The Role of Dendritic Cells in Pancreatic Tumorigenesis

描述（由申请人提供）：纤维炎性肿瘤间质构成胰腺癌的物理主体。此外，最近的证据表明，基质增生远不是胰腺导管上皮瘤的被动成分，而是肿瘤侵袭和转移的关键。胰腺癌相关肿瘤基质中的中心细胞是活化的胰腺星状细胞（PSC）。然而，驱动PSC从静止状态激活并因此驱动间质增殖的细胞信号尚不清楚。我们假设胰腺树突状细胞（DC）驱动PSC激活，并负责间质增殖和胰腺癌的逐步进展。这一假设基于我们实验室最近的三个不同的观察结果：(i)我们报道DC是肝损伤后肝脏中星状细胞的有效激活剂，（ii） DC在早期PanIN病变的LSL-KrasG12D小鼠的胰腺中扩张超过30倍，（iii） DC过继性转移到存在胰腺炎症的小鼠的胰腺周围组织，导致间质结丝增生和胰腺导管上皮发育不良。我们在Aim 1的目标是确定DC在胰腺癌中的作用。我们的实验计划是初步确定小鼠和人类胰腺DC从早期侵袭前病变逐步发展为晚期癌的时间和空间时间表。然后，我们将在嵌合LSL-KrasG12D小鼠中使用DC耗尽策略显示DC与胰腺癌发生之间的因果关系。在Aim 2中，通过体外和体内模型，我们将建立DC激活PSC作为DC诱导间质增殖和肿瘤进展的细胞机制，我们将探索DC有效参与PSC的细胞信号传导要求。我们希望我们的工作对胰腺肿瘤发生的理解和针对DC的新治疗方法都有相当大的影响，因为DC可能是调节胰腺癌进展的一种有吸引力的手段。我们的建议是高度创新的，因为它挑战了DC作为有效抗肿瘤药物的公认作用，即通过激活PSC和引起肿瘤基质的扩张来促进肿瘤的形成，从而直接影响肿瘤的侵袭性。我们的研究也为“炎症-癌症”范式提供了新的线索，因为这项工作将表明DC可能是通过驱动基质扩张导致癌症的炎症序列的核心组成部分。

DESCRIPTION (provided by applicant): Fibro-inflammatory tumor stroma makes up the physical bulk of pancreatic cancer. Moreover, recent evidence suggests that far from being a passive component in pancreatic ductal epithelial neoplasia, stromal proliferation is crucial for tumor invasiveness and metastasis. The central cell in the pancreatic cancer associated tumor stroma is the activated pancreatic stellate cell (PSC). However, the cellular signals that drive PSC activation from their quiescent state, and hence drive stromal proliferation, are unknown. We postulate that pancreatic dendritic cells (DC) drive PSC activation and are responsible for stromal proliferation and the stepwise progression of pancreatic cancer. This hypothesis is based upon three recent disparate observations from our laboratories: (i) We reported that DC are potent activators of stellate cells in the liver after hepatic injury, (ii) DC expand more than 30-fold in the pancreata of LSL-KrasG12D mice with early PanIN lesions, (iii) DC adoptive transfer to the peri-pancreatic tissues of mice with existing pancreatic inflammation precipitates stromal desmoplasia and pancreatic ductal epithelia dysplasia. Our goal in Aim 1 is to establish a role for DC in pancreatic cancer. Our experimental plan is to initially define the temporal and spatial timeline for DC expansion in the pancreas during the stepwise progression from early pre-invasive lesions to advanced carcinoma in mice and humans. We will then show a cause and effect relationship between DC and pancreatic carcinogenesis using a DC depletion strategy in chimeric LSL-KrasG12D mice. In Aim 2, using in vitro and in vivo modeling, we will establish DC activation of PSC as cellular mechanism for DC induction of stromal proliferation and tumor progression, and we will explore the cell signaling requirements for DC to effectively engage PSC. We expect our work to have considerable impact on both the understanding of pancreatic tumorgenesis and on novel therapeutics as targeting DC maybe an attractive means to modulate pancreatic cancer progression. Our proposal is highly innovative as it challenges the accepted role of DC as potent anti-tumor agents to one that is pro-tumorogenic by activating PSC and causing expansion of tumor stroma which has direct influence on tumor invasiveness. Our proposal also sheds new light on the 'inflammation-cancer' paradigm as this work will suggests that DC may be a central component in the sequence of inflammation leading to cancer by driving stromal expansion. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a devastating disease that is fatal in approximately 95% of cases. We postulate that dendritic cells which infiltrate pancreatic tumor are primary stimuli to pancreatic cancer progression by activating the tumor stroma. Our work will show that targeting dendritic cells in pancreatic cancer may be an attractive and novel approach to experimental therapeutics.