Stellate cells and their progenitor precursors in pancreas cancer progression

胰腺癌进展中的星状细胞及其祖细胞前体

基本信息

批准号：
8759844
负责人：
Paolo Provenzano
金额：
$ 30.9万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-05 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8759844
关键词：
AMD3100 Antibodies Automobile Driving Behavior Biochemical Biological Assay Bone Marrow Bone Marrow Transplantation CXCL12 gene CXCR4 Receptors CXCR4 gene Cancer Etiology Carcinoma Cells Cessation of life Chemicals Clinical Coculture Techniques Conditioned Culture Media Country Data Deposition Desmoplastic Disease Disease Progression Disease Resistance Epithelial Cells Epithelium Extracellular Matrix Generations Genetic Genetically Engineered Mouse Growth Factor Hematopoietic Histopathology Home environment Homing Human Human Cell Line Image Immune In Vitro Incidence Indigenous Infiltration Injury Investigation Lesion Life Maintenance Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mesenchymal Mesenchymal Stem Cells Microscopic Modeling Molecular Mouse Cell Line Mus Myofibroblast Neoplasm Metastasis Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pancreatic carcinoma Pancreatitis Paracrine Communication Patients Pharmaceutical Preparations Play Population Process Proteins Proteome Role Signal Transduction Small Interfering RNA Solid Neoplasm Source Staging Stem cells Stromal Cell-Derived Factor 1 Stromal Cells Survival Rate Syndrome System Technology Testing Tissues Transgenic Mice Work Xenograft Model cell behavior cell growth cell motility chemotherapeutic agent combat cytokine human disease improved in vivo inhibitor/antagonist killings mortality mouse model new therapeutic target novel novel therapeutics pancreatic neoplasm paracrine pre-clinical progenitor programs public health relevance research study response small hairpin RNA stellate cell therapy resistant tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer is an extremely lethal disease with the lowest 1-year and 5-year survival rates of any cancer. This is due, in part, to the extremely metastatic behavior of pancreas carcinoma cells, which are also highly resistant to therapy. Importantly, we now know that a strong, but nevertheless unique, stromal response is present in pancreatic ductal adenocarcinoma (PDA). This is highly relevant as it is now recognized that, in many solid tumors, the local microenvironment and the stromal compartment significantly influences disease progression. In conventional pancreatic ductal adenocarcinoma, and its most common precursor PanIN lesions, disease progression is associated with a robust fibrotic response in the stroma, or desmoplastic reaction, that is largely regulated by pancreatic stellate cells. Even at the early stages of preinvasive disease activation of pancreatic stellate cells and extracellular matrix deposition is robust. Through disease progression this desmoplastic reaction continues and often intensifies, offering critical support to carcinoma cells as they progress to fully metastatic disease while also providing drug-free sanctuaries that limit access of chemotherapeutic agents. However, to date, the molecular and physical mechanisms by which PSCs regulate epithelial carcinoma cell behavior in vivo are not well understood. Likewise, the molecular mechanisms by which PSCs are activated as well as the source of activated PSCs in the tumor remains to be fully elucidated. In culture, stellate cells are known to secrete factors that can promote cell behaviors associated with tumor progression, suggesting a paracrine signaling role for stellate cells in indigenous disease in vivo. Therefore, here, using murine models of pancreas cancer that faithfully mimics the human disease and human cell line grafted tumors, we propose specific experiments to explicitly investigate the source of activated pancreatic stellate cells in pancreas cancer, dissect the role of stromal stellate cells population in preinvasive, invasive and metastatic disease, and specifically target a key stellate cell-derive cytokine that promotes carcinoma cell growth and motility and contributes to the generation and maintenance of the desmoplastic reaction in PDA. We hypothesize that bone marrow-derived progenitor cells are a source of activated pancreatic stellate cells that are co-opted, along with endogenous populations of stellate cells, in early preinvasive lesions to help drive conversion to PDA and ultimately establish successful metastases. Furthermore, we hypothesize that chemical signal draws bone marrow-derived progenitor cells to PDA but that physical features of the stroma also influence their infiltration and subsequent differentiation and that specific strom targeting therapy can disrupt these interactions and the tumor supporting influence of stellate cells in PDA.

描述（由申请人提供）：胰腺癌是一种极其致命的疾病，其 1 年和 5 年生存率是所有癌症中最低的。这在一定程度上是由于胰腺癌细胞的极端转移行为，而且对治疗也具有高度抵抗力。重要的是，我们现在知道胰腺导管腺癌（PDA）中存在强烈但独特的基质反应。这是高度相关的，因为现在人们认识到，在许多实体瘤中，局部微环境和基质室显着影响疾病进展。在传统的胰腺导管腺癌及其最常见的前体 PanIN 病变中，疾病进展与间质中强烈的纤维化反应或促结缔组织增生反应相关，这在很大程度上受到胰腺星状细胞的调节。即使在侵袭前疾病的早期阶段，胰腺星状细胞的激活和细胞外基质沉积也是强劲的。在疾病进展过程中，这种促纤维增生反应持续存在，并且常常加剧，为癌细胞进展为完全转移性疾病提供关键支持，同时也提供限制化疗药物使用的无药物避难所。然而，迄今为止，PSC 在体内调节上皮癌细胞行为的分子和物理机制尚不清楚。同样，PSCs 被激活的分子机制以及肿瘤中激活的 PSCs 的来源仍有待完全阐明。在培养中，星状细胞已知分泌可以促进与肿瘤进展相关的细胞行为的因子，表明星状细胞在体内固有疾病中具有旁分泌信号传导作用。因此，在这里，我们利用忠实模拟人类疾病和人类细胞系移植肿瘤的胰腺癌小鼠模型，提出具体实验来明确研究胰腺癌中活化的胰腺星状细胞的来源，剖析基质星状细胞群在胰腺癌中的作用。侵袭前、侵袭性和转移性疾病，并专门针对一种关键的星状细胞衍生细胞因子，该细胞因子促进癌细胞生长和运动，并有助于癌细胞的产生和维持PDA 中的促纤维增生反应。我们假设骨髓来源的祖细胞是活化的胰腺星状细胞的来源，这些星状细胞与内源性星状细胞群一起在早期浸润前病变中被增选，以帮助驱动向 PDA 的转化并最终建立成功的转移。此外，我们假设化学信号将骨髓源性祖细胞吸引到 PDA，但基质的物理特征也会影响它们的浸润和随后的分化，并且特定的基质靶向治疗可以破坏这些相互作用以及 PDA 中星状细胞的肿瘤支持影响。