The Role of Cripto in the Pathogenesis of Breast and Colon Cancer

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。小鼠乳腺上皮细胞过表达Cr-1可促进其体外转化，体内这些Cr-1转导的乳腺上皮细胞可在乳腺内产生导管增生。重组小鼠或人密码子可增强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b-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，例如乳腺（增生和DCIS）、结肠（腺瘤）和胃（肠化生）。虽然EGF-CFC蛋白的特异性受体尚未确定，但oep依赖于激活素型RIIB和RIB受体系统，该系统通过Smad-2起作用。小鼠和人的crypto已被证明可以激活乳腺上皮细胞中的ras/raf/MAPK信号通路。激活PI-3激酶、GSK-3b和Akt对于CR-1刺激细胞迁移和阻断乳原激素诱导的b-酪蛋白和乳清酸性蛋白的表达也很重要。在乳腺上皮细胞中，这些反应的一部分可能取决于CR-1通过src样酪氨酸激酶反激活erbb -4和/或FGFR-1的能力。

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 Cr-1 in mouse mammary epithelial cells can facilitate their in vitro transformation and in vivo these Cr-1 transduced mammary epithelial cells produce ductal hyperplasias in the mammary gland. Recombinant mouse or human cripto can enhance cell motility and branching morphogenesis in 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 b-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 ). Although a specific receptor for the EGF-CFC proteins has not yet been identified, oep depends upon an activin type RIIB and RIB receptor system that functions through Smad-2. Mouse and human cripto have been shown to activate a ras/raf/MAPK signaling pathway in mammary epithelial cells. Activation of PI-3 kinase, GSK-3b and Akt are also important for the ability of CR-1 to stimulate cell migration and to block lactogenic hormone-induced expression of b-casein and whey acidic protein. In mammary epithelial cells part of these responses may depend on the ability of CR-1 to transactivate erb B-4 and/or FGFR-1 through a src-like tyrosine kinase.