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

EGF-cfc基因家族编码一组结构上相关的蛋白质，在非洲爪哇、斑马鱼、小鼠和人类的早期胚胎发育过程中，这些蛋白质是重要的竞争因子。这个多基因家族由非洲爪哇FRL-1、斑马鱼独眼针头(OEP)、小鼠Cripto(CR-1)、隐形和人类Cripto(CR-1)和criptin组成。FRL-1、OEP和小鼠CRIPTO对于中胚层和内胚层的形成以及胚胎前/后轴的正确建立是必不可少的。此外，OEP和CRYPTIC对于左右不对称的建立也很重要。在小鼠中，CR1在成年组织中不表达，而在包括乳腺在内的几个不同组织中低水平表达。在乳腺中，在妊娠和哺乳期间，乳腺导管上皮细胞中铬-1的表达增加，在人乳中可以检测到具有免疫活性和生物活性的铬-1蛋白。在小鼠乳腺上皮细胞中过表达Cr1可以促进其体外转化，在体内这些转导Cr1的乳腺上皮细胞可在乳腺中产生导管增生症。重组小鼠或人CRIPTO可增强乳腺上皮细胞和某些人肿瘤细胞的细胞运动和分支形态发生。这些影响伴随着上皮向间充质的转变，这与b-连环蛋白黏附功能的降低和波形蛋白表达的增加有关。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乳腺癌中的表达增加了几倍。更重要的是，Cripto-1表达的增加首先可以在其中一些组织的癌前病变中检测到，例如乳房(增生症和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发挥作用。小鼠和人CRIPTO已被证明激活了乳腺上皮细胞中的ras/RAF/MAPK信号通路。PI-3激酶、GSK-3b和Akt的激活对于CR-1刺激细胞迁移和阻断乳源激素诱导的b-酪蛋白和乳清酸性蛋白的表达也是重要的。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样酪氨酸激酶反式激活erb B-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.