IGF II AND CATHEPSIN D IN TUMOR GROWTH AND METASTASIS

描述：(改编自调查人员的摘要) 细胞功能是乳腺癌进展的原因吗？一 解决这一根本问题的有前途的研究领域是 胰岛素样生长因子-II与胰岛素样生长因子-II相互作用的研究 组织蛋白酶D与IGF-II/甘露糖-6-磷酸(M6P)受体结合。近期 研究强烈表明，这些多肽之间的复杂相互作用 IGF-II/M6P受体是肿瘤生长和转移所必需的。 因此，阐明了这些细胞的调控机制(S) 有丝分裂原的参与及其与促进细胞分裂的因素的相互作用 乳腺癌的进展将直接应用于改善 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是一种参与肿瘤转移的酶。两者都与IGF-II/M6P结合 不同结合部位的受体。然而，一种相互抑制的 当IGF-II或组织蛋白酶D与IGF-II/M6P结合时，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的升高 分泌而不是进入溶酶体。他们假设 胰岛素样生长因子-II与组织蛋白酶的细胞内外相互作用 D与IGF-II/M6P受体联合应用将促进肿瘤生长和转移。至 检验这一假设，他们将确定(1)IGF-II表达 在体外调节组织蛋白酶D的分泌，2)过度分泌 ProIGF-II/组织蛋白酶D促进体内肿瘤生长和转移 IGF-II和组织蛋白酶D在乳腺肿瘤中的表达增加 并与乳腺癌患者的转移有关。 胰岛素样生长因子-II和组织蛋白酶D在乳腺癌细胞中的表达 肿瘤组织将由Northerns，Westns和 免疫沉淀分析。SCID小鼠的转移将得到帮助 模特。更全面地了解 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 将为肿瘤发生和发展中的作用提供新的见解 进步。研究设计整合了从以下方面获得的信息 体内模型与体外模型系统的表征 组织蛋白酶D/IGF-II在乳腺癌正常组织和肿瘤组织中的研究 病人。然后可能需要更全面的研究来评估 是否从包括特定形式的 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.