Prostate cancer specific integrin αvβ3 modulates bone metastatic growth and tissue remodeling
Prostate cancer specific integrin αvβ3 modulates bone metastatic growth and tissue remodeling
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DOI：
10.1038/sj.onc.1210429
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发表时间：
2007-09-13
期刊：
影响因子：
8
通讯作者：
Byzova, T. V.
中科院分区：
文献类型：
--
作者：
McCabe, N. P.;De, S.;Byzova, T. V.
由于骨骼内癌症的扩散和生长而导致的疼痛和发病率的治疗仍然是临床护理中的首要问题。癌细胞主动改变骨骼，但是，该过程的分子需求和机制尚不清楚。这项研究表明，在骨骼内进展并确定肿瘤诱导的骨组织转化需要对前列腺癌细胞中Alpha V Beta 3整合素受体的功能调节。使用组织学和定量MicroCT分析，我们表明，AVB3整合素不仅需要骨骼内的肿瘤生长，而且还需要肿瘤诱导的骨骼增加，这是前列腺癌患者中骨骼病变的反应。正常功能性AVB3的表达使骨骼中的肿瘤生长（发病率：4/4），而AVB3（ - ），Alpha V Beta 3的无活性或组成性活性突变体没有（发病率：0/4、0/6和1） /7分别在35天的周期内。与亚库的肿瘤发病率大于60％的亚库相比，这种反应似乎是骨特异性的。有趣的是，居住的前列腺癌细胞表达正常或分离的alpha v beta 3（构成活性的无活性），但缺乏β3的骨骼促进了骨骼增长或在存在组织学检测到可检测到的骨质355的情况下可促进骨骼的增加或保护骨出现。植入后的几天。由于骨骼充满了Beta 3整合素的配体，因此我们接下来证明了肿瘤细胞上的AVB3整合素激活对于识别关键骨特异性基质蛋白的必不可少。结果，表达功能完全但不调节的AVB3整合素的前列腺癌细胞能够控制自己的粘附并迁移到骨基质中，这促进了肿瘤生长并控制骨骼病变的发育。
The management of pain and morbidity due to the spreading and growth of cancer within bone remains to be a paramount problem in clinical care. Cancer cells actively transform bone, however, the molecular requirements and mechanisms of this process remain unclear. This study shows that functional modulation of the alpha v beta 3 integrin receptor in prostate cancer cells is required for progression within bone and determines tumor-induced bone tissue transformation. Using histology and quantitative microCT analysis, we show that avb3 integrin is required not only for tumor growth within the bone but for tumor-induced bone gain, a response resembling bone lesions in prostate cancer patients. Expression of normal, fully functional avb3 enabled tumor growth in bone ( incidence: 4/4), whereas avb3 (-), inactive or constitutively active mutants of alpha v beta 3 did not ( incidence: 0/4, 0/6 and 1/7, respectively) within a 35-day-period. This response appeared to be bone-specific in comparison to the subcutis where tumor incidence was greater than 60% for all groups. Interestingly, bone residing prostate cancer cells expressing normal or dis-regulated alpha v beta 3 ( either inactive of constitutively active), but not those lacking beta 3 promoted bone gain or afforded protection from bone loss in the presence or absence of histologically detectable tumor 35 days following implantation. As bone is replete with ligands for beta 3 integrin, we next demonstrated that avb3 integrin activation on tumor cells is essential for the recognition of key bone-specific matrix proteins. As a result, prostate cancer cells expressing fully functional but not dis-regulated avb3 integrin are able to control their own adherence and migration to bone matrix, functions that facilitate tumor growth and control bone lesion development.