessary for the continued growth of solid tumours. Recently we demonstrated that the expression of multiple matrix metalloproteinases (MMPs) and vascular endothelial growth factors (VEGFs) is a common feature in both experimental [10], [11] and clinical models of HNSCC [15], and that the analysis of specific MMPs and VEGFs may be useful to evaluate the malignant potential in individual HNSCC. Our in vitro studies also suggest a link between the c-erbB signalling and regulation of multiple MMPs and VEGFs in HNSCC [8], [9], [10]. The differential regulatory patterns of these key molecules by the aberration of c-erbB receptors may be crucial for the loss of growth regulation, angiogenesis, invasion and metastasis of the tumours expressing them. In the present study, we characterised the expression and prognostic value of four c-erbB receptor family members in HNSCCs and their relationship with clinicopathological characteristics. We also examined the possible roles of c-erbB oncogenes on expression of key molecules involved in HNSCC invasion and metastasis, in particular, the relationships with MMPs and VEGFs.

Section snippets

Patients and tissue samples

The protocol for the following studies was approved by the Ethical Committee of the Royal Marsden Hospital Trust, UK. Fresh tissue samples were obtained from 54 patients undergoing major surgical resection for HNSCC at the Head and Neck Unit, the Royal Marsden Hospital, from July 1997 through October 1999. The patients presented no detectable metastases in distant organs at the time of surgery. None of the patients had previously received preoperative chemotherapy or radiotherapy. All patients

Expression of c-erbB receptors in HNSCC tissues

Lesions from primary HNSCC (n=54), LNM (n=27), as well as histologically normal adjacent mucosae (n=32) were examined for mRNA levels of all four c-erbB receptors. The mRNA expression of EGFR was significantly greater in malignant tissues (primary tumours and/or LNM) in comparison with the mRNA levels in histologically normal mucosae (2.4-fold, P<0.0001). Varying levels of c-erbB-2, c-erbB-3 and c-erbB-4 receptors were detected in tumours (primary HNSCC and LNM) and adjacent histologically

Discussion

The present study demonstrated that a significant proportion of human HNSCC simultaneously expressed several receptors of the c-erbB family. Furthermore, a statistically significant direct correlation among expression of these receptors was observed. Enhanced expression of EGFR or c-erbB-2, infiltrating mode of invasion and nodal involvement were the variables found to be significantly correlated with a reduced survival by univariate analysis, but only EGFR and nodal status were shown to be

Acknowledgements

This research was supported in part by a grant from the Faculty of Medicine, Siriraj Hospital Medical School, Bangkok, Thailand 10700. We thank Gary Box and William Court for excellent technical assistance.

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