RECK in Osteosarcoma A Novel Role in Tumour Vasculature and Inhibition of Tumorigenesis in an Orthotopic Model
RECK in Osteosarcoma A Novel Role in Tumour Vasculature and Inhibition of Tumorigenesis in an Orthotopic Model
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DOI：
10.1002/cncr.25757
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发表时间：
2011-08-01
期刊：
影响因子：
6.2
通讯作者：
Choong, Peter F. M.
中科院分区：
文献类型：
--
作者：
Clark, Jonathan C. M.;Akiyama, Toru;Choong, Peter F. M.
背景：骨肉瘤（OS）需要靶向治疗来改善患者的预后。人类的RECK可能有作用，因为它可以抑制癌症侵袭并调节血管生成。本研究旨在表征RECK在人骨肉瘤中的表达，探讨RECK在体外对血管内皮和骨肉瘤细胞行为的影响，并分析RECK对裸鼠骨肉瘤原位生长的影响。方法：在人OS样品中检测RECK。在组织和细胞中研究了RECK和VEGF的相互作用。在体外和体内研究RECK转染对血管内皮细胞（HMEC-1）和OS细胞（SaOS-2）行为的影响。SaOS-2与RAW 246.7衍生的破骨细胞共培养在骨滑片上，以评估对破骨细胞活性的影响。结果：RECK在OS细胞中不存在，但在肿瘤血管内皮中表达。通过微阵列分析，在低增殖活性的样本中，RECK mRNA表达升高，这一趋势在低分化样本中最为明显。VEGF诱导HMEC-1中RECK的表达。RECK转染抑制了HMEC-1的侵袭，诱导了更厚的管形成，尽管数量更多。RECK抑制SaOS-2的侵袭、增殖、集落形成和破骨细胞活性，但支持SaOS-2与胶原i的粘附。在体内，RECK抑制SaOS-2肿瘤的生长、骨破坏和随后的转移。结论：在高增殖的OS中，RECK表达下调，但在肿瘤血管中存在，并在内皮细胞中被VEGF上调。体内实验证实，RECK可抑制SaOS-2的侵袭性和致瘤性。在操作系统中进一步测试RECK交付是有必要的。癌症2011;117:3517-28。(C) 2011年美国癌症协会。
BACKGROUND: Targeted therapy in osteosarcoma (OS) is needed to improve patient outcomes. Human RECK may have a role because it inhibits cancer invasion and regulates angiogenesis. This study aimed to characterize RECK expression in human OS, to examine in vitro effects of RECK on vascular endothelium and OS cell behavior, and to analyze the effect of RECK on OS grown orthotopically in nude mice. METHODS: RECK was examined in human OS samples. Interactions between RECK and VEGF were studied in tissue and cells. RECK transfection was used to study its effects on vascular endothelial (HMEC-1) and OS (SaOS-2) cell behavior in vitro and in vivo. SaOS-2 co-culture with RAW 246.7-derived osteoclasts on osteoslides was used to assess effects on osteoclast activity. RESULTS: RECK was absent from OS cells but was expressed in tumor vessel endothelium. Via microarray analysis, RECK mRNA was elevated in samples with low proliferative activity, a trend most evident in poorly differentiated samples. VEGF induced RECK expression in HMEC-1. RECK transfection inhibited HMEC-1 invasion and induced thicker, although more numerous, tube formation. RECK inhibited SaOS-2 invasion, proliferation, colony formation, and osteoclast activity but supported SaOS-2 adhesion to collagen I. In vivo, RECK inhibited SaOS-2 tumor growth, bone destruction, and consequent metastasis. CONCLUSIONS: RECK expression is downregulated in highly proliferative OS but is present in tumor vessels and upregulated in endothelium by VEGF. RECK inhibits invasion and tumorigenic properties in SaOS-2, as confirmed in vivo. Further testing of RECK delivery in OS is warranted. Cancer 2011;117:3517-28. (C) 2011 American Cancer Society.