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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy
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Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

机译：赖氨酰氧化酶在间充质干细胞驱动的乳腺癌恶性肿瘤中的关键作用

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摘要

Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the ability to differentiate into multiple mesoderm lineages in the course of normal tissue homeostasis or during injury. We have previously shown that MSCs migrate to sites of tumorigenesis, where they become activated by cancer cells to promote metastasis. However, the molecular and phenotypic attributes of the MSC-induced metastatic state of the cancer cells remained undetermined. Here, we show that bone marrow-derived human MSCs promote de novo production of lysyl oxidase (LOX) from human breast carcinoma cells, which is sufficient to enhance the metastasis of otherwise weakly metastatic cancer cells to the lungs and bones. We also show that LOX is an essential component of the CD44-Twist signaling axis, in which extracellular hyaluronan causes nuclear translocation of CD44 in the cancer cells, thus triggering LOX transcription by associating with its promoter. Processed and enzymatically active LOX, in turn, stimulates Twist transcription, which mediates the MSC-triggered epithelial-to-mesenchymal transition (EMT) of carcinoma cells. Surprisingly, although induction of EMT in breast cancer cells has been tightly associated with the generation of cancer stem cells, we find that LOX, despite being critical for EMT, does not contribute to the ability of MSCs to promote the formation of cancer stem cells in the carcinoma cell populations. Collectively, our studies highlight a critical role for LOX in cancer metastasis and indicate that the signaling pathways controlling stroma-induced EMT are distinct from pathways regulating the development of cancer stem cells.
机译：间充质干细胞（MSCs）是多能祖细胞，具有在正常组织动态平衡过程中或损伤过程中分化为多个中胚层谱系的能力。我们以前已经证明，MSC迁移到肿瘤发生的部位，在那里它们被癌细胞激活以促进转移。然而，MSC诱导的癌细胞转移状态的分子和表型属性仍然不确定。在这里，我们显示了骨髓来源的人类MSC促进了从人类乳腺癌细胞从头产生赖氨酰氧化酶（LOX）的产生，这足以增强原本微弱转移的癌细胞向肺和骨骼的转移。我们还显示，LOX是CD44-Twist信号轴的重要组成部分，其中细胞外透明质酸引起癌细胞中CD44的核易位，从而通过与其启动子相关联触发LOX转录。经过加工和具有酶活性的LOX依次刺激Twist转录，该转录介导MSC触发的癌细胞上皮-间质转化（EMT）。出人意料的是，尽管乳腺癌细胞中EMT的诱导与癌症干细胞的产生紧密相关，但我们发现LOX尽管对EMT至关重要，但并不能促进MSCs促进肿瘤干细胞形成的能力。癌细胞群。总体而言，我们的研究突出了LOX在癌症转移中的关键作用，并表明控制基质诱导的EMT的信号传导途径不同于调节癌症干细胞发育的途径。

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    Christelle P. El-Haibi; George W. Bell; Jiangwen Zhang; Anthony Y. Collmann; David Wood; Cally M. Scherber; Eva Csizmadia; Odette Mariani; Cuihua Zhu; Antoine Campagne; Mehmet Toner; Sangeeta N. Bhatia; Daniel lrimia; Anne Vincent-Salomon; Antoine E. Karnoub;

  • 作者单位

    Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

    Whitehead Institute for Biomedical Research,Cambridge, MA 02142;

    Center for Systems Biology, Faculty of Arts and Sciences, Harvard University, Cambridge, MA 02138;

    Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

    Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Koch Institute for Integrative Cancer Research, Cambridge, MA 02139;

    BioMEMS Resource Center, Center for Engineering m Medicine and Surgical Services, Massachusetts General Hospital/Harvard Medical School and Shriners Hospital for Children, Boston, MA 02114;

    Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215;

    Department of Pathology, Institut Curie, 75248 Paris Cedex 05, France;

    Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

    Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215,Department of Pathology, Institut Curie, 75248 Paris Cedex 05, France;

    BioMEMS Resource Center, Center for Engineering m Medicine and Surgical Services, Massachusetts General Hospital/Harvard Medical School and Shriners Hospital for Children, Boston, MA 02114;

    Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Koch Institute for Integrative Cancer Research, Cambridge, MA 02139;

    BioMEMS Resource Center, Center for Engineering m Medicine and Surgical Services, Massachusetts General Hospital/Harvard Medical School and Shriners Hospital for Children, Boston, MA 02114;

    Department of Pathology, Institut Curie, 75248 Paris Cedex 05, France;

    Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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