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: 2700579
• 负责人: GARY E GALLICK
• 金额: $ 19.85万
• 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 1999-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2700579
• 关键词: antisense nucleic acid; clone cells; colorectal neoplasms; enzyme activity; gastrointestinal epithelium; metastasis; neoplasm /cancer genetics; neoplastic growth; neoplastic process; neoplastic transformation; protein tyrosine kinase; tissue /cell culture; transfection

DESCRIPTION: (adapted from the investigator's abstract) In the past few years, significant advances have been made toward understanding the genetic basis for the development of colorectal cancer. These advances will almost certainly lead to better risk assessment and early diagnosis. However, in the foreseeable future, colorectal cancer will remain a significant disease, with the majority of patients presenting at late stages of the disease for which few major treatment advances have been made. For these patients, therapeutic treatments are likely to arise for a better understanding of the signal transduction pathways which regulate proliferation and differentiation of colonic epithelial cells, and whose alteration may lead to malignant transformation, tumor progression, and the development of metastases. One family of signal transduction enzymes, the non-receptor protein tyrosine kinases (PTKs) related to pp60c-src, is activated in nearly every colon tumor, resulting in specific activities of the enzymes equivalent to that observed for the retroviral oncogene homologues. Activation is first observed in an early stage of tumorigenesis, beginning with polyps of high malignant potential and persisting through subsequent stages of tumor progression. Additional increases in enzymatic activity occur between the primary tumor and development of metastasis. Two members of the src family, pp60c-src and pp62c-yes, are expressed in colonic epithelial cells, and both are activated in the majority of colon tumors. However, while these enzymes play redundant roles in normal growth regulation of colonic epithelial cells, they play distinct roles in aberrant growth of tumor cells. Thus, goals of this proposal are to define the specific and/or collective roles of pp60c-src and pp62c-yes in proliferation, tumorigenicity, and metastatic potential of colon tumor cells, and to attempt to elucidate the mechanism(s) by which these PTKs are activated. By specifically inhibiting and increasing the expression and activity of the c-src and/or c-yes kinases through antisense technology, the studies of this proposal will test the hypothesis that activation of either c- src or c-yes is critical for malignant transformation and/or progression. The aims of the proposal include: (1) studying the effects of inhibition of these PTKs on proliferative kinetics and in vitro invasiveness of well characterized colon tumor cells, (2) generation of expression vectors for these antisense oligonucleotides; and (3) determining the tumorigenicity and metastatic potential of model colon tumor cell lines in which the expression and activity of these PTKs has been decreased via stable transfection of antisense-expression vectors, or increased via stable transfection of specific genetic constructs encoding wild type and "activiated" forms of these enzymes. The studies will lead to a better understanding of the critical role these kinases play in growth control of colonic epithelial cells, and identify which of these enzymes may be a target for development of specific protein tyrosine kinase inhibitors.

描述：（改编自研究者的摘要）在过去的几年里 多年来，在理解 结直肠癌发生的遗传基础。这些进步 几乎肯定会导致更好的风险评估和早期 诊断。然而，在可预见的将来，结直肠癌将 仍然是一种重要的疾病，大多数患者出现 处于疾病晚期，几乎没有重大治疗进展 已经做了。对于这些患者，可能需要进行治疗 出现是为了更好地理解信号转导途径 调节结肠上皮细胞的增殖和分化 细胞，其改变可能导致恶性转化、肿瘤 进展和转移的发展。一族信号 转导酶，非受体蛋白酪氨酸激酶 (PTK) 与 pp60c-src 相关，几乎在每个结肠肿瘤中都被激活， 导致酶的比活性相当于 观察到逆转录病毒癌基因同源物。激活是第一位的 在肿瘤发生的早期阶段观察到，从息肉开始 高度恶性潜力并持续到后续阶段 肿瘤进展。酶活性进一步增加 原发肿瘤和转移瘤之间的关系。两名成员 src 家族的 pp60c-src 和 pp62c-yes 在结肠中表达 上皮细胞，并且两者在大部分结肠中都被激活 肿瘤。然而，虽然这些酶在正常情况下发挥着多余的作用 结肠上皮细胞的生长调节，它们发挥着不同的作用 肿瘤细胞的异常生长。因此，本提案的目标是 定义 pp60c-src 和 pp62c-yes 的特定和/或集体角色 结肠的增殖、致瘤性和转移潜力 肿瘤细胞，并试图阐明这些细胞的机制 PTK 已激活。通过专门抑制和增加 c-src 和/或 c-yes 激酶的表达和活性 反义技术，本提案的研究将测试 假设 c-src 或 c-yes 的激活对于 恶性转化和/或进展。该提案的目的 包括：（1）研究这些PTK的抑制作用 充分表征的增殖动力学和体外侵袭性 结肠肿瘤细胞，(2) 生成这些细胞的表达载体 反义寡核苷酸； (3) 确定致瘤性和 模型结肠肿瘤细胞系的转移潜力，其中 这些 PTK 的表达和活性已通过稳定的 转染反义表达载体，或通过稳定表达增加 转染编码野生型和 这些酶的“活化”形式。这些研究将带来更好的结果 了解这些激酶在生长控制中发挥的关键作用 结肠上皮细胞，并确定这些酶中的哪些可能是 开发特定蛋白酪氨酸激酶抑制剂的目标。