Conditional ablation of stellate cells to determine their role in pancreatitis an

有条件消融星状细胞以确定其在胰腺炎中的作用

• 批准号: 8213583
• 负责人: Rosa F. Hwang
• 金额: $ 17.18万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-02 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213583
• 关键词: Ablation; Address; Applications Grants; Cells; Characteristics; Detection; Development; Diphtheria Toxin; Disease; Distant Metastasis; Fibrosis; Genes; Genetically Engineered Mouse; Growth; Human; Inflammation; Invasive Lesion; Knowledge; Lead; Lesion; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mus; Neoplasm Metastasis; Organ; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatitis; Play; Primary Neoplasm; Process; Radiation; Reporting; Resistance; Risk Factors; Role; Screening for cancer; Staging; Testing; Time; Tissues; Toxin; Transgenic Mice; Work; base; cancer cell; cancer prevention; cell killing; cell stroma; chemotherapy; chronic pancreatitis; diphtheria toxin receptor; effective therapy; innovation; insight; mouse model; novel; novel strategies; promoter; public health relevance; stellate cell; therapy development; tumor; tumor progression

DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma (PAC) is a fatal disease with no effective treatment. Clearly new means of detection and new approaches to treatment are urgently needed. It is increasingly recognized that the tumor microenvironment plays a key role in cancer. Pancreatic cancer has a very pronounced and abundant fibrosis (stroma) that it shares with the disease chronic pancreatitis. We have recently isolated the stroma cell in human PAC (pancreatic stellate cell, PSC) and found that it is an important contributor to tumor progression and renders cancer cells more resistant to chemotherapy and radiation. The PSC also increases growth and metastasis of pancreatic cancer in mice. Chronic pancreatitis (CP) is a known risk factor for PAC, however, the exact mechanism by which CP may lead to PAC is unknown. We hypothesize that the PSC, which is present in both CP and PAC, is the common link and contributes to both the fibrosis and inflammation in CP and the progression to early lesions of pancreatic cancer (PanIN) and invasive PAC. We will test this hypothesis using a novel genetically engineered mouse model of pancreatic cancer which displays all of the steps of PAC development: fibrosis and chronic pancreatitis at early stages, and PanINs and finally invasive PAC with metastasis at later stages. We will selectively destroy the PSCs in these mice by using a gene promoter that is specific for PSCs and forcing only these cells to express a receptor for Diphtheria toxin (DTR). When diphtheria toxin (DT) is given to the mice, all cells that express DTR will be eliminated. To determine the role of PSCs in the continuum of PAC development, we will administer diphtheria toxin to the genetically engineered mouse at different time points. For Specific Aim 1, we will determine whether PSCs are essential for the development of fibrosis in CP by giving Diphtheria toxin to the mice at early time points. The pancreas tissue of these mice will be examined for inflammation and CP, as well as subsequent development of PAC at later time points. For Specific Aim 2, the PSCs will be destroyed later by giving the toxin at later time points when PanIN lesions and invasive PAC should be developed. With this strategy, we will be able to determine whether PSCs have a critical role in development of pancreatic cancer. To date, a mouse model of pancreatic cancer that targets the stellate cells has not yet been reported. Using this innovative approach, we expect to gain a better understanding of the role of PSCs in the progression of pancreatic cancer. This knowledge will enable us to develop novel treatments for this disease that target the tumor microenvironment. PUBLIC HEALTH RELEVANCE: In this project, we will determine whether stellate cells in the tumor microenvironment are necessary for the development of pancreatic cancer. The results from this project will provide a greater understanding of how these cells contribute to early and late pancreatic cancer. This information provides valuable insight towards the development of novel treatments for pancreatic cancer, as well as possible approaches to early cancer detection and cancer prevention.

描述（由申请人提供）：胰腺腺癌（PAC）是一种致命疾病，没有有效治疗。 显然，迫切需要新的检测方法和新的治疗方法。 越来越多地认识到，肿瘤微环境在癌症中起关键作用。 胰腺癌具有非常明显且丰富的纤维化（基质），与疾病慢性胰腺炎共享。 我们最近分离了人PAC中的基质细胞（胰腺星状细胞，PSC），发现它是导致肿瘤进展的重要因素，并使癌细胞对化学疗法和放射线更具耐药性。 PSC还增加了小鼠胰腺癌的生长和转移。 慢性胰腺炎（CP）是PAC的已知危险因素，但是，CP可能导致PAC的确切机制尚不清楚。 我们假设CP和PAC中存在的PSC是共同的联系，并有助于CP的纤维化和炎症以及胰腺癌（Panin）和侵入性PAC的早期病变的发展。 我们将使用一种新型的胰腺癌的基因工程小鼠模型来检验这一假设，该模型在早期阶段显示了PAC发育的所有步骤：纤维化和慢性胰腺炎，Panins和Panins和最终在后期带有转移的侵入性PAC。 我们将通过使用针对PSC的基因启动子有选择地破坏这些小鼠的PSC，并仅强迫这些细胞表达白喉毒素（DTR）的受体。 当给小鼠毒素毒素（DT）时，所有表达DTR的细胞都将被消除。 为了确定PSC在PAC发育的连续性中的作用，我们将在不同时间点对遗传工程小鼠的白喉毒素施用。 对于特定目标1，我们将通过在早期时间点给小鼠白喉毒素来确定PSC是否对CP的纤维化发展至关重要。 这些小鼠的胰腺组织将检查是否有炎症和CP，以及随后在以后的时间点开发PAC。 对于特定的目标2，PSC将在稍后的时间点进行毒素，而Panin病变和侵入性PAC应开发出来。 通过这种策略，我们将能够确定PSC在胰腺癌的发展中是否具有关键作用。 迄今为止，尚未报道针对星状细胞的胰腺癌小鼠模型。 使用这种创新方法，我们希望更好地了解PSC在胰腺癌进展中的作用。 这些知识将使我们能够为靶向肿瘤微环境的这种疾病开发新的治疗方法。 公共卫生相关性：在这个项目中，我们将确定肿瘤微环境中的星状细胞是否对于胰腺癌的发展是必要的。 该项目的结果将对这些细胞如何促进早期和晚期胰腺癌的贡献有更深入的了解。 该信息为开发胰腺癌的新型治疗方法提供了宝贵的见解，以及早期癌症检测和预防癌症的可能方法。