Hepatic Stellate Cells and Liver Cancer

肝星状细胞和肝癌

• 批准号: 8801797
• 负责人: Robert F. Schwabe
• 金额: $ 37.02万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-02 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8801797
• 关键词: Ablation; Affect; Apoptosis; BAY 54-9085; Cancer Etiology; Candidate Disease Gene; Chemical Models; Chemicals; Chronic; Clinical; Clinical Research; Data; Desmoplastic; Development; Diphtheria; Epithelial Cells; Fibroblasts; Fibrosis; Future; Gene Expression; Genetic; Genetic Models; Growth; Healed; Health; Hepatic; Hepatic Stellate Cell; Hepatocarcinogenesis; Human; Incidence; Inflammation; Inflammatory; Injury; Interferons; Knockout Mice; Label; Lesion; Link; Liver; Liver Fibrosis; Malignant Neoplasms; Malignant neoplasm of liver; Mediator of activation protein; Medical; Microarray Analysis; Modeling; Mus; Myofibroblast; Nutritional; Organ; Patients; Peptides; Pharmaceutical Preparations; Platelet-Derived Growth Factor Receptor; Platelet-Derived Growth Factor beta Receptor; Play; Population; Premalignant; Prevention; Prevention approach; Primary carcinoma of the liver cells; Role; Solid; Source; Staging; Surgical Models; Techniques; Tenascin; Testing; Therapeutic; Time; Tissues; Toxin; Transgenic Mice; angiogenesis; base; carcinogenesis; fibrogenesis; healing; kinase inhibitor; lecithin-retinol acyltransferase; liver cancer prevention; liver injury; mortality; mouse model; novel; novel therapeutic intervention; preclinical study; promoter; receptor; receptor binding; receptor expression; recombinase; response; targeted delivery; targeted treatment; transcription factor; tumor; wound

DESCRIPTION (provided by applicant): 80% of hepatocellular carcinomas (HCC) arise in fibrotic livers. Notably, chronic injury, inflammation and fibrosis are sufficient to trigger HCC i mice, suggesting that HCC truly represents "a wound that does not heal" and that the hepatic microenvironment exerts a profound tumor-promoting influence. In contrast to other organs, myofibroblast (MF) accumulation in the liver occurs not only as a desmoplastic response to established tumors with accumulation of cancer-associated fibroblasts (CAF), but there is also an abundance of MF in the precancerous liver. Thus, HCC may be affected by different MF subsets, namely tissue fibrosis-associated MF and CAF, at different stages. Despite the strong association between fibrosis and HCC, it is currently not known whether fibrosis promotes HCC development, or whether fibrosis and hepatocarcinogenesis represent two parallel but functionally independent responses. This is largely due to the lack of models, in which hepatic MF activation can be selectively modulated without confounding effects on the inflammatory and epithelial cell compartments that accompany all current models. Here, we seek to test the hypothesis that hepatic MF and CAF are important contributors to hepatocarcinogenesis. For this purpose, we will employ a novel Cre-transgenic mouse that not only marks 99% of hepatic stellate cells (HSC), the precursors of MF in the liver, but also enables us to selectively increas or decrease the number of activated MF in the liver. In Aim 1 of this proposal, we seek to test the hypothesis that HSC are the key source of fibrosis-associated MF and CAF in fibrosis-associated hepatocarcinogenesis using fate tracing via LratCre. We will furthermore establish the functional contribution of HSC-derived MF, employing LratCre to genetically deplete or activate HSC in combination with Cre-inducible diphtheria receptor and activated PDGFRß, respectively. In Aim 2, we seek to determine mechanisms by which MF promote carcinogenesis in the liver. For this purpose, we will determine time points at which HSC-derived MF promote HCC and analyze how MF activation or ablation change tumor proliferation, apoptosis and the tumor kinome. In addition, we seek to compare gene expression between highly-purified MF and CAF, and to investigate the involvement of candidate mediators from MF and CAF in hepatocarcinogenesis. In Aim 3, we will employ a novel and highly efficient anti-fibrotic, HSC-targeted IFNγ, to determine whether inhibiting MF activation and liver fibrosis reduces HCC development. We also seek to determine whether HSC-targeted IFNγ, either as monotherapy or in combination with sorafenib, inhibits HCC progression. The proposed studies will not only reveal origin and functions of MF in hepatocarcinogenesis, but may provide a basis for targeting MF for HCC prevention or therapy.

描述（由申请人提供）：80% 的肝细胞癌 (HCC) 出现在纤维化肝脏中。值得注意的是，慢性损伤、炎症和纤维化足以引发 HCC i 小鼠，这表明 HCC 真正代表了“无法愈合的伤口”。与其他器官相比，肝脏微环境发挥着深远的促肿瘤影响，肌成纤维细胞（MF）在肝脏中的积累不仅是对已建立的促纤维增生反应的发生。尽管肿瘤中存在癌症相关成纤维细胞（CAF）的积累，但癌前肝脏中也存在丰富的 MF，因此，HCC 可能在不同阶段受到不同 MF 子集（即组织纤维化相关 MF 和 CAF）的影响。尽管纤维化与 HCC 之间存在密切关联，但目前尚不清楚纤维化是否会促进 HCC 的发展，或者纤维化和肝癌发生是否代表两种平行但功能独立的反应，这在很大程度上是由于。缺乏可以选择性调节肝脏 MF 激活而不会对所有当前模型所伴随的炎症和上皮细胞区室产生混杂影响的模型。在这里，我们试图检验肝脏 MF 和 CAF 是肝癌发生的重要因素的假设。为此，我们将采用一种新型 Cre 转基因小鼠，它不仅标记 99% 的肝星状细胞 (HSC)（肝脏中 MF 的前体），而且还使我们能够选择性地增加或减少肝脏中活化 MF 的数量。在该提案的目标 1 中，我们试图利用命运来检验 HSC 是纤维化相关 MF 和 CAF 的关键来源这一假设。通过 LratCre 进行追踪，我们将进一步确定 HSC 衍生的 MF 的功能贡献，利用 LratCre 与 Cre 诱导组合从基因上耗尽或激活 HSC。分别是白喉受体和激活的 PDGFRß 在目标 2 中，我们试图确定 MF 促进肝脏癌变的机制。为此，我们将确定 HSC 衍生的 MF 促进 HCC 的时间点，并分析 MF 如何激活或消融。此外，我们还试图比较高度纯化的 MF 和 CAF 之间的基因表达，并研究 MF 和 CAF 中候选介质的参与。在目标 3 中，我们将采用一种新型高效抗纤维化、HSC 靶向 IFNγ 来确定抑制 MF 激活和肝纤维化是否会减少 HCC 发展。或与索拉非尼联合，抑制 HCC 进展。拟议的研究不仅将揭示 MF 在肝癌发生中的起源和功能，而且可能为靶向 MF 提供基础。 HCC 预防或治疗。