SRC KINASES IN COLON TUMORIGENESIS AND METASTASIS

描述：(改编自调查人员的摘要)在过去的几年中 多年来，在理解这些问题方面取得了重大进展 结直肠癌发生的遗传学基础。这些进展 几乎肯定会带来更好的风险评估和早期 诊断。然而，在可预见的未来，结直肠癌将 仍然是一种重要的疾病，大多数患者表现为 在疾病的晚期，几乎没有重大的治疗进展 已经被制造了。对于这些患者，治疗性治疗是可能的 为了更好地理解信号转导途径 它们调节结肠上皮细胞的增殖和分化 细胞，其变化可能导致恶性转化，肿瘤 进展和转移的发展。一个信号族 转导酶非受体蛋白酪氨酸激酶(PTKs) 与pp60c-src相关，几乎在每个结肠肿瘤中都被激活， 产生与之相当的酶的特定活性 观察逆转录病毒癌基因同源物。激活是第一步 在肿瘤形成的早期阶段观察到的，从息肉开始 高度恶性潜能，并持续到随后的阶段 肿瘤进展。酶活性的额外增加 原发肿瘤与转移发展之间的关系。两名成员 在src家族中，pp60c-src和pp62c-yes在结肠中表达。 上皮细胞，两者在大部分结肠中都被激活 肿瘤。然而，尽管这些酶在正常情况下扮演着多余的角色 结肠上皮细胞的生长调节，它们发挥着不同的作用 在肿瘤细胞的异常生长中。因此，这项提案的目标是 定义pp60c-src和pp62c-yes的特定和/或集体角色 对结肠的增殖、致瘤性和转移潜能的影响 肿瘤细胞，并试图阐明这些机制(S) PTK被激活。通过特别地抑制和增加 C-src和/或c-yes激酶的表达和活性 反义技术，这一提议的研究将检验 假设c-src或c-yes的激活对 恶变和/或进展。这项提案的目的 包括：(1)研究这些蛋白酪氨酸激酶的抑制作用 细胞增殖动力学和体外侵袭力的研究 结肠肿瘤细胞，(2)表达载体的产生 反义寡核苷酸；(3)测定致瘤性和 模型结肠肿瘤细胞系的转移潜能 这些PTKs的表达和活性已经通过稳定的 反义表达载体的转染，或通过稳定的方式增加 野生型和野生型编码的特定基因构建物的转染 这些酶的“激活”形式。这些研究将导致更好的 对这些激酶在生长控制中的关键作用的理解 结肠上皮细胞，并确定这些酶中哪些可能是 开发特定蛋白酪氨酸激酶抑制剂的目标。

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.