小柯机器人

E-钙粘蛋白是乳腺癌转移所需
2019-09-05 15:59

近日,美国约翰霍普金斯大学Andrew J. Ewald课题组发现E-钙粘蛋白(E-cadherin)在多种乳腺癌模型中都是转移所需的。相关论文2019年9月4日在线发表在《自然》上。

研究人员表示,转移是癌症患者死亡的主要驱动因素。侵入周围组织和转移已被认为是在细胞外粘附蛋白E-钙粘蛋白丢失后开始,这是基于体外迁移与E-钙粘蛋白水平相反的相关性而得出的。然而,这一假设与观察到结果不一致,即大多数乳腺癌是侵袭性导管癌,并在原发性肿瘤和转移灶中表达E-钙粘蛋白。

为了解决这种差异,研究人员使用管腔和基底浸润性导管癌的小鼠和人类模型,测试了转移时对E-钙粘蛋白的遗传需求。研究人员发现E-钙粘蛋白促进多种侵袭性导管癌模型的转移。虽然E-钙粘蛋白的缺失增加了侵袭,但它也降低了癌细胞的增殖和存活、循环肿瘤细胞数量、远端器官中癌细胞的繁殖和转移生长。在转录水平上,E-钙粘蛋白的缺失与TGF-β(transforming growth factor-β)、活性氧和凋亡信号传导途径的基因的上调有关。在细胞水平,扩散的E-钙粘蛋白阴性细胞表现出SMAD2/3蛋白的核富集、氧化应激和细胞凋亡的增加。通过抑制TGF-β与受体之间的信号传导、活性氧积累或凋亡能够恢复E-钙粘蛋白阴性细胞的集落形成能力。这些研究结果表明,E-钙粘蛋白通过限制活性氧介导的细胞凋亡,在转移的剥离、全身性传播和繁殖阶段成为侵袭性导管癌的存活因子。鉴定抑制转移性乳腺癌中E-钙粘蛋白介导细胞存活的分子策略,可能具有作为乳腺癌治疗方案的潜力。

附:英文原文

Title: E-cadherin is required for metastasis in multiple models of breast cancer

Author: Veena Padmanaban, Ilona Krol, Yasir Suhail, Barbara M. Szczerba, Nicola Aceto, Joel S. Bader, Andrew J. Ewald

Issue&Volume: 2019-09-04

Abstract: Metastasis is the major driver of death in patients with cancer. Invasion of surrounding tissues and metastasis have been proposed to initiate following loss of the intercellular adhesion protein, E-cadherin1,2, on the basis of inverse correlations between in vitro migration and E-cadherin levels3. However, this hypothesis is inconsistent with the observation that most breast cancers are invasive ductal carcinomas and express E-cadherin in primary tumours and metastases4. To resolve this discrepancy, we tested the genetic requirement for E-cadherin in metastasis using mouse and human models of both luminal and basal invasive ductal carcinomas. Here we show that E-cadherin promotes metastasis in diverse models of invasive ductal carcinomas. While loss of E-cadherin increased invasion, it also reduced cancer cell proliferation and survival, circulating tumour cell number, seeding of cancer cells in distant organs and metastasis outgrowth. Transcriptionally, loss of E-cadherin was associated with upregulation of genes involved in transforming growth factor- (TGF), reactive oxygen species and apoptosis signalling pathways. At the cellular level, disseminating E-cadherin-negative cells exhibited nuclear enrichment of SMAD2/3, oxidative stress and increased apoptosis. Colony formation of E-cadherin-negative cells was rescued by inhibition of TGF-receptor signalling, reactive oxygen accumulation or apoptosis. Our results reveal that E-cadherin acts as a survival factor in invasive ductal carcinomas during the detachment, systemic dissemination and seeding phases of metastasis by limiting reactive oxygen-mediated apoptosis. Identifying molecular strategies to inhibit E-cadherin-mediated survival in metastatic breast cancer cells may have potential as a therapeutic approach for breast cancer.

DOI: 10.1038/s41586-019-1526-3

Source:https://www.nature.com/articles/s41586-019-1526-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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