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Sci Signal:抑制整合素受体或促发癌症转移

来源:生物谷 2014-02-17 22:01

2014年2月17日讯 /生物谷BIOON/--近日,来自LACDR 由Erik Danen领导的研究团队发现一种癌症治疗策略可能实际上在某些情况下,可能导致癌症转移增加。这一发现发表在Science Signaling杂志上。

该正被质疑的治疗策略涉及阻断所谓的“整合素”受体。癌细胞使用这些受体与他们的环境交互,当这一过程被阻断,癌症细胞变得更弱,引起肿瘤萎缩。

最近的一些遗传学研究表明,整合素抑制剂也有可能导致一些癌症变得更加“咄咄逼人”,产生不利影响。

这种现象目前还不被完全理解,LACDR研究人员发现,所谓的三阴性乳腺癌细胞响应整合素抑制治疗后,细胞迁移会明显变化。

已知的是,整合素蛋白受体发送重要的信号进入细胞,当这些信号缺失时,癌细胞不再有效地形成肿瘤。然而,事实证明,这也能刺激癌细胞“重新编程”。

研究人员发现,上皮细胞起源的三阴性乳腺癌,会失去上皮细胞的形状,变得更加能动。

对于这个“开关”,癌细胞很像正常上皮细胞重新布线细胞内信号网络,其结果是,癌细胞不再粘在一起,开始遍及全身扩散。

这项研究工作表明,虽然抑制整合素蛋白受体能有效地抑制肿瘤的生长,但也可引起肿瘤细胞的重编程,导致转移增强。(生物谷Bioon.com)

 

β1 Integrin Inhibition Elicits a Prometastatic Switch Through the TGFβ–miR-200–ZEB Network in E-Cadherin–Positive Triple-Negative Breast Cancer

Hoa H. Truong,et al.

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.

 

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