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， 非洲爪蟾、斑马鱼、小鼠和小鼠早期胚胎发生过程中重要的感受态因子 人类这个多基因家族包括爪蟾FRL-1，斑马鱼独眼针头（oep）， 小鼠cripto（Cr-1）和隐型criptic以及人cripto（CR-1）和criptin。FRL-1、oep和小鼠 cripto对于中胚层和内胚层的形成以及正确的建立是必需的 胚胎前/后轴。此外，oep和cryptic对于 建立左右不对称。在小鼠中，隐蔽蛋白在成年组织中不表达。 而Cr-1在几种不同的组织中以低水平表达， 腺。在乳腺中，导管上皮细胞中Cr-1的表达增加 在妊娠和哺乳期间，免疫反应性和生物活性Cr-1蛋白可以 在母乳中检测到。人CR-1转基因在小鼠乳腺中的过表达 使用MMTV或WAP启动子导致乳腺导管增生的出现， 经产女性腺癌的腺体和乳头状amd组织学混合亚型 小鼠重组小鼠或人cripto可以增强细胞运动和分支形态发生 在小鼠乳腺上皮细胞和一些人类肿瘤细胞中。这些影响伴随着 通过与β-连环蛋白减少相关的上皮-间质转化 粘附功能和波形蛋白表达的增加。CR-1表达增加 在人结肠癌、胃癌、胰腺癌、宫颈癌、卵巢癌和肺癌中， 各种不同类型的小鼠和人类乳腺癌。更重要的是这个 cripto-1表达的增加可以首先在这些疾病中的一些的癌前病变中检测到， 组织如乳腺（增生和DCIS）、结肠（腺瘤）和胃 （肠化生）。我们最近发现激活素ALK 4类型 1受体作为CR-1的共受体，其将Nodal呈递给ALK 4，从而可以刺激 Smad-2磷酸化和通过SBE-荧光素酶报告基因构建体的转录。 此外，CR-1可以通过Nodal和ALK 4非依赖性信号通路发挥作用， 通过结合GPI连接的含硫酸乙酰肝素的 蛋白聚糖，磷脂酰肌醇蛋白聚糖-1，然后可以激活c-SRC。MAPK，PI-3激酶， 乳腺上皮细胞中的GSK-3 β和Akt通过CR-1是CR-1的能力所必需的， 刺激上皮向间质转化、细胞迁移和细胞侵袭， 参与转移和血管生成。CR-1的侵袭作用可以通过以下方式拮抗： 神经导向蛋白Netrin-1通过乳腺上皮细胞中的UNC5b受体。 CR-1还参与维持胚胎干细胞的多能性， 在乳腺和结肠的成体干细胞中也有类似的功能。CR-1可以在 乳腺癌和结肠癌患者血浆中的显著水平，因此可能 代表了检测这些疾病的发作或进展的新标志物。

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.