A Mouse model of TGFbeta1 and ras oncogene interactions

描述(申请人提供)：TGFbeta1在人类癌症发展中既有肿瘤抑制作用，也有致癌作用，但这种功能转换的潜在机制仍然不清楚。改变TGFbeta1与ras等癌细胞中被激活的致癌途径的相互作用可能是这种双重功能的基础。我们开发了一种转基因小鼠模型，允许对小鼠表皮中的TGFbeta1和致癌ras进行有条件的调节。我们发现通过这两个途径的联合表达，可以协同诱导血管生成和表皮解体。在原代角质形成细胞中这种相互作用的转录图谱显示了反映肿瘤抑制和肿瘤进展途径的拮抗和协同反应。这项研究的中心假设是，在多阶段癌变过程中，调节癌细胞表型的ras和TGFbeta信号通路之间发生了特异性的拮抗和协同作用。第一个特定目的是通过检测在正常表皮中诱导ras和TGFbeta1的转基因并监测肿瘤的发展来检验ras和TGFbeta1共同表达导致快速恶性和转移的假说。特定目的2检测在三重转基因表皮中观察到的快速血管生成反应的性质和机制，并测试在特定Aim1中观察到的肿瘤表型的意义。特异靶3验证ras和TGFbeta1通过改变基质和连接成分表达而破坏表皮正常结构完整性的假说。特定目的4使用体外原代角质形成细胞模型来研究ras和TGFbeta1信号通路的组成部分如何相互作用来调节与肿瘤抑制和肿瘤进展相关的基因表达。这项研究的长期目标是了解ras和TGFbeta1相互作用的分子基础，以便设计合理的治疗策略来阻断这些途径的协同前转移相互作用。人类的癌症是通过控制肿瘤细胞行为、与邻近细胞、局部微环境和生物体相互作用的信号通路的逐步激活和丢失而发展起来的。在许多人类肿瘤中，TGFbeta1和ras通路都发生了改变，协同作用在转移中很重要。本研究的长期目标是了解ras和TGFbeta1相互作用的分子基础，以便设计合理的治疗策略来阻断这些通路的协同促进转移相互作用。

DESCRIPTION (provided by applicant): TGFbeta1 has both tumor suppressor and oncogenic roles in human cancer development, but the mechanisms underlying this switch in function remain elusive. Changing interactions of TGFbeta1 with oncogenic pathways that are activated in cancer cells such as ras may underlie this dual function. We have developed a transgenic mouse model that allows conditional regulation of both TGFbeta1 and oncogenic ras in the mouse epidermis. We find a synergistic induction of angiogenesis and epidermal disorganization by the combined expression of both pathways. Transcriptional profiling of this interaction in primary keratinocytes reveals antagonistic and synergistic responses that reflect both tumor suppression and tumor progression pathways. The central hypothesis of this research proposal is that during multistage carcinogenesis specific antagonistic and synergistic interactions occur between ras and TGFbeta signaling pathways that regulate the phenotype of the cancer cell. The first specific aim will test the hypothesis that coexpression of ras and TGFbeta1 leads to rapid malignancy and metastasis by examining inducing both transgenes in the normal epidermis and monitoring tumor development. Specific Aim 2 examines the nature and mechanism of the rapid angiogenic response observed in the triple transgenic epidermis and tests the significance for tumor phenotypes observed in Specific Aim1. Specific Aim 3 tests the hypothesis that ras and TGFbeta1 disrupt the normal structural integrity of the epidermis through altered matrix and junctional component expression. Specific Aim 4 uses an in vitro primary keratinocyte model to examine how components of ras and TGFbeta1 signaling pathways interact to regulate gene expression associated with tumor suppression and tumor progression. The long-range goals of this research project are to understand the molecular basis of the interaction between ras and TGFbeta1 so that rational therapeutic strategies can be devised that block the synergistic prometastatic interactions of these pathways. Cancer in humans develops through from the stepwise activation and loss of signaling pathways that govern the behavior of the tumor cell, its interaction with neighboring cells, local microenvironment and organism. The TGFbeta1 and ras pathways are altered in many human cancers and synergistic interactions are important in metastases The long-range goals of this research project are to understand the molecular basis of the interaction between ras and TGFbeta1 so that rational therapeutic strategies can be devised that block the synergistic prometastatic interactions of these pathways.