Science2014-06-12 3:46 PM

一种治疗加剧肿瘤转移 β1 Integrin Inhibition Elicits a Prometastatic Switch Through the TGFβ–miR-200–ZEB Network in E-Cadherin–Positive Triple-Negative Breast Cancer

论文摘要 

一项新的研究显示,一项旨在治疗原发性肿瘤的策略可能会促使身体其他部位肿瘤细胞的扩散。在癌症病人中,治疗的目的是为了杀死原发性肿瘤并防止其扩散。当许多细胞与其细胞外基质分离时,它们就会死亡;一个正在进行当中的临床乳腺癌研究的疗法可阻断β1整合素,后者是一种在细胞粘附中起作用的特别蛋白。如今,HoaTruong等人报告说,阻断β1整合素的疗法可能会在特定的患者中引起肿瘤转移性疾病。在体外研究中——研究人员在这些研究中阻断了被称作细胞系的乳腺癌细胞系中的β1整合素的功能,这些癌细胞获得了单独迁移的能力;在培养的情况下,它们可移动并侵入一个三维的胶原基质。当被注射到斑马鱼体内时,缺乏β1整合素的TNBC细胞会比其亲本的TNBC细胞播散得更远;当这些细胞被植入到小鼠体内时,这些细胞会形成更多的非转移性肿瘤,尽管其与植入的亲本细胞所产生的原发性肿瘤相比会产生较小的原发性肿瘤。由Truong等人所作的研究提示,β1整合素控制着一个可抑制癌症细胞扩散的信号传递网络,而且更进一步地说,以β1整合素作为标靶的疗法可能不适合于某些乳腺癌患者。

Abstract 

Interactions with the extracellular matrix (ECM) through integrin adhesion receptors provide cancer cells with physical and chemical cues that act together with growth factors to support survival and proliferation. Antagonists that target integrins containing the β1 subunit inhibit tumor growth and sensitize cells to irradiation or cytotoxic chemotherapy in preclinical breast cancer models and are under clinical investigation. We found that the loss of β1 integrins attenuated breast tumor growth but markedly enhanced tumor cell dissemination to the lungs. When cultured in three-dimensional ECM scaffolds, antibodies that blocked β1 integrin function or knockdown of β1 switched the migratory behavior of human and mouse E-cadherin–positive triple-negative breast cancer (TNBC) cells from collective to single cell movement. This switch involved activation of the transforming growth factor–β (TGFβ) signaling network that led to a shift in the balance between miR-200 microRNAs and the transcription factor zinc finger E-box–binding homeobox 2 (ZEB2), resulting in suppressed transcription of the gene encoding E-cadherin. Reducing the abundance of a TGFβ receptor, restoring the ZEB/miR-200 balance, or increasing the abundance of E-cadherin reestablished cohesion in β1 integrin–deficient cells and reduced dissemination to the lungs without affecting growth of the primary tumor. These findings reveal that β1 integrins control a signaling network that promotes an epithelial phenotype and suppresses dissemination and indicate that targeting β1 integrins may have undesirable effects in TNBC.

KEYWORDS

SHARE & LIKE

COMMENTS

ABOUT THE AUTHOR

Science

Science Magazine

0 Following 18 Fans 0 Projects 236 Articles

SIMILAR ARTICLES

AbstractThe conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical funct

Read More

Introduction Recent decades have seen a major international effort to inventory tree communities in the Amazon Basin and Guiana Shield (Amazonia), but

Read More

IntroductionInitiation of protein synthesis is a key step in the control of gene expression. In eukaryotes, initiation is a highly complex process that

Read More

Abstract For decades, social psychological theories have posited that the automatic processes captured by implicit measures have implications for soci

Read More

论文摘要动物界最复杂的眼睛可以在物种口足类甲壳动物(濑尿虾)中找到,其中一些有12种不同类型的光感受器,每种各取样较窄的一组波长,范围包含了深紫外光到远红光(300到720纳米)。在功能上,这种彩色复杂性被视作是谜。当3种或4种色彩通道对色彩辨认来说已经足够时,为何要使用12种色彩通道?对口足类动物行

Read More

论文摘要 首先,在一篇“评论”文章中,Thomas Piketty 和 Emmanuel Saez用“世界顶级收入数据库(WTID)”来比较这两个数值多年来是如何在欧洲和美国演变的;WTID包括了一个世纪之久的有关全球收入的数据以及2个世纪之久的有关个人财富的数据。据研究人员披露,在20世纪之交的时候

Read More

IntroductionCensorship has a long history in China, extending from the efforts of Emperor Qin to burn Confucian texts in the third century BCE to the c

Read More

Many animals, on air, water, or land, navigate in three-dimensional (3D) environments, yet it remains unclear how brain circuits encode the animal's 3D

Read More

Many animals, on air, water, or land, navigate in three-dimensional (3D) environments, yet it remains unclear how brain circuits encode the animal's 3D

Read More

Like mammalian neurons, Caenorhabditis elegans neurons lose axon regeneration ability as they age, but it is not known why. Here, we report that let-7

Read More