Albanell J, Codony-Servat J, Rojo F, Del Campo J M, Sauleda S, Anido J, Raspall G, Giralt J, Roselló J, Nicholson R I, Mendelsohn J, Baselga J
Laboratory of Oncology Research, Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona, Spain.
Cancer Res. 2001 Sep 1;61(17):6500-10.
The expression of the activated mitogen-activated kinases/extracellular signal-regulated kinases (ERKs) ERK1 and ERK2 was characterized in 101 humanhead and neck squamous carcinoma specimens. Activated ERK1/2were detected at different levels in the majority of these tumors, as assayed by immunostaining with an antibody specific for the dually phosphorylated and activated ERK1 and ERK2. ERK1/2 activation levels were higher in tumors with advanced regional lymph node metastasis (P = 0.048) and in relapsed tumors (P = 0.021). The expression of epidermal growth factor (EGF) receptor (P = 0.037), transforming growth factor alpha (TGF-alpha; P < 0.001), and HER2 (P = 0.066; positive trend) correlated with activation of ERK1/2. In a multivariate analysis, both TGF-alpha (P < 0.0001) and HER2 (P = 0.045) were independently correlated with ERK1/2 activation. In turn, activation of ERK1/2 was associated with a higher Ki-67 proliferative index (P = 0.002). In EGF receptor-dependent model cells (A431 and DiFi), a specific EGF receptor tyrosine kinase inhibitor ("Iressa"; ZD1839) and a chimeric anti-EGF receptor antibody ("Cetuximab"; C225) inhibited ERK 1/2 activation at concentrations that inhibited autocrine cell proliferation. In patients on treatment with C225, the activation of ERK1/2 in skin, an EGF receptor-dependent tissue, was lower compared with control skin. Parallel changes were seen in keratinocyte Ki67 proliferation indexes in skin from C225-treated patients. Taken together, these studies provide support for a role of activation of ERK1/2 in head and neck squamous carcinoma and a correlation with EGF receptor/TGF-alpha expression. The inhibition of ERK1/2 activation in vitro and in vivo by compounds targeting the EGF receptor points to the interest of ERK1/2 as potential surrogate markers of EGF-receptor signaling in clinical therapeutic studies.
在101例人头颈部鳞状癌标本中对活化的丝裂原活化蛋白激酶/细胞外信号调节激酶（ERK）ERK1和ERK2的表达进行了表征。通过用针对双磷酸化和活化的ERK1和ERK2的特异性抗体进行免疫染色分析，在大多数这些肿瘤中检测到不同水平的活化ERK1/2。在有晚期区域淋巴结转移的肿瘤（P = 0.048）和复发肿瘤（P = 0.021）中，ERK1/2的活化水平更高。表皮生长因子（EGF）受体（P = 0.037）、转化生长因子α（TGF-α；P < 0.001）和HER2（P = 0.066；呈阳性趋势）的表达与ERK1/2的活化相关。在多变量分析中，TGF-α（P < 0.0001）和HER2（P = 0.045）均与ERK1/2的活化独立相关。反过来，ERK1/2的活化与较高的Ki-67增殖指数相关（P = 0.002）。在依赖EGF受体的模型细胞（A431和DiFi）中，一种特异性EGF受体酪氨酸激酶抑制剂（“易瑞沙”；ZD1839）和一种嵌合抗EGF受体抗体（“西妥昔单抗”；C225）在抑制自分泌细胞增殖的浓度下抑制ERK 1/2的活化。在用C225治疗的患者中，与对照皮肤相比，皮肤（一种依赖EGF受体的组织）中ERK1/2的活化较低。在接受C225治疗患者的皮肤中，角质形成细胞Ki67增殖指数也出现了类似变化。综上所述，这些研究支持ERK1/2活化在头颈部鳞状癌中的作用以及与EGF受体/TGF-α表达的相关性。在体外和体内通过靶向EGF受体的化合物抑制ERK1/2活化表明，在临床治疗研究中，ERK1/2作为EGF受体信号潜在替代标志物具有研究价值。
