The Role of Cripto in the Pathogenesis of Breast and Col

EGF-CFC基因家族编码一组结构相关的蛋白质，在非洲爪蟾、斑马鱼、小鼠和人类的早期胚胎发生中作为重要的感受态因子。这个多基因家族包括非洲爪蟾FRL-1、斑马鱼独眼针头（oep）、小鼠cripto（Cr-1）和隐蔽的cripto（CR-1）以及人criptin。FRL-1、oep和小鼠cripto对中胚层和内胚层的形成以及胚胎前/后轴的正确建立至关重要。另外，oep和cryptic对左右不对称的建立也很重要。在小鼠中，隐蔽蛋白在成体组织中不表达，而Cr-1在包括乳腺在内的几种不同组织中以低水平表达。在乳腺中，在妊娠和哺乳期间导管上皮细胞中Cr-1的表达增加，并且在人乳中可以检测到免疫反应性和生物活性Cr-1蛋白。使用MMTV启动子在小鼠乳腺中过表达人CR-1转基因导致经产雌性小鼠乳腺中出现导管增生和乳头状腺癌。重组小鼠或人cripto可以增强小鼠乳腺上皮细胞和一些人肿瘤细胞的细胞运动性和分支形态发生。这些作用伴随着上皮-间充质转化，其与β-连环蛋白粘附功能的降低和波形蛋白表达的增加相关。CR-1的表达在人结肠癌、胃癌、胰腺癌、宫颈癌、卵巢癌和肺癌以及各种不同类型的小鼠和人乳腺癌中增加数倍。更重要的是，cripto-1表达的这种增加可以首先在这些组织中的一些的癌前病变中检测到，例如在乳腺（增生和DCIS）、结肠（腺瘤）和胃中 （肠化生）。我们最近鉴定了活化素ALK 4 1型受体作为CR-1的共受体，其将Nodal呈递给ALK 4，从而可以通过SBE-荧光素酶报告基因构建体刺激Smad-2磷酸化和转录。此外，CR-1可以通过Nodal和ALK 4非依赖性信号通路发挥作用，并通过结合GPI连接的含硫酸乙酰肝素的蛋白聚糖激活MAPK、PI-3激酶和Akt，磷脂酰肌醇蛋白聚糖-1，其然后可以激活c-src。CR-1激活乳腺上皮细胞中的MAPK、PI-3激酶、GSK-3 β和Akt是CR-1刺激细胞增殖、体外转化、细胞迁移和阻断催乳素诱导的β-酪蛋白和乳清酸性蛋白表达的能力所必需的。在乳腺上皮细胞中，这些反应的一部分也可能取决于CR-1通过磷脂酰肌醇蛋白聚糖-1激活c-src的能力，erbB-4和/或FGFR-1受体的酪氨酸转磷酸化。

The EGF-CFC gene family encodes a group of structurally related proteins that serve as important competence factors during early embryogenesis in Xenopus, zebrafish, mice and humans. This multigene family consists of Xenopus FRL-1, zebrafish one-eyed-pinhead (oep ), mouse cripto (Cr-1) and cryptic and human cripto (CR-1) and criptin. FRL-1, oep and mouse cripto are essential for the formation of mesoderm and endoderm and for correct establishment of the embryonic anterior/posterior axis. In addition, oep and cryptic are important for the establishment of left-right asymmetry. In the mouse cryptic is not expressed in adult tissues whereas Cr-1 is expressed at a low level in several different tissues including the mammary gland. In the mammary gland, expression of Cr-1 in the ductal epithelial cells increases during pregnancy and lactation and immunoreactive and biologically active Cr-1 protein can be detected in human milk. Overexpression of a human CR-1 transgene in the mouse mammary gland using an MMTV promoter results in the appearance of ductal hyperplasias in the mammary gland and papillary adenocarcinomas in multiparous female mice. Recombinant mouse or human cripto can enhance cell motility and branching morphogenesis in mouse mammary epithelial cells and in some human tumor cells. These effects are accompanied by an epithelial-mesenchymal transition which is associated with a decrease in beta-catenin adherens function and an increase in vimentin expression. Expression of CR-1 is increased several-fold in human colon, gastric, pancreatic, cervical, ovarian and lung carcinomas and in a variety of different types of mouse and human breast carcinomas. More importantly, this increase in cripto-1 expression can first be detected in premalignant lesions in some of these tissues such as in the breast ( hyperplasias and DCIS ), colon ( adenomas ) and stomach ( intestinal metaplasias ). We have recently identied the Activin ALK4 type 1 receptor as a co-receptor for CR-1 which presents Nodal to ALK4 and thereby can stimulate Smad-2 phosphorylation and transcription through an SBE-luciferase reporter construct.In addition, CR-1 can function through a Nodal and ALK4-independent signaling pathway and activate MAPK, PI-3 kinase and Akt by binding to the GPI-linked heparan sulphate-containing proteoglycan, glypican-1 which can then activate c-src. Activation of MAPK, PI-3 kinase, GSK-3beta and Akt in mammary epithelial cells by CR-1 are required for the ability of CR-1 to stimulate cell proliferation, transformation in vitro, cell migration and to block lactogenic hormone-induced expression of beta-casein and whey acidic protein. In mammary epithelial cells part of these responses may also depend on the ability of CR-1 by activating c-src through glypican-1 the tyrosine transphosphorylation of the erbB-4 and/or FGFR-1 receptors.