Tumor-inhibitory monoclonal antibodies to the HER-2/Neu receptor induce differentiation of human breast cancer cells.
Tumor-inhibitory monoclonal antibodies to the HER-2/Neu receptor induce differentiation of human breast cancer cells.
复制标题
DOI：
--
复制
发表时间：
1992-05
期刊：
影响因子：
11.2
通讯作者：
S. Bacus;I. Stancovski;E. Huberman;D. Chin;E. Hurwitz;G. Mills;A. Ullrich;M. Sela;Y. Yarden
中科院分区：
文献类型：
--
作者：
S. Bacus;I. Stancovski;E. Huberman;D. Chin;E. Hurwitz;G. Mills;A. Ullrich;M. Sela;Y. Yarden
HER-2/neu原癌基因(也称为erbB-2)编码多肽生长调节分子的酪氨酸激酶受体。该基因的扩增和过度表达在人类腺癌中经常被观察到，并与不良预后相关。为了探索针对HER-2/Neu受体的抗体治疗的可能性，我们提出了一组针对HER-2/Neu受体的鼠源性单抗，并测试了它们对HER-2/neu转基因成纤维细胞在裸鼠体内致瘤生长的影响。我们之前曾报道过IP。注射抗体可抑制或加速HER-2/neu转基因裸鼠的成瘤生长。在这里，我们报告，这些相反的效应也是由静脉注射引起的。注射抗体后，它们持续了7周以上，可能是由受体分子上的不同表位介导的。为了了解抗体诱导肿瘤抑制的细胞机制，我们测试了单抗对各种培养的人乳腺癌细胞的影响。我们的分析表明，肿瘤抑制抗体特异性地诱导表型细胞分化，包括在细胞周期的晚期或G2期早期停止生长，显著改变细胞质和核的形态，乳汁成分(酪蛋白和脂)的合成和分泌，以及HER-2/Neu蛋白移位到细胞质和核周。不同抗体的细胞分化程度可能与它们的肿瘤抑制潜力有关，而促进肿瘤的单抗或对照免疫球蛋白在细胞分化方面完全无效。综上所述，我们的体内和体外研究表明，抗HER-2/Neu的单抗的肿瘤抑制潜力与它们在体外诱导细胞分化的能力有关。这一观察结果可能为表达HER-2/neu癌基因的癌症的免疫治疗带来希望。
The HER-2/neu protooncogene (also called erbB-2) encodes a tyrosine kinase receptor for a polypeptide growth-regulatory molecule. Amplification and overexpression of the gene have been frequently observed in human adenocarcinomas and correlated with poor prognosis. To explore the potential of antibody therapy directed at the HER-2/Neu receptor, we have raised a panel of murine monoclonal antibodies to the human protein, and tested their effect on the tumorigenic growth of HER-2/neu-transfected fibroblasts in athymic mice. We previously reported that the i.p. injected antibodies either inhibited or accelerated the tumorigenic growth of HER-2/neu transfectants in athymic mice. Here we report that these opposing effects were induced also by i.v. injected antibodies, they lasted over 7 weeks, and were probably mediated by distinct epitopes on the receptor molecule. To understand the cellular mechanisms underlying antibody-induced tumor inhibition, we tested the effect of the monoclonal antibodies on various cultured human breast cancer cells. Our analysis revealed that the tumor-inhibitory antibodies specifically induced phenotypic cellular differentiation that included growth arrest at late S or early G2 phase of the cell cycle, markedly altered cytoplasm and nuclear morphology, synthesis and secretion of milk components (casein and lipids), and translocation of the HER-2/Neu protein to cytoplasmic and perinuclear sites. The extent of cellular differentiation by various antibodies could be correlated with their tumor-inhibitory potential, whereas a tumor-stimulatory monoclonal antibody or control immunoglobulin were completely inactive with respect to cellular differentiation. Taken together, our in vivo and in vitro studies correlate the tumor inhibitory potential of monoclonal antibodies to HER-2/Neu with their capacity to induce cellular differentiation in vitro. This observation may hold promise for immunotherapy of cancers that express the HER-2/neu oncogene.