The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase.
The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase.
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DOI：
10.1038/nature14492
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发表时间：
2015-06-04
期刊：
影响因子：
64.8
通讯作者：
Erler JT
中科院分区：
文献类型：
--
作者：
Cox TR;Rumney RMH;Schoof EM;Perryman L;Høye AM;Agrawal A;Bird D;Latif NA;Forrest H;Evans HR;Huggins ID;Lang G;Linding R;Gartland A;Erler JT
肿瘤转移是一个复杂的过程，涉及癌细胞与宿主间质在原发和继发部位的相互作用，并受缺氧等微环境因素的强烈影响。肿瘤分泌蛋白在这些相互作用中起着至关重要的作用，并呈现出战略性的治疗潜力。大约85%的晚期乳腺癌患者会发生骨转移，这使得他们在很大程度上无法治愈。具体地说，骨溶解性病变，即骨被破坏，会导致骨骼衰弱的并发症，增加患者的发病率和死亡率。控制早期溶骨损伤形成的分子相互作用目前尚不清楚。在这里，我们表明缺氧与er阴性乳腺癌患者的骨复发特异性相关。缺氧分泌组的全球定量分析确定赖氨酸氧化酶（LOX）与骨向性和复发显著相关。原发乳腺肿瘤中LOX的高表达或LOX的全身递送可导致溶骨性病变形成，而沉默或抑制LOX活性可消除肿瘤驱动的溶骨性病变形成。我们发现LOX是nfatc1驱动的破骨细胞形成的一种新的调节剂，独立于RANK配体，它破坏正常的骨稳态，导致局灶性转移前病变的形成。我们发现这些病变随后为循环肿瘤细胞定植和形成骨转移提供了一个平台。我们的研究确定了一种调节骨稳态和转移的新机制，为具有重要临床意义的新型治疗干预开辟了机会。
Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia. Tumour-secreted proteins play a crucial role in these interactions and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in ER-negative breast cancer patients. Global quantitative analysis of the hypoxic secretome identified Lysyl Oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis, independent of RANK Ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonise and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications.