The Role of Cripto in the Pathogenesis of Breast and Col

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MMTV或WAP启动子作用下，人CR-1转基因在小鼠乳腺中过表达，导致乳腺导管增生症和经产雌性小鼠乳头状腺癌和组织学混合亚型腺癌的出现。重组小鼠或人CRIPTO可增强小鼠乳腺上皮细胞和某些人肿瘤细胞的细胞运动能力和分支形态发生。这些效应伴随着上皮向间充质的转变，这与β-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)。我们最近发现激活素ALK41型受体是CR-1的共同受体，它向ALK4递送Nodal，从而通过构建SBE-荧光素酶报告结构来刺激Smad-2的磷酸化和转录。此外，CR-1可以通过Nodal和ALK4不依赖的信号通路发挥作用，并通过与GPI连接的含有硫酸乙酰肝素的蛋白多糖Glypcan-1激活MAPK、PI-3激酶和Akt，从而激活c-src。CR-1激活乳腺上皮细胞MAPK、PI-3、GSK-3β和Akt是CR-1刺激上皮细胞向间充质转化、细胞迁移和细胞侵袭所必需的，参与肿瘤转移和血管生成。乳腺上皮细胞中的神经引导蛋白Netrin-1可通过Unc5b受体拮抗CR-1的侵袭作用。CR-1还参与维持胚胎干细胞的多能性，并可能在乳腺和结肠的成体干细胞中发挥类似的功能。在乳腺癌和结肠癌患者的血浆中可以发现CR-1的显著水平，因此它可能是检测这些疾病发生或发展的一个新的标志物。

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 orWAP promoter results in the appearance of ductal hyperplasias in the mammary gland and papillary amd histologically mixed subtypes of 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 epithelial to mesenchymal transition, cell migration and cell invasion which is invovled in metastasis and angiogenesis. The invasive effects of CR-1 can be antagonized by the neural guidance protein Netrin-1 through the UNC5b receptor in mammary epithelial cells. CR-1 is also invovled in maintaing embryonic stem cell pluripotentiality and may perform a similar function in adult stem cells in the mammary gland and colon. CR-1 can be found at significant levels in the plasma of breast and colon cancer paptients and may therefore represent a novel marker to detect the onset or progression of these diseases.