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Pathophysiology of Post-Transplantation Cancer

移植后癌症的病理生理学

基本信息

批准号：
8444355
负责人：
Soumitro Pal
金额：
$ 32.92万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444355
关键词：
1-Phosphatidylinositol 3-Kinase Acute Disease Allografting Alternative Splicing Animals Binding Biological Blood Vessels CCL2 gene CXC chemokine receptor 3 CXCL10 gene CXCL11 gene CXCL12 gene CXCL9 gene CXCR3 gene Cell Proliferation Cell Proliferation Regulation Cell Survival Cell surface Cells Chemotactic Factors Chemotaxis Chronic Disease Cyclic AMP Cyclosporine Dendritic Cells Development Down-Regulation Endothelial Cells Epithelial Cells Equilibrium Event Functional disorder G-Protein-Coupled Receptors Gene Expression General Population Generations Growth Human Human Development IL8 gene Immigration Immunosuppressive Agents Injection of therapeutic agent Kidney Kidney Neoplasms Kidney Transplantation Lead Leukocytes Ligand Binding Ligands Link Lymphoid MAP Kinase Gene Malignant Neoplasms Measures Mediating Messenger RNA Modeling Molecular Molecular Profiling Mus Oncogenes Organ Organ Transplantation Pathway interactions Patients Plasmids Process Property Protein Isoforms Protein Kinase C Proteins RANTES RNA Splicing Ras Signaling Pathway Renal Cell Carcinoma Renal carcinoma Reporting Research Proposals Role Signal Pathway Signal Transduction Signaling Molecule Skin Skin Cancer Small Interfering RNA Solid Staging Surface T-Lymphocyte Testing Tissues Transcriptional Activation Transplant Recipients Transplantation Tubular formation Tumor Angiogenesis Tumor Tissue Variant base cancer cell cancer recurrence cancer transplantation cell growth chemokine chemokine receptor citrate carrier cytokine genetically modified cells in vivo insight isoimmunity knock-down mRNA Expression mRNA Stability mutant neoplastic cell neutralizing antibody novel overexpression public health relevance ras Oncogene receptor trafficking tumor tumor growth tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Chemokines are well established to function in the recruitment of leucocytes into an allograft, and may facilitate graft dysfunction and rejection. However, some recent studies have demonstrated that chemokines may also be functional in tumor development. The chemokine CXCL10, also known as IP-10 is a T-cell chemoattractant, and is classically thought to have tumor inhibitory properties. Nevertheless, paradoxically, some recent reports have indicated that CXCL10 can also promote tumor growth. We recently discovered that this controversy in the function of CXCL10 is in part related to alternative splicing of its receptor (CXCR3). CXCR3 exists as two novel variants called CXCR3-A and CXCR3-B, having different functions; CXCR3-A promotes chemotaxis and cell proliferation, whereas CXCR3-B signals for growth inhibition. Our recent studies identified that activation of the Ras signaling pathway in human cancer cells promotes the overexpression of CXCL10, and also downregulates the expression of the growth inhibitory receptor CXCR3-B in these cells. We also demonstrated that in absence of CXCR3-B, there is a marked increase in cancer cell proliferation, likely mediated through CXCR3-A. It is now established that the development of cancer is a major and increasing problem following solid organ transplantation, and some forms of cancer (e.g., kidney cancer) increase markedly after kidney transplantation. Moreover, different oncogenes including Ras may become activated during the post-transplantation period. Our preliminary studies have shown that the immunosuppressive agent Cyclosporine A (CsA) (known to activate Ras, and to promote tumor growth) can induce CXCL10, and can also markedly downregulate the expression of CXCR3-B in human renal epithelial cells. We propose that chemokines, in particular the CXCR3-binding chemokine CXCL10 and its receptor CXCR3, which are significantly increased during the post-transplantation period, may mechanistically "link" alloimmunity and tumor development. Our hypothesis is that Ras-induced overexpression of the CXCR3-binding chemokine CXCL10, and the differential distribution and signaling through CXCR3 splice variants (CXCR3-A and CXCR3-B) mediate the development of renal tumors, having direct relevance to post-transplantation cancer. Our Specific Aims evaluate the differential signaling mechanisms mediated through CXCR3-A and CXCR3-B in human renal cancer cells (Aim 1), the mechanism whereby CsA and Ras inhibit CXCR3-B, and promote CXCL10 expression (Aim 2), and the in vivo significance of CXCR3 splice variants in the development of renal cancer, and the phenotypic profiles of CXCR3-A and CXCR3-B, and their ligands in tumor tissues obtained from transplant and non-transplant patients (Aim 3).

描述(由申请人提供)：趋化因子在同种异体移植物中白细胞的募集中起作用，并可能促进移植物功能障碍和排斥反应。然而，最近的一些研究表明，趋化因子也可能在肿瘤的发生发展中发挥作用。趋化因子CXCL10，也被称为IP-10，是一种T细胞趋化物质，经典地被认为具有肿瘤抑制特性。然而，矛盾的是，最近的一些报告表明，CXCL10也可以促进肿瘤的生长。我们最近发现，关于CXCL10功能的争论部分与其受体(CXCR3)的选择性剪接有关。CXCR3作为两种新的突变体CXCR3-A和CXCR3-B存在，它们具有不同的功能；CXCR3-A促进趋化作用和细胞增殖，而CXCR3-B信号抑制生长。我们最近的研究发现，RAS信号通路的激活促进了CXCL10的过度表达，同时也下调了这些细胞中生长抑制受体CXCR3-B的表达。我们还证明，在缺乏CXCR3-B的情况下，癌细胞的增殖显著增加，这可能是通过CXCR3-A介导的。现已证实，癌症的发展是实体器官移植后的一个主要且日益严重的问题，某些形式的癌症(如肾癌)在肾移植后显著增加。此外，包括RAS在内的不同癌基因可能在移植后期间被激活。我们的初步研究表明，免疫抑制剂环孢素A(CsA)(已知可以激活RAS，促进肿瘤生长)可以诱导CXCL10，并能显著下调人肾上皮细胞CXCR3-B的表达。我们认为，趋化因子，特别是CXCR3结合的趋化因子CXCL10及其受体CXCR3，在移植后显著增加，可能从机械上将同种免疫与肿瘤的发生联系起来。我们的假设是RAS诱导CXCR3结合趋化因子CXCL10的过度表达，通过CXCR3剪接变异体(CXCR3-A和CXCR3-B)的差异分布和信号传递介导了肾肿瘤的发展，与移植后癌症有直接关系。我们的具体目标是评估CXCR3-A和CXCR3-B在人肾癌细胞中介导的差异信号机制(目标1)，CsA和RAS抑制CXCR3-B并促进CXCL10表达的机制(目标2)，CXCR3剪接变异体在肾癌发生发展中的体内意义，以及移植和非移植患者肿瘤组织中CXCR3-A和CXCR3-B及其配体的表型特征(目标3)。