Cripto in the Pathogenesis of Breast and Colon Cancer

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。Cr-1在小鼠乳腺上皮细胞中的过表达可以促进它们的体外转化，并且这些Cr-1转导的乳腺上皮细胞在体内在乳腺中产生导管增生。重组小鼠或人cripto可以增强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b-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（肠化生）中。尽管EGF-CFC蛋白的特异性受体尚未被鉴定，但oep依赖于通过Smad-2起作用的激活素型RIIB和RIB受体系统。最近，我们已经证明CR-1与ALK 4和Nodal结合，并且可以通过TGF β/Activin反应元件激活Smad-2磷酸化和信号传导。小鼠和人cripto也显示激活乳腺上皮细胞中的ras/raf/MAPK和PI 3-激酶和Akt信号传导途径，并且人CR-1对这些途径的激活不依赖于Nodal或ALK 4。PI-3激酶、GSK-3 β和Akt的活化对于CR-1刺激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er B 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. Recently, we have shown that CR-1 binds to ALK4 and Nodal and can activate Smad-2 phosphorylation and signaling through a TGFbeta/Activin response element. Mouse and human cripto have also been shown to activate ras/raf/MAPK and PI3-kinase and Akt signaling pathways in mammary epithelial cells and activation of these pathways by human CR-1 is independent of Nodal or ALK4. Activation of PI-3 kinase, GSK-3beta and Akt are important for the ability of CR-1 to stimulate 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 depend on the ability of CR-1 to transactivate erb B-4 and/or FGFR-1 through a src-like tyrosine kinase.