Pancreatic Integrin Contribution to Perineural Invasion

描述(由申请人提供)： 胰腺癌患者在确诊时几乎肯定会死亡，因为与这种疾病相关的侵袭和转移的发生率很高。神经侵袭是胰腺癌常见而显著的特征，它通过广泛的扩散和早期转移使根治性肿瘤切除复杂化，从而积极地增加患者的死亡率。我们对神经周围侵袭的理解很差。如果我们要为胰腺癌患者开发更有效的治疗方法，我们必须更好地理解和学习控制神经周围侵袭。为了这个目标，我们研究整合素，它是细胞外基质的受体，传递对肿瘤侵袭至关重要的信号。在我们的初步数据中，我们已经确定了两种整合素物种，α6beta4和alpha4beta7，它们与胰腺癌侵袭性的增加有很好的相关性。然而，这些整合素如何促进神经侵袭在很大程度上还不清楚。该项目的长期目标是阐明胰腺癌细胞侵袭周围神经的总体机制。这项建议的目的是了解胰腺癌细胞整合素如何促进神经周围间隙的侵袭。我们的第一个目标是确定α6β4整合素在胰腺癌侵袭表型中的作用，该整合素已被证明促进其他肿瘤系统的侵袭。我们的下一个目标是确定促炎性整合素α4β7在胰腺癌神经侵袭中的功能意义。这一目标是基于我们独特的初步观察结果，即整合素α4beta7可以在胰腺癌细胞上表达，并可能有助于更全面地解释炎症如何在胰腺癌进展中发挥作用。对于这些研究，我们将使用三管齐下的方法，其中包括：对已确定其整合素含量的人胰腺癌细胞株进行体外研究；评估切除的肿瘤组织中α4beta7和alpha6beta4整合素及其各自的配体；以及胰腺癌的转基因小鼠模型。每种方法的选择都是为了利用各自的优势，以便我们可以更好地了解胰腺癌的神经侵袭，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.