O-charoenrat P, Rhys-Evans P, Court W J, Box G M, Eccles S A
Department of Head and Neck Surgery, Royal Marsden Hospital, London, UK.
Clin Exp Metastasis. 1999;17(7):631-9. doi: 10.1023/a:1006751016860.
Evidence suggests that there is an association between the abnormal expression of members of the c-erbB receptor tyrosine kinase family and poor prognosis in head and neck squamous cell carcinomas (HNSCC). Until now, the relative contributions of different c-erbB ligands to HNSCC progression have not been clearly defined. In this paper we examined the effects of ligands with different c-erbB receptor specificities in terms of their stimulation of HNSCC proliferation, expression of matrix metalloproteinases (MMPs) and invasion. Heregulin-beta1 (HRG-beta1; selective c-erbB3/B4 ligand) was found to stimulate proliferation in the majority of cell lines, whereas epidermal growth factor (EGF; EGFR ligand) and betacellulin (BTC; EGFR/B4 ligand) induced variable responses. All three ligands up-regulated multiple MMPs including collagenases, stromelysins, matrilysin and gelatinase B (MMP-9) but had minimal or no effects on gelatinase A (MMP-2), MT1-MMP and tissue inhibitors of MMPs (TIMPs). MMP-9 mRNA was induced to a higher level than other MMPs, although with slower kinetics. HRG-beta1 was less active than EGF and BTC at the optimal concentration (relative potency of EGF:BTC:HRG = 3:4:1). In vitro invasion through Matrigel was also increased by all three ligands in proportion to their MMP up-regulation. A specific anti-EGFR monoclonal antibody (mAb ICR62) inhibited MMP up-regulation, migration and invasion induced by all three ligands, whereas an anti-c-erbB-2 mAb ICR12 inhibited mitogenic and motogenic responses following ligand stimulation but had no effect on MMP expression. These results suggest that c-erbB ligands may differentially potentiate the invasive phenotype of HNSCC via co-operative induction of cell proliferation, migration and proteolysis. The EGFR signalling pathway appears to be the dominant component controlling the proteolytic and invasive phenotype in HNSCC, whereas the c-erbB-2 signalling pathway is responsible, in part, for the mitogenic and motogenic effects of ligands.
有证据表明，c-erbB受体酪氨酸激酶家族成员的异常表达与头颈部鳞状细胞癌（HNSCC）的不良预后相关。到目前为止，不同的c-erbB配体对HNSCC进展的相对作用尚未明确界定。在本文中，我们研究了具有不同c-erbB受体特异性的配体对HNSCC增殖、基质金属蛋白酶（MMPs）表达和侵袭的刺激作用。发现这里调节素-β1（HRG-β1；选择性c-erbB3/B4配体）能刺激大多数细胞系的增殖，而表皮生长因子（EGF；EGFR配体）和β细胞素（BTC；EGFR/B4配体）则引起不同的反应。所有这三种配体均上调多种MMPs，包括胶原酶、基质溶解素、基质溶素和明胶酶B（MMP-9），但对明胶酶A（MMP-2）、MT1-MMP和MMP组织抑制剂（TIMPs）影响极小或无影响。MMP-9 mRNA的诱导水平高于其他MMPs，尽管动力学较慢。在最佳浓度下，HRG-β1的活性低于EGF和BTC（EGF:BTC:HRG的相对效力 = 3:4:1）。所有这三种配体均可使通过基质胶的体外侵袭按其MMP上调比例增加。一种特异性抗EGFR单克隆抗体（mAb ICR62）抑制所有这三种配体诱导的MMP上调、迁移和侵袭，而抗c-erbB-2单克隆抗体ICR12抑制配体刺激后的促有丝分裂和促运动反应，但对MMP表达无影响。这些结果表明，c-erbB配体可能通过协同诱导细胞增殖、迁移和蛋白水解，以不同方式增强HNSCC的侵袭表型。EGFR信号通路似乎是控制HNSCC蛋白水解和侵袭表型的主要成分，而c-erbB-2信号通路部分负责配体的促有丝分裂和促运动作用。
