Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors.
Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors.
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发表时间：
1997-12
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通讯作者：
Alicia M. Viloria Petit;J. Rak;M. Hung;P. Rockwell;N. Goldstein;B. Fendly;R. Kerbel
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作者：
Alicia M. Viloria Petit;J. Rak;M. Hung;P. Rockwell;N. Goldstein;B. Fendly;R. Kerbel
肿瘤细胞中（原）致癌受体酪氨酸激酶如表皮生长因子受体（EGFR）或ErbB2/neu（也称为HER-2）的过度表达通常被认为主要通过促进不受控制的细胞增殖而促进实体瘤的发展。然而，已知拮抗这些（原）癌基因编码的蛋白产物功能的药物在体内表现为细胞毒性样方式。这意味着这些致癌基因可能调节关键的细胞存活功能，包括血管生成。后者可能是由这些致癌基因调控相关生长因子的结果。因此，我们试图通过检测EGFR或ErbB2/neu对血管内皮细胞生长因子(VEGF)/血管通透性因子（VPF）表达的影响来确定它们是否有助于肿瘤血管生成，VPF是已知最重要的肿瘤血管生成诱导剂之一。我们发现，在体外用C225抗egfr中和抗体处理egfr阳性的A431人表皮样癌细胞（已知在体内高度依赖VEGF/VPF作为血管生成生长因子）可引起VEGF蛋白表达的剂量依赖性抑制。在裸鼠体内注射抗体四次后，在已建立的A431肿瘤中也观察到VEGF/VPF在体内表达的显著抑制，以及肿瘤血管计数的显著减少。用突变体ErbB2/neu（另一种egfr样致癌酪氨酸激酶）转化NIH 3T3成纤维细胞，可显著诱导VEGF/VPF，并且这种作用的程度在缺氧的情况下进一步升高。此外，在体外用特异性中和抗ErbB2/neu单克隆抗体（4D5）治疗ErbB2/neu阳性SKBR-3人乳腺癌细胞可导致VEGF/VPF蛋白表达呈剂量依赖性降低。综上所述，研究结果表明，EGFR和ErbB2/neu的致癌特性可能（至少在一定程度上）是通过上调有效的血管生成生长因子（如VEGF/VPF）来刺激肿瘤血管生成而介导的。这些遗传变化可能与表观遗传/环境效应（如缺氧）共同作用，最大限度地刺激VEGF/VPF的表达。因此，在体内对EGFR或ErbB2/neu蛋白功能的治疗性破坏可能导致血管生成的部分抑制，这一特征可以增强这些药物在体内的治疗指数，并赋予它们抗肿瘤作用，其程度可能与它们在单层组织培养中观察到的细胞抑制作用不成比例。
The overexpression in tumor cells of (proto)-oncogenic receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) or ErbB2/neu (also known as HER-2) is generally thought to contribute to the development of solid tumors primarily through their effects on promoting uncontrolled cell proliferation. However, agents that antagonize the function of the protein products encoded by these (proto)-oncogenes are known to behave in vivo in a cytotoxic-like manner. This implies that such oncogenes may regulate critical cell survival functions, including angiogenesis. The latter could occur as a consequence of regulation of relevant growth factors by such oncogenes. We therefore sought to determine whether EGFR or ErbB2/neu may contribute to tumor angiogenesis by examining their effects on the expression of vascular endothelial cell growth factor (VEGF)/vascular permeability factor (VPF), one of the most important of all known inducers of tumor angiogenesis. We found that in vitro treatment of EGFR-positive A431 human epidermoid carcinoma cells, which are known to be heavily dependent on VEGF/VPF in vivo as an angiogenesis growth factor, with the C225 anti-EGFR neutralizing antibody caused a dose-dependent inhibition of VEGF protein expression. Prominent suppression of VEGF/VPF expression in vivo, as well as a significant reduction in tumor blood vessel counts, were also observed in established A431 tumors shortly after injection of the antibody as few as four times into nude mice. Transformation of NIH 3T3 fibroblasts with mutant ErbB2/neu, another EGFR-like oncogenic tyrosine kinase, resulted in a significant induction of VEGF/VPF, and the magnitude of this effect was further elevated by hypoxia. Moreover, treatment of ErbB2/neu-positive SKBR-3 human breast cancer cells in vitro with a specific neutralizing anti-ErbB2/neu monoclonal antibody (4D5) resulted in a dose-dependent reduction of VEGF/VPF protein expression. Taken together, the results suggest that oncogenic properties of EGFR and ErbB2/neu may, at least in part, be mediated by stimulation of tumor angiogenesis by up-regulating potent angiogenesis growth factors such as VEGF/VPF. These genetic changes may cooperate with epigenetic/environmental effects such as hypoxia to maximally stimulate VEGF/VPF expression. Therapeutic disruption of EGFR or ErbB2/neu protein function in vivo may therefore result in partial suppression of angiogenesis, a feature that could enhance the therapeutic index of such agents in vivo and endow them with anti-tumor effects, the magnitude of which may be out of proportion with their observed cytostatic effects in monolayer tissue culture.