IGF II AND CATHEPSIN D IN TUMOR GROWTH AND METASTASIS

IGF II 和组织蛋白酶 D 在肿瘤生长和转移中的作用

基本信息

批准号：
2468718
负责人：
DAISY D. DE LEON
金额：
$ 22.71万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-30 至 2001-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2468718
关键词：
MCF7 cell SCID mouse breast neoplasms cathepsin D chemical binding enzyme induction /repression gene expression growth factor receptors human tissue immunoprecipitation insulin receptor insulinlike growth factor mannose 6 phosphate metastasis molecular site northern blottings receptor binding western blottings

项目摘要

DESCRIPTION: (adapted from the investigator's abstract) What changes in cellular function account for the progression of breast cancer? One promising research area that addresses this fundamental question is the study of the interactions of insulin-like growth factor-II (IGF-II) and cathepsin D with the IGF-II/mannose-6-phosphate (M6P) receptor. Recent studies strongly suggest that complex interactions between these peptides and the IGF-II/M6P receptor are required for tumor growth and metastasis. Thus, elucidation of the regulatory mechanism(s) in which these cellular mitogens participate and their interactions with factors contributing to the progression of breast cancer will have direct applications for improvements in patient treatment and follow-up. IGF-II is a mitogen for breast cancer. Cathepsin D is an enzyme involved in metastasis. Both bind the IGF-II/M6P receptor at distinct binding sites. Nevertheless, a reciprocal inhibitory interaction is observed when IGF-II or cathepsin D bind the IGF-II/M6P receptor. Thus, intracellular IGF-II may cause increased cathepsin-D secretion instead of routing to the lysosomes. They hypothesize that intracellular as well as extracellular interactions of IGF-II and cathepsin D with the IGF-II/M6P receptor will promote tumor growth and metastasis. To test this hypothesis, they will determine whether (1) IGF-II expression modulates cathepsin D secretion in vitro, 2) oversecretion of proIGF-II/cathepsin D increases tumor growth and metastasis in vivo and 3) specific forms of IGF-II and cathepsin D are increased in breast tumor tissues and are associated with metastases in breast cancer patients. IGF-II and cathepsin D expression in transfected breast cancer cells and tumor tissues will be assessed by Northerns, Westerns and immunoprecipitation assays. Metastasis will be assisted in the SCID mouse model. A more complete understanding of the physiological consequences of the interactions of cathepsin D and IGF-II with the IGF-II/M6P receptor may have important therapeutic value as treatment targets for breast cancer and will provide new insights into the role in tumor development and progression. The research design integrates information obtained from characterization of the in vitro model system with the in vivo model and cathepsin D/IGF-II studies of normal and tumor tissues from breast cancer patients. More comprehensive studies may then be warranted to assess whether additional benefit is gained from including specific forms of cathepsin D and IGF-II among the prognostic indicators for tumor cell metastasis.

描述：（改编自研究者的摘要）细胞功能是乳腺癌进展的原因吗？一解决这一基本问题的有前途的研究领域是胰岛素样生长因子-II (IGF-II) 和胰岛素样生长因子-II 相互作用的研究组织蛋白酶 D 与 IGF-II/6-磷酸甘露糖 (M6P) 受体。最近的研究强烈表明这些肽之间存在复杂的相互作用 IGF-II/M6P受体是肿瘤生长和转移所必需的。因此，阐明这些细胞的调节机制有丝分裂原参与及其与促进有丝分裂的因素的相互作用乳腺癌的进展将有直接的改善应用在患者治疗和随访中。 IGF-II 是乳腺癌的有丝分裂原。组织蛋白酶 D 是一种参与转移的酶。两者均结合 IGF-II/M6P 受体位于不同的结合位点。然而，相互抑制当 IGF-II 或组织蛋白酶 D 结合 IGF-II/M6P 时观察到相互作用受体。因此，细胞内 IGF-II 可能导致组织蛋白酶-D 增加分泌而不是进入溶酶体。他们假设 IGF-II 和组织蛋白酶的细胞内和细胞外相互作用 D与IGF-II/M6P受体结合会促进肿瘤生长和转移。到检验这个假设，他们将确定 (1) IGF-II 表达是否体外调节组织蛋白酶 D 分泌，2) 过度分泌 proIGF-II/组织蛋白酶 D 增加体内肿瘤生长和转移，3) 乳腺肿瘤中特定形式的 IGF-II 和组织蛋白酶 D 增加组织并与乳腺癌患者的转移有关。转染乳腺癌细胞中 IGF-II 和组织蛋白酶 D 的表达肿瘤组织将由北方人、西方人和免疫沉淀测定。将有助于 SCID 小鼠的转移模型。对生理后果有更全面的了解组织蛋白酶 D 和 IGF-II 与 IGF-II/M6P 受体的相互作用可能作为乳腺癌的治疗靶点具有重要的治疗价值将为肿瘤发展中的作用提供新的见解进展。研究设计整合了从以下方面获得的信息体外模型系统与体内模型的表征乳腺癌正常组织和肿瘤组织的组织蛋白酶 D/IGF-II 研究患者。然后可能需要进行更全面的研究来评估包括特定形式的内容是否可以获得额外的好处组织蛋白酶 D 和 IGF-II 是肿瘤细胞的预后指标转移。