IGF II AND CATHEPSIN D IN TUMOR GROWTH AND METASTASIS

描述：（改编自研究者摘要） 乳腺癌的发展与细胞功能有关吗 一 解决这一基本问题的有前途的研究领域是 研究胰岛素样生长因子-II（IGF-II）和 组织蛋白酶D与IGF-II/甘露糖-6-磷酸（M6 P）受体。 最近 研究强烈表明这些肽之间复杂的相互作用 和IGF-II/M6 P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， 有丝分裂原参与和它们与促成细胞分裂的因子的相互作用。 乳腺癌的进展将直接应用于改善 患者治疗和随访。 IGF-II是乳腺癌的有丝分裂原。 组织蛋白酶D是参与转移的酶。 两者均结合IGF-II/M6 P 在不同的结合位点的受体。 然而，一种相互抑制的 当IGF-II或组织蛋白酶D结合IGF-II/M6 P时，观察到相互作用 受体的 因此，细胞内IGF-II可能导致组织蛋白酶-D增加， 分泌而不是路由到溶酶体。 他们假设， IGF-II和组织蛋白酶的细胞内以及细胞外相互作用 D与IGF-II/M6 P受体结合后会促进肿瘤的生长和转移。 到 为了验证这一假设，他们将确定（1）IGF-II表达 调节体外组织蛋白酶D分泌，2） proIGF-II/组织蛋白酶D增加体内肿瘤生长和转移，以及3） 乳腺肿瘤中特定形式的IGF-II和组织蛋白酶D增加 乳腺癌患者的乳腺癌转移与乳腺癌组织相关。 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。 将在SCID小鼠中辅助转移 模型 更全面地了解 组织蛋白酶D和IGF-II与IGF-II/M6 P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： 用体内模型表征体外模型系统， 乳腺癌组织中组织蛋白酶D/IGF-II的研究 患者 然后可能需要进行更全面的研究， 是否可以从纳入特定形式的 组织蛋白酶D和IGF-II在肿瘤细胞预后指标中的作用 转移

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.