Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model
Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model
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DOI：
10.1074/jbc.m211498200
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发表时间：
2003-05-02
影响因子：
4.8
通讯作者：
Wang, XF
中科院分区：
文献类型：
--
作者：
Rich, JN;Shi, Q;Wang, XF
我们采用基因定义的人类癌症模型来研究几种癌症中上调的两个基因对肿瘤发生晚期相关表型变化的贡献。具体来说，肿瘤细胞表达两种结构上不相关的骨相关基因，骨连接素和骨激活素，当植入免疫功能低下的小鼠脑内时，获得了高度侵袭性的表型。肿瘤细胞模仿神经胶质瘤的一个子集，沿着血管侵入大脑，并在脑肿瘤界面处形成改变的脉管系统，这表明肿瘤细胞产生的这两种蛋白质可能在入侵肿瘤和肿瘤侵袭过程中增选的脉管系统之间建立了复杂的关系。有趣的是，同样的肿瘤细胞在皮下植入后形成了大量的自发转移。肿瘤表型的这种显著变化表明，细胞微环境在确定这些基因产物在肿瘤行为中的特定作用方面起着重要作用。对表达骨连接素或骨激活素的肿瘤细胞进行体外检测，发现对细胞生长或死亡没有影响，但侵袭性和MMP-9和MMP-3的表达增加。MMP-2/9和MMP-3的特异性药物抑制剂阻断了骨活化素表达增加的体外侵袭，但只有MMP-3抑制改变了骨连接素介导的体外侵袭表型。这种基因定义的模型系统的结果得到了从最初来自人类患者的几种已建立的肿瘤细胞系中获得的类似结果的支持。总之，这些结果表明，单个骨相关基因的表达可以显著改变或修饰肿瘤细胞的行为，并可能在不同的微环境中赋予不同的生长特征。基因定义的人类癌症模型为功能基因组学提供了有用的工具，以确定特定基因在癌变晚期的作用。
We employed a genetically defined human cancer model to investigate the contributions of two genes up-regulated in several cancers to phenotypic changes associated with late stages of tumorigenesis. Specifically, tumor cells expressing two structurally unrelated bone-related genes, osteonectin and osteoactivin, acquired a highly invasive phenotype when implanted intracranially in immunocompromised mice. Mimicking a subset of gliomas, tumor cells invaded brain along blood vessels and developed altered vasculature at the brain-tumor interface, suggesting that production of those two proteins by tumor cells may create a complex relationship between invading tumor and vasculature co-opted during tumor invasion. Interestingly, the same tumor cells formed massive spontaneous metastases when implanted subcutaneously. This dramatic alteration in tumor phenotype indicates that cellular microenvironment plays an important role in defining the specific effects of those gene products in tumor behavior. In vitro examination of tumor cells expressing either osteonectin or osteoactivin revealed that there was no impact on cellular growth or death but increased invasiveness and expression of MMP-9 and MMP-3. Specific pharmacologic inhibitors of MMP-2/9 and MMP-3 blocked the increased in vitro invasion associated with osteoactivin expression, but only MMP-3 inhibition altered the invasive in vitro phenotype mediated by osteonectin. Results from this genetically defined model system are supported by similar findings obtained from several established tumor cell lines derived originally from human patients. In sum, these results reveal that the expression of a single bone-related gene can dramatically alter or modify tumor cell behavior and may confer differential growth characteristics in different microenvironments. Genetically defined human cancer models offer useful tools in functional genomics to define the roles of specific genes in late stages of carcinogenesis.