TGF-beta signaling and colon cancer

TGF-β信号传导与结肠癌

基本信息

批准号：
7211867
负责人：
William Mallory Grady
金额：
$ 34.05万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7211867
关键词：
Affect Apoptosis Area Behavior Biological Biological Models Biological Process CDKN1A gene Cell Proliferation Cell Surface Receptors Cell physiology Cells Cessation of life Chromosomal Stability Colon Colon Carcinoma Colorectal Cancer Complement Factor B Complex Data Dependence Ectoderm Endoderm Epigenetic Process Epithelial Cells Event Extracellular Matrix Genes Genetic Genetic Models Genome Stability Genus Cola Hormones Human Hyperplastic Polyp In Vitro Intestinal Cancer Intestinal Neoplasms Investigation KRAS2 gene Lead Malignant Neoplasms Mediating Mesoderm Modeling Mus Mutate Mutation Neoplasms Pathway interactions Phosphorylation Play Pongidae Protein-Serine-Threonine Kinases Ras/Raf Regulation Research Personnel Resistance Role Signal Pathway Signal Transduction Stem cells System TGFBR1 gene TGFBR2 gene TP53 gene Testing Transforming Growth Factor beta Transforming Growth Factors Tumor Suppressor Genes Tumor Suppressor Proteins United States adenoma angiogenesis cancer cell cell behavior cell growth cell motility colon carcinogenesis cytokine human TGFBR2 protein in vivo mouse model mutant neoplastic neoplastic cell novel oncoprotein p21 p21 K-Ras Protein programs receptor response senescence tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Transforming growth factor B receptor type II (TGFBR2) is a tumor suppressor gene that is commonly mutated in colon cancer, and its inactivation plays an important and potentially paradoxical role in colon carcinogenesis. TGFBR2 is an essential component of the TGF-B receptor complex, which mediates the effects of the multi-functional cytokine, TGF-B. TGF-B and TGFBR2 regulate a variety of cell functions including cell growth, senescence, differentiation; extracellular matrix remodeling, and genomic stability. Thus, TGFBR2 inactivation likely affects tumor formation through a variety of mechanisms, including excess cell proliferation, increased cell invasiveness, regulation of genomic stability, etc. Interestingly, unlike classical hormones whose actions are few and specific, TGF-B can cause these myriad effects on a cell because TGF-B's effects depend on the type and state of the cell, termed the 'cellular context'. Our preliminary data demonstrates that the cellular context dependence of TGF-B's effects dictates the consequences of the loss of TGF-B signaling in colon cancer and that those consequences are a result of cooperation of TGFBR2 inactivation with other genes commonly mutated in colon cancer. We now propose to study the effects of TGFBR2 inactivation in the context of known genetic events that occur in colon cancer (e.g. ARC, KRAS2, and TRP53 mutations). We will employ novel model systems to determine how TGFBR2 inactivation affects tumor cell behavior, especially in the context of mutant APC, KRAS2, and TP53. Of note, these studies have yielded novel genetic models for the classic adenoma-cancer pathway and an unprecedented model for the hyperplastic polyp-cancer path. The Specific Aims are as follows: Aim 1) To determine the effect of TGF-B signaling pathway inactivation in the setting of Apc mutation and Wnt signaling activation on intestinal cancer formation. Aim 2) To determine if TGF-B signaling pathway inactivation cooperates with Kras2 mutation and Ras-Raf pathway activation in intestinal cancer formation. Aim 3) To determine the in vivo consequences of TGFBR2 inactivation on colon cancer initiation and progression using novel mouse models of intestinal cancer that genetically recapitulate human colon cancer, Apc1638N;LSL-Kras2G12D ;Tgfbr2IEKO, and Apc1638N;LSL-Trp53R172H;Tgfbr2IEKO mice.

描述（由申请人提供）：转化生长因子B受体II型（TGFBR2）是一种通常在结肠癌中突变的肿瘤抑制基因，其失活在结肠癌发生中起重要且潜在的矛盾作用。 TGFBR2是TGF-B受体复合物的重要组成部分，它介导了多功能细胞因子TGF-B的作用。 TGF-B和TGFBR2调节各种细胞功能，包括细胞生长，衰老，分化；细胞外基质重塑和基因组稳定性。因此，TGFBR2失活可能会通过多种机制（包括过量的细胞增殖，增加的细胞侵袭性，基因组稳定性的调节等调节）来影响肿瘤的形成。我们的初步数据表明，TGF-B效应的细胞环境依赖性决定了结肠癌中TGF-B信号传导丧失的后果，这些后果是TGFBR2与其他基因与其他通常突变在结肠癌中突变的基因合作的结果。现在，我们建议在结肠癌中发生的已知遗传事件（例如ARC，KRAS2和TRP53突变）中研究TGFBR2失活的影响。我们将采用新型模型系统来确定TGFBR2灭活如何影响肿瘤细胞行为，尤其是在突变APC，KRAS2和TP53的背景下。值得注意的是，这些研究为经典的腺瘤癌症途径和增生息肉癌症路径的前所未有的模型产生了新的遗传模型。具体目的如下：目标1）确定在APC突变和Wnt信号激活中TGF-B信号通路失活对肠癌形成的影响。目的2）确定TGF-B信号通路途径是否与KRAS2突变和RAS-RAF途径激活在肠道癌的形成中合作。目的3）使用新型的肠道癌的小鼠模型来确定TGFBR2对结肠癌开始和进展的体内后果，这些模型在遗传上概括了人类结肠癌，APC1638N； LSL-KRAS2G12D; tgfbr2ieko和apc1638n; apc1638n; lsl-lsl-trp53rp53rp53r1 trp53r1 trp53r1 trp53r1 trp53r1 trp53r1 trp53r1 trp53r1 trp53r1。