PLEIOTROPHIN-- AN ANGIOGENIC SWITCH IN TUMOR PROGRESSION

多效素——肿瘤进展中的血管生成开关

• 批准号: 6329106
• 负责人: Thomas F Deuel
• 金额: $ 37.61万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-20 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6329106
• 关键词: angiogenesis; athymic mouse; biological signal transduction; breast neoplasms; cardiovascular neoplasm; disease /disorder model; enzyme activity; fibroblast growth factor; gene expression; gene mutation; isozymes; mitogens; neoplasm /cancer genetics; neoplastic cell; neoplastic process; neoplastic transformation; nerve growth factors; oncogenes; pleiotropism; protein kinase C; protein structure function; tissue /cell culture

The long-range goals of this research are to identify and characterize whereby pleiotrophin (PTN) and midkine (MK) signal neovascularization in tumors (i.e., "tumor angiogenesis") and to identify and exploit the sites and methods to therapeutically control pathological angiogenesis and human tumors. Both PTN and MK are highly expressed in many aggressive human tumors and cell lines from these tumors constitutively express PTN and MK, suggesting that their expression is the result of a genetically stable mutation in the transformed cell. PTN transformed cells and tumor cells in which constitutive expression of PTN or its C-terminal domain alone have been established develop highly vascular tumors in the nude mouse. Remarkably, the cells that express PTN release basic fibroblast growth factor (bFGF) to extracellular sites but non-transformed control cells do not, suggesting that bFGF release is transformation-dependent and the result of a PTN signaled pathway. Basic FGF release from transformed cells is also stipulated by PMA, suggesting that bFGF release is dependent on an activated protein kinase C (PKC) isoform. These findings may be very relevant to human tumors, since interruption of endogenous PTN signaling by a dominant negative PTN effector reverses aggressive growth of human breast cancer cells. Since there is a striking similarity of both structure and functions of PTN and MK and expression of these highly related cytokines is a feature of many aggressive and high vascularized tumors, it is mow proposed to exploit the models used to generate the Preliminary Data cited above to functionally dissect and compare the different domains of PTN and MK that lead to tumor promotion and tumor angiogenesis. The proposal seeks to define oncogenic pathways with which PTN- OR mk- "cooperates to initiate transformation and tumor promotion, to identify downstream genes and pathways which are activated by PTN or MK stimulated signaling that lead to tumor angiogenesis, to seek the factor(s) such as an activated PKC isoform or bFGF which may directly mediate PTN and MK signaled tumor angiogenesis and to define new targets in PTN and MK signaling pathways for therapies to reverse the stepwise progression of tumors in man. The results are likely to identify "angiogenic switch(s)" of potential broad importance in human tumors, advance knowledge of vasculogenesis and identify potential sites for therapeutic intervention.

这项研究的长期目标是确定和表征多营养素(PTN)和中期因子(MK)信号在肿瘤中新血管生成(即肿瘤血管生成)的作用，并确定和开发用于治疗控制病理性血管生成和人类肿瘤的部位和方法。PTN和MK在许多侵袭性人类肿瘤中都高表达，这些肿瘤的细胞系结构性地表达PTN和MK，这表明它们的表达是转化细胞中遗传稳定突变的结果。PTN转化细胞和已建立PTN或其C末端结构域单独表达的肿瘤细胞在裸鼠体内发生高度的血管肿瘤。值得注意的是，表达PTN的细胞将碱性成纤维细胞生长因子(BFGF)释放到细胞外部位，而未转化的对照细胞不释放，这表明bFGF的释放是转化依赖的，是PTN信号通路的结果。PMA还规定转化细胞释放碱性成纤维细胞生长因子，表明碱性成纤维细胞生长因子的释放依赖于活化的蛋白激酶C(PKC)亚型。这些发现可能与人类肿瘤非常相关，因为内源性PTN信号被显性的负PTN效应阻断，逆转了人类乳腺癌细胞的侵袭性生长。由于PTN和MK在结构和功能上有着惊人的相似性，而这些高度相关的细胞因子的表达是许多侵袭性和高度血运的肿瘤的特征，现建议利用上述模型来从功能上剖析和比较导致肿瘤促进和肿瘤血管生成的PTN和MK的不同结构域。该提案旨在确定Ptn-或MK-“协同启动转化和促癌作用的致癌途径，确定Ptn或MK刺激信号激活的下游基因和导致肿瘤血管生成的途径，寻找可能直接介导Ptn和MK信号的肿瘤血管生成的因子(S)，并在Ptn和MK信号通路中确定新的靶点，以逆转人类肿瘤的逐步发展。本研究结果可能有助于确定在人类肿瘤中具有潜在广泛重要性的”血管生成开关(S)“，增进对血管生成的了解，并确定潜在的治疗干预部位。