Multipotential mesenchymal stem cell-like cells in pancreatic tumorigenesis

多能间充质干细胞样细胞在胰腺肿瘤发生中的作用

• 批准号: 8448301
• 负责人: GABRIELE BERGERS
• 金额: $ 30.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448301
• 关键词: Adipocytes; Affect; Automobile Driving; Blood Vessels; Cell Differentiation process; Cell Proliferation; Cells; Cellular biology; Clinical; Data; Development; Endocrine; Endothelial Cells; Exhibits; Generations; Genetic; Healed; Human; In Vitro; Injury; Islets of Langerhans; Malignant Neoplasms; Mesenchymal; Mesenchymal Stem Cells; Modeling; Mus; NGFR Protein; Natural regeneration; Nature; Neoplasm Metastasis; Nerve Growth Factor Receptors; Neuroendocrine Tumors; Neurons; Normal tissue morphology; Pancreas; Pathway interactions; Pericytes; Population; Premalignant; Production; Property; Publishing; Receptor Protein-Tyrosine Kinases; Regulation; Reporter; Role; Signal Transduction; Specimen; Stem cells; System; Testing; Tissues; Transgenic Organisms; Tumor Expansion; Xenograft Model; angiogenesis; base; cell type; diabetic patient; healing; in vivo; injured; islet; neovascularization; novel; pancreatic tumorigenesis; progenitor; public health relevance; response; self-renewal; therapeutic target; tissue regeneration; tissue repair; tumor; tumor progression; tumor xenograft; tumorigenesis; wound

DESCRIPTION (provided by applicant): We recently discovered a p75NTR+/CD133+ population of multipotent mesenchymal stem-cell-like cells (MPMSC) in pancreatic neuroendocrine tumors that exhibit high self-renewal capacity and differentiate into endothelial, pericytes and probably other mesenchymal cells as well as into neuronal-like cells. MPMSC appear unique as they share only some markers with mesenchymal stem cells and have features that are distinct from MSC suggestive of eliciting tissue-specific functions in islets. Our discovery raises various questions as to the nature, the regulation and functional significance of MPMSC in PNET tumorigenesis. Since the function of MSC relies in tissue repair, and tumors have been described as a wound that never heals, we propose that MPMSC become activated in their perivascular niche probably at the onset of angiogenesis in dysplastic premalignant islets and support neovascularization by differentiating into endothelial cells and pericytes as well as by producing proangiogenic factors and factors that could potentially support invasion or metastasis formation. We will test the hypothesis that while MPMSC exhibit multi-potency in normal tissue, they are steered to predominantly producing vascular cells in a tumor setting to support neovascularization and repress the formation of other mesenchymal cell types such as neurons or adipocytes. This would argue that tumors activate differentiation pathways in MPMSC that are advantageous for tumor progression but inhibitory to those that are not beneficial. To determine MPMSC fate determination in vivo, we will utilize an established genetic reporter mouse system that will enable us to trace MPMSC and their progeny in vivo in the normal scenario as well as during multi-step tumorigenesis in RipTag2 mice. To elucidate the underlying mechanisms of fate determination we will test the hypothesis that PDGFR¿ and the neurotrophin receptor p75NTR are implicated in differentiation pathways of MPMSC. .

描述(申请人提供)：我们最近在胰腺神经内分泌肿瘤中发现了p75NTR+/CD133+多潜能间充质干细胞样细胞(MPMSC)，它们具有很高的自我更新能力，可以分化为内皮细胞、周细胞和其他间充质细胞，也可以分化为神经元样细胞。MPMSC似乎是独一无二的，因为它们与间充质干细胞只有一些共同的标记，并且具有与MSC不同的特征，提示在胰岛中诱导组织特异性功能。我们的发现引发了关于MPMSC在PNET肿瘤发生中的性质、调控和功能意义的各种问题。由于MSC的功能依赖于组织修复，而肿瘤被描述为永远不会愈合的伤口，我们认为MPMSC可能在发育不良的癌前胰岛的血管生成开始时激活，并通过分化为内皮细胞和周细胞以及通过产生促血管生成因子和可能支持侵袭或转移形成的因子来支持新生血管的形成。我们将测试这一假设，即虽然MPMSC在正常组织中表现出多潜能，但它们被引导到肿瘤环境中主要产生血管细胞，以支持新生血管并抑制其他类型间充质细胞的形成，如神经元或脂肪细胞。这会认为肿瘤激活了MPMSC中有利于肿瘤进展但抑制了那些不利于肿瘤进展的分化途径。为了确定MPMSC在体内的命运决定，我们将利用已建立的遗传报告鼠系统，该系统将使我们能够在正常情况下以及在RipTag2小鼠的多步骤肿瘤形成过程中在体内追踪MPMSC及其后代。为了阐明决定命运的潜在机制，我们将检验PDGFR和神经营养因子受体p75NTR参与MPMSC分化途径的假设。。