Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor scatter factor
Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor scatter factor
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DOI：
10.1073/pnas.94.2.701
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发表时间：
1997-01-21
影响因子：
11.1
通讯作者：
Merlino, G
中科院分区：
文献类型：
--
作者：
Takayama, H;LaRochelle, WJ;Merlino, G
肝细胞生长因子/散射因子（HGF/SF）是一种间质来源的多功能旁分泌调节因子，在含有其酪氨酸激酶受体Met的培养的上皮细胞中具有促有丝分裂、促有丝分裂和形态发生活性。c-met通过在特定细胞系和肿瘤中的表达与恶性表型相关而参与肿瘤发生。HGF/SF还能抑制某些肿瘤细胞的生长。为了阐明HGF/SF在体内的致癌作用，建立了转基因小鼠，使得HGF/SF不适当地靶向多种组织，HGF/SF转基因小鼠产生了非常广泛的组织学上不同的肿瘤，其来源于间充质和上皮来源。许多肿瘤产生于表现出异常发育的组织，包括乳腺、骨骼肌和黑素细胞，大多数肿瘤，特别是黑色素瘤，表现出HGF/SF转基因和内源性c-met的过表达，并且具有增强的Met激酶活性，强烈地表明自分泌信号广泛地促进肿瘤发生。因此，通过HGF/SF表达的强制性错误方向，正常间充质-上皮旁分泌调节的颠覆诱导了异常的形态发生和随后的不同来源细胞的恶性转化。
Hepatocyte growth factor/scatter factor (HGF/SF) is a mesenchymally derived, multifunctional paracrine regulator possessing mitogenic, mitogenic, and morphogenetic activities in cultured epithelial cells containing its tyrosine kinase receptor, Met, c-met has been implicated in oncogenesis through correlation of expression with malignant phenotype in specific cell lines and tumors, Paradoxically, however, HGF/SF can also inhibit the growth of some tumor cells. To elucidate the oncogenic role of HGF/SF in vivo, transgenic mice were created such that HGF/SF was inappropriately targeted to a variety of tissues, HGF/SF transb genic mice developed a remarkably broad array of histologically distinct tumors of both mesenchymal and epithelial origin, Many neoplasms arose from tissues exhibiting abnormal development, including the mammary gland, skeletal muscle, and melanocytes, suggesting a functional link between mechanisms regulating morphogenesis and those promoting tumorigenesis, Most neoplasms, especially melanomas, demonstrated overexpression of both the HGF/SF transgene and endogenous c-met, and had enhanced Met kinase activity, strongly suggesting that autocrine signaling broadly promotes tumorigenesis. Thus, subversion of normal mesenchymal-epithelial paracrine regulation through the forced misdirection of HGF/SF expression induces aberrant morphogenesis and subsequent malignant transformation of cells of diverse origin.