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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）：趋化因子在将白细胞募集到同种异体移植物中的过程中发挥作用，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展中发挥作用。趋化因子CXCL 10，也称为IP-10，是一种T细胞化学引诱物，传统上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，CXCL 10也可以促进肿瘤生长。我们最近发现，CXCL 10功能的争议部分与其受体（CXCR 3）的选择性剪接有关。CXCR 3以两种新的变体存在，称为CXCR 3-A和CXCR 3-B，具有不同的功能; CXCR 3-A促进趋化性和细胞增殖，而CXCR 3-B发出生长抑制信号。我们最近的研究发现，Ras信号通路在人癌细胞中的激活促进了CXCL 10的过表达，并且还下调了这些细胞中生长抑制受体CXCR 3-B的表达。我们还证明，在CXCR 3-B缺失的情况下，癌细胞增殖显著增加，可能通过CXCR 3-A介导。现在已经确定，癌症的发展是实体器官移植后的主要且日益严重的问题，并且某些形式的癌症（例如，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）（已知激活Ras，并促进肿瘤生长）可以诱导CXCL 10，也可以显着下调CXCR 3-B在人肾上皮细胞的表达。我们提出，趋化因子，特别是CXCR 3结合趋化因子CXCL 10及其受体CXCR 3，这是显着增加，在移植后期间，可能会机械地“链接”同种异体免疫和肿瘤的发展。我们的假设是Ras诱导的CXCR 3结合趋化因子CXCL 10的过表达，以及通过CXCR 3剪接变体（CXCR 3-A和CXCR 3-B）的差异分布和信号传导介导肾肿瘤的发展，与移植后癌症直接相关。我们的具体目的是评估人肾癌细胞中通过CXCR 3-A和CXCR 3-B介导的差异信号传导机制（目的1），CsA和Ras抑制CXCR 3-B并促进CXCL 10表达的机制（目的2），以及CXCR 3剪接变体在肾癌发展中的体内意义，以及CXCR 3-A和CXCR 3-B的表型特征，和它们的配体在从移植和非移植患者获得的肿瘤组织中的作用（目的3）。