Dissecting Tumor-Stromal Interactions in Breast Cancer Bone Metastasis.
Dissecting Tumor-Stromal Interactions in Breast Cancer Bone Metastasis.
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DOI：
10.3803/enm.2016.31.2.206
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Kang Y
中科院分区：
文献类型：
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作者：
Kang Y
骨转移是乳腺癌中常见的现象，影响70%以上的晚期癌症患者，并伴有骨折、骨痛、高钙血症等严重并发症。溶骨性骨转移的发病机制取决于肿瘤细胞与骨微环境中的各种基质细胞之间的交叉通讯。多种生长因子信号通路、分泌的微小 RNA (miRNA) 和外泌体是骨转移中肿瘤-基质相互作用的功能介质。我们开发了一种功能基因组方法来系统地识别乳腺癌细胞利用的分子途径来参与骨基质以产生溶骨性骨转移。我们发现，播散性乳腺肿瘤细胞中血管细胞粘附分子 1 (VCAM1) 的表达升高介导了前破骨细胞的募集，并在骨转移形成过程中促进其分化为成熟破骨细胞。转化生长因子 β (TGF-β) 在骨质破坏时从骨基质中释放出来，并向乳腺癌发出信号，进一步增强其骨转移的恶性程度。我们进一步确定 Jagged1 是肿瘤细胞中的 TGF-β 靶基因，它通过激活 Notch 信号传导与骨基质细胞结合，提供正反馈，促进肿瘤生长并激活破骨细胞分化。在破骨细胞分化和成熟过程中观察到 miRNA 表达的显着变化，可将其用作新兴骨转移的循环生物标志物和治疗骨转移的治疗靶点。这个方向的进一步研究可能会改善骨转移的诊断和治疗策略。
Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients with severe complications such as fracture, bone pain, and hypercalcemia. The pathogenesis of osteolytic bone metastasis depends on cross-communications between tumor cells and various stromal cells residing in the bone microenvironment. Several growth factor signaling pathways, secreted micro RNAs (miRNAs) and exosomes are functional mediators of tumor-stromal interactions in bone metastasis. We developed a functional genomic approach to systemically identified molecular pathways utilized by breast cancer cells to engage the bone stroma in order to generate osteolytic bone metastasis. We showed that elevated expression of vascular cell adhesion molecule 1 (VCAM1) in disseminated breast tumor cells mediates the recruitment of pre-osteoclasts and promotes their differentiation to mature osteoclasts during the bone metastasis formation. Transforming growth factor β (TGF-β) is released from bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis. We furthered identified Jagged1 as a TGF-β target genes in tumor cells that engaged bone stromal cells through the activation of Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. Substantially change in miRNA expression was observed in osteoclasts during their differentiation and maturation, which can be exploited as circulating biomarkers of emerging bone metastasis and therapeutic targets for the treatment of bone metastasis. Further research in this direction may lead to improved diagnosis and treatment strategies for bone metastasis.