Ottaiano Alessandro, Pisano Carmela, De Chiara Anna, Ascierto Paolo Antonio, Botti Gerardo, Barletta Emiddio, Apice Gaetano, Gridelli Cesare, Iaffaioli Vincenzo Rosario
Division of Medical Oncology B, National Cancer Institute G Pascale, Naples, Italy.
Tumori. 2002 Sep-Oct;88(5):361-6. doi: 10.1177/030089160208800502.
CD40, a cell surface molecule, is expressed on B-cell malignancies and many different solid tumors. It is capable of mediating diverse biological phenomena such as the induction of apoptosis in tumors and stimulation of the immune response. It has thus been studied as a possible target for antitumor therapy. The general aim of this review is to focus the attention of clinical oncologists on the involvement of CD40 in tumors and the rationale of CD40-activation-based therapies in new, biologically oriented antitumor protocols.
A Medline review of published papers about the role of CD40 activation in cancer therapy.
Many authors have shown that CD40 activation promotes apoptotic death of tumor cells and that the presence of the molecule on the surface of carcinoma lines is an important factor in the generation of tumor-specific T-cell responses that contribute to tumor cell elimination. The CD40 ligand (CD40L) is the natural ligand for CD40; it is expressed primarily on the surface of activated T lymphocytes. Preclinical studies suggest that CD40-CD40L interaction could be useful for cytotoxicity against CD40-expressing tumors and for immune stimulation. Tumor inhibition was observed when tumor cells were treated with agonistic anti-CD40 monoclonal antibodies or with the soluble form of CD40L. The results of the first phase I clinical trial to treat cancer patients with subcutaneous injection of recombinant human CD40L have been recently reported. Immunohistochemical studies have revealed that detection of CD40 in primary cutaneous malignant melanoma and lung cancer may have a negative prognostic value. Interestingly, up-regulation of CD40 was observed in the tumor vessels of renal carcinomas and Kaposi's sarcoma, suggesting possible involvement of CD40 in tumor angiogenesis. Recently, it has also been shown that CD40 engagement on endothelial cells induces in vitro tubule formation and expression of matrix metalloproteinases, two processes involved in the neovascularization and progression of tumors.
CD40 activation represents an exciting target for hematological malignancies and solid tumors expressing the molecule, but its functional role in cancer development still remains unclear and controversial.
CD40是一种细胞表面分子，在B细胞恶性肿瘤和许多不同的实体瘤中均有表达。它能够介导多种生物学现象，如诱导肿瘤细胞凋亡和刺激免疫反应。因此，它已被作为抗肿瘤治疗的一个可能靶点进行研究。本综述的总体目的是使临床肿瘤学家关注CD40在肿瘤中的作用以及基于CD40激活的疗法在新的、以生物学为导向的抗肿瘤方案中的基本原理。
对发表的关于CD40激活在癌症治疗中作用的论文进行Medline检索。
许多作者已表明，CD40激活可促进肿瘤细胞的凋亡性死亡，并且癌系细胞表面该分子的存在是产生有助于肿瘤细胞清除的肿瘤特异性T细胞反应的一个重要因素。CD40配体（CD40L）是CD40的天然配体；它主要表达于活化的T淋巴细胞表面。临床前研究表明，CD40-CD40L相互作用可能有助于对表达CD40的肿瘤产生细胞毒性作用以及进行免疫刺激。当用激动性抗CD40单克隆抗体或可溶性CD40L处理肿瘤细胞时，可观察到肿瘤抑制作用。最近报道了首例皮下注射重组人CD40L治疗癌症患者的I期临床试验结果。免疫组织化学研究显示，在原发性皮肤恶性黑色素瘤和肺癌中检测CD40可能具有负面预后价值。有趣的是，在肾癌和卡波西肉瘤的肿瘤血管中观察到CD40上调，提示CD40可能参与肿瘤血管生成。最近还表明，内皮细胞上的CD40结合可在体外诱导小管形成和基质金属蛋白酶表达，这两个过程均参与肿瘤的新生血管形成和进展。
对于表达该分子的血液系统恶性肿瘤和实体瘤而言，CD40激活是一个令人关注的靶点，但其在癌症发生发展中的功能作用仍不明确且存在争议。
