Pathophysiology of Post-Transplantation Cancer

移植后癌症的病理生理学

• 批准号: 7786278
• 负责人: Soumitro Pal
• 金额: $ 38.31万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7786278
• 关键词: Acute; Allografting; Alternative Splicing; Animals; Binding; Biological; 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; 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; Lymphoid Cell; MAP Kinase Gene; Malignant Neoplasms; Measures; Mediating; Messenger RNA; Modeling; Molecular; Molecular Profiling; Mus; Neoplasms in Vascular Tissue; 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; chemokine; chemokine receptor; 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

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). PUBLIC HEALTH RELEVANCE: This research proposal focuses to study a mechanism by which the tumor growth may be enhanced in the patients with organ transplantation. Our objective is to evaluate the role of the chemokine CXCL10 and its receptor splice variants (CXCR3-A and CXCR3-B) in the development of post-transplantation cancer.

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方面已得到充分证实，并且可能促进移植物功能障碍和排斥。然而，最近的一些研究表明，趋化因子也可能在肿瘤发展中发挥作用。趋化因子 CXCL10，也称为 IP-10，是一种 T 细胞趋化剂，通常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也可以促进肿瘤生长。我们最近发现，CXCL10 功能的争议部分与其受体（CXCR3）的选择性剪接有关。 CXCR3以两种新变体形式存在，称为CXCR3-A和CXCR3-B，具有不同的功能； CXCR3-A 促进趋化性和细胞增殖，而 CXCR3-B 则发出抑制生长的信号。我们最近的研究发现，人类癌细胞中 Ras 信号通路的激活会促进 CXCL10 的过度表达，并下调这些细胞中生长抑制性受体 CXCR3-B 的表达。我们还证明，在缺乏 CXCR3-B 的情况下，癌细胞增殖显着增加，这可能是通过 CXCR3-A 介导的。现在已经确定，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，并且某些形式的癌症（例如肾癌）在肾移植后显着增加。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）（已知可激活Ras并促进肿瘤生长）可诱导CXCL10，并可显着下调人肾上皮细胞中CXCR3-B的表达。我们提出趋化因子，特别是CXCR3结合趋化因子CXCL10及其受体CXCR3，在移植后期间显着增加，可能在机制上“连接”同种免疫和肿瘤发展。我们的假设是 Ras 诱导的 CXCR3 结合趋化因子 CXCL10 过度表达，以及 CXCR3 剪接变体（CXCR3-A 和 CXCR3-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。我们的具体目标评估人肾癌细胞中通过 CXCR3-A 和 CXCR3-B 介导的差异信号传导机制（目标 1）、CsA 和 Ras 抑制 CXCR3-B 并促进 CXCL10 表达的机制（目标 2）、CXCR3 剪接变体在肾癌发展中的体内意义，以及 CXCR3-A 和 CXCR3-A 和 CXCR3-B 的表型特征。 从移植和非移植患者获得的肿瘤组织中的 CXCR3-B 及其配体（目标 3）。 公共健康相关性：本研究计划的重点是研究器官移植患者肿瘤生长可能增强的机制。我们的目标是评估趋化因子 CXCL10 及其受体剪接变体（CXCR3-A 和 CXCR3-B）在移植后癌症发展中的作用。