Multipotential mesenchymal stem cell-like cells in pancreatic tumorigenesis

描述（由申请人提供）：我们最近在胰腺神经内分泌肿瘤中发现了p75NTR+/CD133+多能间充质干细胞样细胞（MPMSC），它们表现出高度的自我更新能力，并分化为内皮细胞、周细胞和可能的其他间充质细胞以及神经元样细胞。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，提示在胰岛中激发组织特异性功能。我们的发现提出了关于MPMSC在PNET肿瘤发生中的性质、调控和功能意义的各种问题。由于间充质干细胞的功能依赖于组织修复，肿瘤被描述为永不愈合的伤口，我们提出，可能在发育不良的癌前胰岛血管生成开始时，MPMSC在其血管周围生态位被激活，并通过分化为内皮细胞和周细胞以及产生促血管生成因子和可能支持入侵或转移形成的因子来支持新血管形成。我们将验证这一假设，即当MPMSC在正常组织中表现出多能性时，它们被引导到肿瘤环境中主要产生血管细胞，以支持新血管的形成，并抑制其他间充质细胞类型（如神经元或脂肪细胞）的形成。这将证明肿瘤激活MPMSC中有利于肿瘤进展的分化途径，但抑制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，我们将利用一个已建立的遗传报告小鼠系统，使我们能够在正常情况下以及在RipTag2小鼠的多步骤肿瘤发生过程中追踪MPMSC及其后代。为了阐明命运决定的潜在机制，我们将验证PDGFR¿和神经营养因子受体p75NTR参与MPMSC分化途径的假设。

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. .