Targeting the heparin-binding epidermal growth factor-like growth factor in ovarian cancer therapy
Targeting the heparin-binding epidermal growth factor-like growth factor in ovarian cancer therapy
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DOI：
10.1097/gco.0b013e3283409c91
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发表时间：
2011-02-01
影响因子：
2.1
通讯作者：
Miyamoto, Shingo
中科院分区：
文献类型：
--
作者：
Tsujioka, Hiroshi;Yotsumoto, Fusanori;Miyamoto, Shingo
综述目的针对ErbB蛋白家族受体的治疗在目前的癌症治疗中并不总是取得良好或成功的结果。本文综述了针对ErbB系统的配体之一--肝素结合的表皮生长因子样生长因子(HB-EGF)靶向治疗卵巢癌的可能性。总之，脂磷脂酸(LPA)和HB-EGF在晚期卵巢癌中主要表达，LPA诱导的去整合素和金属蛋白酶介导的HB-EGF胞外区脱落是肿瘤形成的关键。我们还注意到，外源HB-EGF的表达促进了肿瘤的形成，但抑制抑制了细胞外信号相关激酶和丝氨酸/苏氨酸蛋白激酶的激活。最后，我们通过评价人卵巢癌细胞的增殖情况，研究了特异性的HB-EGF抑制剂CRM197对卵巢癌细胞的抗肿瘤作用。CRM197治疗晚期卵巢癌的I期研究已经开始，这是ErbB配体靶向治疗的第一个被批准的试验。我们还讨论了CRM197与其他常规化疗药物联合应用的临床适应性。
Purpose of reviewTherapeutics targeting the ErbB protein family receptors have not always yielded favorable or successful results in present cancer therapy. This review discusses the possibility of the clinical adaptation of targeting against heparin-binding epidermal growth factor-like growth factor (HB-EGF), one of the ligands of the ErbB system, in ovarian cancer therapy.Recent findingsWe have previously described the results of studies concerning roles of HB-EGF in tumor formation in ovarian cancer. In brief, lisophosphatidic acid (LPA) and HB-EGF are predominantly expressed in advanced ovarian cancer, and LPA-induced, a disintegrin and metalloprotease-mediated ectodomain shedding of HB-EGF was found to be critical to tumor formation. We also noted that exogenous expression of HB-EGF enhanced tumor formation but inhibition blocked both extracellular signal-related kinase and serine/threonine protein kinase activation. Finally we investigated the antitumor effects of CRM197 - a specific HB-EGF inhibitor - on ovarian cancer cells by evaluating human ovarian cancer cell proliferation.SummaryWe discuss alternative strategies to develop the chemotherapeutic agent based on targeting ErbB family ligands rather than their receptors. A phase I study of CRM197 for advanced ovarian cancer has already begun, which is the first approved trial of ErbB-ligand-targeted therapy. We also discuss clinical adaptations based on combination of CRM197 with other conventional chemotherapeutic agents.