Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche.
Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche.
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DOI：
10.1016/j.ccr.2008.11.012
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发表时间：
2009-01-06
期刊：
影响因子：
50.3
通讯作者：
Giaccia AJ
中科院分区：
文献类型：
--
作者：
Erler JT;Bennewith KL;Cox TR;Lang G;Bird D;Koong A;Le QT;Giaccia AJ
肿瘤细胞转移是通过侵入骨髓来源的细胞（BMDC）在目的器官中形成的“转移前小生境”来促进的。赖氨酰氧化酶（LOX）对于转移前的小生境形成至关重要。由缺氧乳腺肿瘤细胞分泌的LOX在转移前部位积累，交联基底膜中的胶原-IV，并且对于CD 11b+髓样细胞募集是必需的。CD 11b+细胞粘附于交联的胶原-IV并产生基质金属蛋白酶-2，其切割胶原，增强BMDC的侵袭和募集以及转移肿瘤细胞。LOX抑制可防止CD 11b+细胞募集和转移生长。CD 11b+细胞和LOX也共定位于人转移瘤的活检组织中。我们的研究结果证明了LOX在转移前小生境形成中的关键作用，并支持靶向LOX治疗和预防转移性疾病。
Tumor cell metastasis is facilitated by “pre-metastatic niches” formed in destination organs by invading bone marrow-derived cells (BMDCs). Lysyl oxidase (LOX) is critical for pre-metastatic niche formation. LOX secreted by hypoxic breast tumor cells accumulates at pre-metastatic sites, cross-links collagen-IV in the basement membrane, and is essential for CD11b+ myeloid cell recruitment. CD11b+ cells adhere to cross-linked collagen-IV and produce matrix metalloproteinase-2 which cleaves collagen, enhancing the invasion and recruitment of BMDCs and metastasizing tumor cells. LOX inhibition prevents CD11b+ cell recruitment and metastatic growth. CD11b+ cells and LOX also co-localize in biopsies of human metastases. Our findings demonstrate a critical role for LOX in pre-metastatic niche formation and support targeting LOX for the treatment and prevention of metastatic disease.
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