Pancreatic Integrin Contribution to Perineural Invasion

描述（由申请人提供）： 胰腺癌患者在癌症被诊断时几乎肯定会死亡，因为与这种疾病相关的侵袭和转移的发生率很高。神经周围浸润是胰腺癌的常见和突出特征，通过广泛传播和早期转移使治愈性肿瘤切除复杂化，从而积极促成患者死亡率。我们对神经周围侵犯的认识还很差。如果我们要为胰腺癌患者开发更有效的治疗方法，我们必须更好地了解和学习控制神经周围浸润。为了实现这一目标，我们研究了整合素，它是细胞外基质的受体，可以传递对肿瘤侵袭至关重要的信号。在我们的初步数据中，我们已经鉴定了两种整合素，α 6 β 4和α 4 β 7，它们与胰腺癌的侵袭性增加具有良好的相关性。然而，这些整合素如何促进神经浸润在很大程度上是未知的。本项目的长期目标是阐明胰腺癌细胞侵袭周围神经的整体机制。本研究的目的是了解胰腺癌细胞整合素如何促进沿着神经周围间隙的侵袭。我们的第一个目的是确定α 6 β 4整合素在胰腺癌侵袭性表型中的作用，该整合素已被证明可促进其他癌系统的侵袭。我们的下一个目标是确定促炎性整合素α 4 β 7在胰腺癌神经浸润中的功能意义。这一目标是基于我们独特的初步观察，即α 4 β 7整合素可以在胰腺癌细胞上表达，这可能有助于更充分地解释胰腺癌中炎症的进展。对于这些研究，我们将使用三管齐下的方法，其中包括：在体外研究与人胰腺癌细胞系，其特征在于其整合素含量;评估切除的肿瘤组织的α 4 β 7和α 6 β 4整合素及其各自的配体;和胰腺癌的转基因小鼠模型。选择这些方法中的每一种都是为了利用每个系统的优势，以便我们可以更好地了解胰腺癌的神经浸润并确定治疗干预的靶点。

DESCRIPTION (provided by applicant): Pancreatic carcinoma patients face almost certain death at the time their cancer is diagnosed because of the high incidence of invasion and metastasis associated with this disease. Perineural invasion is a common and prominent feature of pancreatic cancer that actively contributes to patient mortality by complicating curative tumor resection through widespread dissemination and early metastasis. Our understanding of perineural invasion is poor. If we are to develop more effective treatments for pancreatic cancer patients, we must better understand and learn to control perineural invasion. Toward this goal, we study integrins, which are receptors for the extracellular matrix that transduce signals that are critical for tumor invasion. In our preliminary data, we have identified two integrin species, alpha6beta4 and alpha4beta7, that show a good correlation with the increased aggressiveness of pancreatic carcinoma. However, how these integrins contribute to perineural invasion is largely unknown. The long-term goal of this project is to elucidate the overall mechanism of pancreatic carcinoma cell invasion of the peripheral nerves. The objective of this proposal is to understand how pancreatic carcinoma cell integrins contribute to invasion along perineural spaces. Our first aim is to define the role of the alpha6beta4 integrin, which has been shown to promote invasion other carcinoma systems, in the invasive phenotype of pancreatic carcinomas. Our next aim is to determine the functional significance of the proinflammatory integrin alpha4beta7 in pancreatic carcinoma perineural invasion. This aim is based on our unique preliminary observation that the alpha4beta7 integrin can be expressed on pancreatic carcinoma cells and may help to more fully explain how inflammation in pancreatic carcinoma progression. For these studies, we will use three-pronged approach, which includes: in vitro studies with human pancreatic carcinoma cell lines that have been characterized for their integrin content; assessment of resected tumor tissue for the alpha4beta7 and alpha6beta4 integrins and their respective ligands; and a transgenic mouse model of pancreatic carcinoma. Each of these approaches is chosen to utilize the strengths of each system so that we may better understand perineural invasion of pancreatic carcinoma and identify targets for therapeutic intervention.