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蛋白，在爪蟾、斑马鱼、小鼠和人类的早期胚胎发生过程中起着重要的能力因子作用。该多基因家族包括爪蟾FRL-1、斑马鱼单眼针头（oep）、小鼠密码子（Cr-1）以及隐密码子和人密码子（Cr-1）和密码子。FRL-1、oep和小鼠cripto对于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。此外，oep和cryptic对于左右不对称的建立也很重要。在小鼠中，隐型在成人组织中不表达，而Cr-1在包括乳腺在内的几种不同组织中表达水平较低。在乳腺中，妊娠和哺乳期导管上皮细胞中Cr-1的表达增加，在人乳中可以检测到免疫反应性和生物活性的Cr-1蛋白。使用MMTV启动子在小鼠乳腺中过度表达人CR-1转基因可导致多胎雌性小鼠乳腺导管增生和乳头状腺癌的出现。重组小鼠或人密码子可增强小鼠乳腺上皮细胞和部分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-间质转化，这与β -连环蛋白粘附功能的降低和vimentin表达的增加有关。CR-1在人类结肠癌、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类乳腺癌中的表达增加了数倍。更重要的是，这种cripto-1表达的增加可以首先在这些组织中的一些癌前病变中检测到，如乳腺（增生和DCIS）、结肠（腺瘤）和胃

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.