ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis
ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis
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DOI：
10.1101/gad.1824809
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发表时间：
2009-08-15
影响因子：
10.5
通讯作者：
Kang, Yibin
中科院分区：
文献类型：
--
作者：
Lu, Xin;Wang, Qiongqing;Kang, Yibin
骨转移是由骨微环境中肿瘤细胞与常驻基质细胞之间复杂的相互作用介导的。尽管金属蛋白酶在基质降解和肿瘤侵袭中发挥了重要作用，但它们在器官特异性转移中的功能仍不明确。在这里，我们展示了一种机制，即两种不同的金属蛋白酶，崩解素和带有血栓反应蛋白基序的金属蛋白酶（ADAMTS1）和基质金属蛋白酶-1 (MMP1)，协调旁分泌信号级联来调节骨微环境，有利于破骨细胞的发生和骨转移。从肿瘤细胞中释放的膜结合表皮生长因子（EGF）样生长因子，包括双侧调节蛋白（AREG）、肝素结合EGF （HB-EGF）和转化生长因子α (TGF α)，可抑制成骨细胞中骨保护素（OPG）的表达，从而增强破骨细胞的分化。EGF受体（EGFR）抑制剂通过靶向骨基质细胞中的EGFR信号传导阻断骨溶解性骨转移。此外，MMP1和ADAMTS1表达升高与乳腺癌患者骨转移风险增加有关。本研究确定肿瘤细胞中的MMP1和ADAMTS1以及成骨细胞中的EGFR信号是抑制乳腺癌骨转移的有希望的治疗靶点。
Bone metastasis is mediated by complex interactions between tumor cells and resident stromal cells in the bone microenvironment. The functions of metalloproteinases in organ-specific metastasis remain poorly defined despite their well-appreciated role in matrix degradation and tumor invasion. Here, we show a mechanism whereby two distinct metalloproteinases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1) and matrix metalloproteinase-1 (MMP1), orchestrate a paracrine signaling cascade to modulate the bone microenvironment in favor of osteoclastogenesis and bone metastasis. Proteolytic release of membrane-bound epidermal growth factor (EGF)-like growth factors, including Amphiregulin (AREG), heparin-binding EGF (HB-EGF), and transforming growth factor alpha (TGF alpha) from tumor cells suppress the expression of osteoprotegerin (OPG) in osteoblasts and subsequently potentiate osteoclast differentiation. EGF receptor (EGFR) inhibitors block osteolytic bone metastasis by targeting EGFR signaling in bone stromal cells. Furthermore, elevated MMP1 and ADAMTS1 expression is associated with increased risk of bone metastasis in breast cancer patients. This study established MMP1 and ADAMTS1 in tumor cells, as well as EGFR signaling in osteoblasts, as promising therapeutic targets for inhibiting bone metastasis of breast cancer.