Role of endothelin-1 in osteoblastic bone metastases
Role of endothelin-1 in osteoblastic bone metastases
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DOI：
10.1002/cncr.11129
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发表时间：
2003-02-01
期刊：
影响因子：
6.2
通讯作者：
Mohammad, KS
中科院分区：
文献类型：
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作者：
Guise, TA;Yin, JJ;Mohammad, KS
背景资料。某些实体瘤转移到骨骼并引起成骨反应。Turner细胞刺激这种新骨形成的机制尚不完全清楚。方法：作者鉴定了三个乳腺癌株，它们导致了裸鼠成骨细胞的转移，并提供了肿瘤产生的内皮素-1(ET-1)介导成骨细胞反应的证据。结果：肿瘤条件培养液和外源性ET-1在小鼠颅骨培养中刺激成骨细胞增殖和新骨形成。这些作用可被内皮素A(ETA)受体拮抗剂阻断，但不能被ETB受体拮抗剂阻断。接种ZR-75-1乳腺癌株并经选择性ETA受体拮抗剂(ABT-627)治疗的小鼠，与未治疗的小鼠相比，成骨细胞性骨转移显著减少，肿瘤负担也较轻。相反，ABT-627对ET-1阴性的乳腺癌MDA-MB-231引起的溶骨性骨转移没有影响。ABT-627对ZR-75-1或MDA-MB-231细胞的体外生长和原位生长均无影响。结论肿瘤产生的ET-1可能通过刺激成骨细胞增殖和新骨形成来介导成骨细胞骨转移。阻断ETA受体可能有助于预防和治疗乳腺癌或前列腺癌引起的成骨细胞骨转移。(C)2003年美国癌症协会。
BACKGROUND. Certain solid tumors metastasize to bone and cause an osteoblastic response. The mechanisms by which turner cells stimulate this new bone formation are not completely understood.METHODS. The authors identified three breast cancer lines that cause osteoblastic metastases in female nude mice and provided evidence that tumor-produced endothelin-1 (ET-1) mediates the osteoblastic response.RESULTS. Tumor conditioned media, as well as exogenous ET-1, stimulated osteoblast proliferation and new bone formation in cultures of mouse calvariae. These effects were blocked by antagonists of the endothelin A (ETA), but not ETB, receptors. Mice inoculated with the ZR-75-1 breast cancer line and treated with a selective ETA receptor antagonist (ABT-627) had significantly fewer osteoblastic bone metastases and less tumor burden compared with untreated mice. In contrast, there was no effect of ABT-627 on osteolytic bone metastases caused by ET-1-negative breast cancer, MDA-MB-231. ABT-627 had no effect on growth in vitro or at the orthotopic site of ZR-75-1 or MDA-MB-231 cells.CONCLUSIONS. Collectively, the data suggested that tumor-produced ET-1 mediates osteoblastic bone metastases by stimulating osteoblast proliferation and new bone formation. ETA receptor blockade may be useful for prevention and the treatment of osteoblastic bone metastases due to breast or prostate cancer. (C) 2003 American Cancer Society.