肿瘤衍生的 JAGGED1 通过与骨细胞中的 Notch 信号通路结合促进乳腺癌溶骨性骨转移。
Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells.
机构信息
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
出版信息
Cancer Cell. 2011 Feb 15;19(2):192-205. doi: 10.1016/j.ccr.2010.12.022. Epub 2011 Feb 3.
Abstract
Despite evidence supporting an oncogenic role in breast cancer, the Notch pathway's contribution to metastasis remains unknown. Here, we report that the Notch ligand Jagged1 is a clinically and functionally important mediator of bone metastasis by activating the Notch pathway in bone cells. Jagged1 promotes tumor growth by stimulating IL-6 release from osteoblasts and directly activates osteoclast differentiation. Furthermore, Jagged1 is a potent downstream mediator of the bone metastasis cytokine TGFβ that is released during bone destruction. Importantly, γ-secretase inhibitor treatment reduces Jagged1-mediated bone metastasis by disrupting the Notch pathway in stromal bone cells. These findings elucidate a stroma-dependent mechanism for Notch signaling in breast cancer and provide rationale for using γ-secretase inhibitors for the treatment of bone metastasis.
摘要
尽管有证据表明 Notch 通路在乳腺癌中具有致癌作用，但它在转移中的作用仍不清楚。在这里，我们报告 Notch 配体 Jagged1 通过激活骨细胞中的 Notch 通路，是骨转移的一个临床和功能上重要的介质。Jagged1 通过刺激成骨细胞释放 IL-6 并直接激活破骨细胞分化来促进肿瘤生长。此外，Jagged1 是骨破坏过程中释放的骨转移细胞因子 TGFβ 的一个强有力的下游介质。重要的是，γ-分泌酶抑制剂通过破坏基质骨细胞中的 Notch 通路来减少 Jagged1 介导的骨转移。这些发现阐明了 Notch 信号在乳腺癌中的一种依赖于基质的机制，并为使用 γ-分泌酶抑制剂治疗骨转移提供了依据。
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