SRC KINASES IN COLON TUMORIGENESIS AND METASTASIS

SRC 激酶在结肠肿瘤发生和转移中的作用

• 批准号: 6328945
• 负责人: GARY E GALLICK
• 金额: $ 21.7万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6328945
• 关键词: apoptosis; biological signal transduction; carcinoma; cell growth regulation; cell line; colorectal neoplasms; enzyme activity; focal adhesion kinase; gene expression; laboratory mouse; metastasis; neoplasm /cancer genetics; neoplastic growth; neoplastic process; neoplastic transformation; phenotype; protein protein interaction; protein tyrosine kinase; tissue /cell culture; vascular endothelial growth factors

Colorectal carcinoma currently ranks as the second most frequent form of cancer in the United States, with an estimated 150,000 cases discovered each year, and 56,000 deaths as a result of the disease. In the past several years, remarkably progress has been made toward identifying the genetic changes which lead to the development of the disease. However, this progress has yet to result in the development of new therapies that prolong the survival of patients with late stage colon cancer. A promising area of research that may also lead to the development of novel therapeutic agents is the study of signal transduction pathways in colon tumor cells. My laboratory and others have been studying the expression and activity of the non-receptor tyrosine kinases of the src family and their potential roles in the growth regulation of colonic epithelial cells. Src activation is one of the most frequent epigenetic events in colon cancer, and occurs early in the development of the disease. We have demonstrated that inhibition of Src activity alone decreases tumorigenicity of human colon carcinoma cells. To determine the role of Src activation in tumorigenicity, we have examined the regulation of Src- mediated pathways critical to growth control. We have shown that Src activation directly induces expression of vascular endothelial growth factor (VEGF), and further, through constitutive association with focal adhesion kinase (FAK), inhibits apoptosis. The studies proposed for the renewal of this grant are designed to better understand the molecular basis by which Src activation promotes these biological events. We will test the hypothesis that aberrant Src/FAK signaling complexes deregulate downstream intermediates of a common "Survival" pathway leading to VEGF expression and inhibition of apoptosis. While Src alone may be important to tumorigenic growth, both Src and Yes activation can occur in hepatic metastases, and with different prognostic results. Therefore, a second hypothesis to be tested in this proposal is that Src and Yes activation play distinct roles in tumor progression from those of tumorigenic growth. The specific aims of the proposal are to: (1) determine the requirement of interaction with focal adhesion kinase (FAK) for Src/Yes to exhibit their tumorigenic and/or metastatic potentials; (2) determine the role(s) of Src and FAK in mediating a common survival pathway leading to expression of vascular endothelial growth factor and inhibiting apoptosis; and (3) Determine the structural domains of Src required for its tumorigenic phenotype and if specific structural domains of Src and Yes induce differences in metastatic potential of establish colon tumor cell lines. Results from these studies will clarify important signal transduction pathways required for tumorigenic growth and metastasis of colon tumor cells, and intermediates in these pathways may serve as prognostic markers and/or targets for the disease.

结直肠癌目前在美国排名第二，每年估计有150，000例发现，56，000例死亡。在过去的几年里，在确定导致疾病发展的遗传变化方面取得了显着进展。然而，这一进展尚未导致新疗法的开发，以延长晚期结肠癌患者的生存期。一个有前途的研究领域，也可能导致新的治疗药物的发展是在结肠肿瘤细胞的信号转导途径的研究。我的实验室和其他人一直在研究src家族非受体酪氨酸激酶的表达和活性，以及它们在结肠上皮细胞生长调节中的潜在作用。Src激活是结肠癌中最常见的表观遗传事件之一，并且发生在疾病发展的早期。我们已经证明，抑制Src活性单独降低人结肠癌细胞的致瘤性。为了确定Src激活在致瘤性中的作用，我们已经检查了对生长控制至关重要的Src介导的途径的调节。我们已经表明，Src激活直接诱导血管内皮生长因子（VEGF）的表达，并进一步通过与粘着斑激酶（FAK）的组成性关联，抑制细胞凋亡。这项研究的目的是为了更好地了解Src激活促进这些生物学事件的分子基础。我们将测试的假设，异常Src/FAK信号复合物去调节下游中间体的一个共同的“生存”途径，导致VEGF的表达和抑制细胞凋亡。虽然Src单独可能对致瘤性生长很重要，但Src和Yes活化均可发生在肝转移瘤中，并且具有不同的预后结果。因此，在本提案中要检验的第二个假设是Src和Yes激活在肿瘤进展中与致瘤性生长中发挥不同的作用。该提案的具体目的是：（1）确定Src/Yes与粘着斑激酶（FAK）相互作用是否需要表现出其致瘤和/或转移潜力;（2）确定Src和FAK在介导共同生存途径中的作用，导致血管内皮生长因子的表达并抑制细胞凋亡;和（3）确定其致瘤表型所需的Src的结构域，以及Src和Yes的特定结构域是否诱导建立的结肠肿瘤细胞系的转移潜能的差异。这些研究的结果将阐明结肠肿瘤细胞致瘤性生长和转移所需的重要信号转导途径，这些途径中的中间体可作为疾病的预后标志物和/或靶点。