Role of Inflammation in tumor promotion and progression

炎症在肿瘤促进和进展中的作用

• 批准号: 8446964
• 负责人: Michael Karin
• 金额: $ 41.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446964
• 关键词: Accounting; Adult; Appearance; CD44 gene; Carcinogens; Cell Separation; Cell Surface Proteins; Cell Transplantation; Cells; Chronic; Development; Event; Exhibits; Exons; Gene Expression Profile; Generations; Genetic; Hepatitis; Hepatocarcinogenesis; Hepatocyte; Human; Inflammation; Interleukin-6; Intrinsic factor; Knockout Mice; Lead; Lesion; Liver; MAP3K7 gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Modeling; Mus; Normal tissue morphology; Notch Signaling Pathway; Oncogenic; Pathway interactions; Prevention strategy; Preventive; Primary carcinoma of the liver cells; Production; Protein Isoforms; Proto-Oncogene Protein c-met; Publishing; RNA Splicing; Refractory; Regulation; Reporting; Rodent; Role; STAT3 gene; Signal Pathway; Signal Transduction; Staging; Stem cells; Survival Rate; Techniques; Therapeutic; Tissues; Tumor Promotion; Up-Regulation; Work; base; chemical carcinogen; conventional therapy; cytokine; genetic manipulation; injury and repair; liver inflammation; liver injury; meetings; men; neoplastic; neoplastic cell; notch protein; oval cell; progenitor; receptor upregulation; repaired; research study; response to injury; therapeutic development; transcription factor; tumor progression

DESCRIPTION (provided by applicant): This renewal application is based on a conceptual and technological breakthrough made during the current project period - identification and isolation of pre-neoplastic cells that serve as precursors for hepatocellular carcinoma (HCC) in mice. HCC is one of the most aggressive and difficult to treat cancers, with a current 5 year survival rate of 8%, yet HCC develops over the course of 20-40 years in the context of chronic liver inflammation (hepatitis) and damage. HCC development is preceded by appearance of foci of altered hepatocytes (FAH), which have been suspected (but never proven) to represent pre-neoplastic lesions. We succeeded in isolating HCC progenitor cells (HPC) from two different mouse HCC models and obtained evidence suggesting that HPC reside within FAH in mice treated with a chemical carcinogen that targets hepatocytes. Curiously, HPC appear to be related, based on their gene expression profile, to oval cells, a bipotential progenitor cell involved in repair of certain liver injuries in mice and men. However, it is not clear whether HPC arise from oval cells or from differentiated hepatocytes which are the target for the carcinogen. Understanding the mechanisms that control formation of HPC and their progression to full blown HCC will enable the development of preventive and therapeutic strategies for HCC eradication at an early stage, before this malignancy becomes refractory to all known therapies. In addition to cell intrinsic factors, progression of HPC to HCC is subject to micro environmental control. Correspondingly, we will investigate the mechanisms responsible for initiation and maintenance of activated STAT3, a critical oncogenic transcription factor, in HPC. These studies will explain how STAT3 activation is maintained within HPC and HCCs, but not in the adjacent normal liver, even though the normal tissue is exposed to STAT3-activating cytokines. We will investigate the contribution of these mechanisms to HPC to HCC progression by their genetic manipulation within isolated HPC. We will also study the role of the cell surface protein and stem cell marker CD44 in HPC formation and HPC to HCC progression, as our preliminary results indicate that HPC express CD44 and that CD44 is essential for FAH formation and HCC development. We will study the mechanisms responsible for CD44 upregulation in HPC and for production of the alternatively spliced CD44v6 isoform that interacts with c-Met and potentiates its signaling activity. Another marker expressed by HPC is the transcription factor Sox9, which is also expressed in oval cells. We will investigate the mechanisms responsible for Sox9 expression in HPC, focusing on the role of the Notch pathway and will exploit Sox9 in lineage tracing experiments that will determine the origin of HPC.

描述（由申请人提供）：该更新申请基于当前项目期间取得的概念和技术突破-作为小鼠肝细胞癌（HCC）前体的肿瘤前细胞的鉴定和分离。HCC是最具侵袭性和最难治疗的癌症之一，目前5年生存率为8%，但HCC在慢性肝脏炎症（肝炎）和损伤的背景下发展了20-40年。肝细胞癌发生之前出现肝细胞改变灶（FAH），这被怀疑（但从未被证实）代表肿瘤前病变。我们成功地从两种不同的小鼠HCC模型中分离出HCC祖细胞（HPC），并获得了表明HPC存在于用靶向肝细胞的化学致癌物治疗的小鼠FAH中的证据。奇怪的是，HPC似乎与卵圆细胞有关，卵圆细胞是一种双能祖细胞，参与小鼠和人类某些肝损伤的修复。然而，目前尚不清楚HPC是否来自卵圆细胞或分化的肝细胞，这是致癌物质的目标。了解控制HPC形成及其进展为完全成熟的HCC的机制将使在这种恶性肿瘤变得对所有已知疗法都难治之前，在早期阶段制定HCC根除的预防和治疗策略成为可能。除了细胞内在因素外，HPC向HCC的进展还受到微环境控制。相应地，我们将调查的机制，负责启动和维持激活的STAT 3，一个关键的致癌转录因子，在HPC。这些研究将解释STAT 3激活是如何在HPC和HCC中维持的，而不是在相邻的正常肝脏中，即使正常组织暴露于STAT 3激活细胞因子。我们将研究这些机制的贡献HPC肝癌进展的遗传操纵孤立HPC。我们还将研究细胞表面蛋白和干细胞标志物CD 44在HPC形成和HPC向HCC进展中的作用，因为我们的初步结果表明HPC表达CD 44，并且CD 44对FAH形成和HCC发展至关重要。我们将研究HPC中CD 44上调的机制，以及与c-Met相互作用并增强其信号传导活性的可变剪接CD 44 v6亚型的产生机制。HPC表达的另一个标志物是转录因子Sox 9，其也在卵圆细胞中表达。我们将研究Sox 9在HPC中表达的机制，重点关注Notch通路的作用，并将在谱系追踪实验中利用Sox 9来确定HPC的起源。