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: 6045379
• 负责人: GARY E GALLICK
• 金额: $ 21.07万
• 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/6045379
• 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.

目前，结直肠癌是美国第二大癌症形式的排名，估计每年发现15万例病例，由于该疾病而导致56,000例死亡。在过去的几年中，在确定导致疾病发展的遗传变化方面取得了显着进步。但是，这种进步尚未导致新疗法的发展，从而延长了晚期结肠癌患者的生存。一个有希望的研究领域也可能导致新型治疗剂的发展是对结肠肿瘤细胞中信号转导途径的研究。我的实验室和其他人一直在研究SRC家族的非受体酪氨酸激酶的表达和活性及其在结肠上皮细胞的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，发生在疾病的发展。我们已经证明，单独抑制SRC活性会降低人类结肠癌细胞的肿瘤性。为了确定SRC激活在肿瘤性中的作用，我们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，并通过与局部粘附激酶（FAK）的本构相关性抑制凋亡。提出的该赠款续签的研究旨在更好地了解SRC激活促进这些生物学事件的分子基础。我们将检验以下假设：异常的SRC/FAK信号传导复合物会在通用“生存”途径的下游中间体放松调节，从而导致VEGF表达和抑制凋亡。虽然仅SRC对于肿瘤生长可能很重要，但SRC和YES激活都可能在肝转移中发生，并且预后的结果不同。因此，在该提案中要检验的第二个假设是SRC和是激活在肿瘤进展中起着与肿瘤生长的作用不同的作用。该提案的具体目的是：（1）确定与局灶性粘附激酶（FAK）相互作用的SRC/Yes的相互作用，以表现出其肿瘤性和/或转移性电位； （2）确定SRC和FAK在介导通用生存途径中的作用，导致表达血管内皮生长因子并抑制细胞凋亡； （3）确定SRC的结构结构域的结构结构域以及SRC的特定结构结构域以及是否引起建立结肠肿瘤细胞系的转移潜力差异。这些研究的结果将阐明结肠肿瘤细胞的肿瘤生长和转移所需的重要信号转导途径，并且这些途径中的中间体可以用作预后标记和/或疾病的靶标。