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: 6598803
• 负责人: Thomas F Deuel
• 金额: $ 41.26万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 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/6598803
• 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.

本研究的长期目标是鉴定和表征多效生长因子（PTN）和中期因子（MK）信号在肿瘤中的新血管形成（即，“肿瘤血管生成”）以及鉴定和利用治疗性控制病理性血管生成和人肿瘤的位点和方法。PTN和MK在许多侵袭性人类肿瘤中高度表达，并且来自这些肿瘤的细胞系组成性表达PTN和MK，表明它们的表达是转化细胞中遗传稳定突变的结果。PTN转化的细胞和其中PTN或其C-末端结构域单独的组成型表达已经建立的肿瘤细胞在裸鼠中发展为高度血管化的肿瘤。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）释放到细胞外位点，但未转化的对照细胞不释放，这表明bFGF释放是转化依赖性的，并且是PTN信号传导途径的结果。碱性成纤维细胞生长因子从转化细胞释放也规定PMA，这表明bFGF的释放是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，因为显性负性PTN效应子中断内源性PTN信号传导可逆转人类乳腺癌细胞的侵袭性生长。由于PTN和MK的结构和功能都有惊人的相似性，并且这些高度相关的细胞因子的表达是许多侵袭性和高度血管化肿瘤的特征，因此现在建议利用用于产生上述初步数据的模型来功能性地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。该提案试图定义致癌途径，PTN-或MK-与之合作以启动转化和肿瘤促进，以鉴定由PTN或MK刺激的导致肿瘤血管生成的信号传导激活的下游基因和途径，求因数例如活化PKC同种型或bFGF，其可直接介导PTN和MK信号肿瘤血管生成，并确定PTN和MK信号中的新靶点这些结果有可能确定在人类肿瘤中具有潜在广泛重要性的“血管生成开关”，推进血管发生的知识，并确定治疗干预的潜在位点。