PROJECT 4:MECHANISMS FACILITATING GROWTH & METASTASIS OF PANCREATIC CANCER

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 胰腺癌是美国癌症相关死亡的第四大常见原因，且仅 大约有5%的病人能存活下来提高对胰腺肿瘤生长方式的理解， 为了开发更好的治疗方法，转移是必要的。在某些系统中，主要 神经系统，淀粉样前体蛋白（APP）和淀粉样前体蛋白样蛋白2（APLP 2）已被 与细胞生长和迁移有关。最近的研究表明APP的过度表达， APLP 2在包括胰腺癌在内的人类癌症中，以及在一些癌症中较高的APP表达已经被证实。 与更差的存活率相关。前列腺癌和胰腺癌细胞系分泌的APP 通过与未鉴定的细胞表面受体结合增加增殖，APP和APLP 2 有助于几种细胞类型的粘附和运动。有证据表明APP和APLP 2具有新的 胰腺癌中的作用，但它们如何导致这种疾病的机制尚不清楚。在这 项目，我们的总体目标是了解胰腺癌生长的机制 传播开来我们的中心假设是APP和APLP 2刺激肿瘤细胞的增殖和转移。 胰腺癌细胞为了实现这一目标，我们的目标是，首先，确定调解机制， APP和APLP 2促进胰腺癌细胞生长。我们的工作假设是， 分泌的APLP 2和APP通过NF-B途径触发胰腺癌细胞的增殖。的 第二个目的是确定APP和APLP 2介导的增加肿瘤扩散的机制。 胰腺癌细胞将在此目的中测试的工作假设是跨膜APP 和APLP 2是胰腺癌细胞粘附和扩散的关键调节因子。我们的结果 从这些研究将提供一个新的角度对细胞生长和运动的调节， 与正常细胞和癌细胞，特别是胰腺癌细胞相关。此外，结果来自 这项研究有望支持针对APP的胰腺癌新疗法的使用， APLP2.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Pancreatic cancer is the fourth most frequent cause of cancer-related death in the U.S., and only about 5% of patients with this disease survive. Improved comprehension of how pancreatic tumors grow and metastasize is necessary in order for better therapies to be developed. In some systems, principally the nervous system, amyloid precursor protein (APP) and amyloid precursor-like-protein 2 (APLP2) have been associated with cellular growth and migration. Recent studies have shown over-expression of APP and APLP2 in human cancer, including pancreatic cancer, and in some cancers higher APP expression has been shown to correlate with a worse survival rate. APP secreted by prostate and pancreatic cancer cell lines increases proliferation by binding to an unidentified cell surface receptor, and both APP and APLP2 contribute to adhesion and motility in several cell types. There is evidence that APP and APLP2 have novel roles in pancreatic cancer, but the mechanisms for how they contribute to this disease are not known. In this project, our overall objective is to gain understanding of mechanisms underlying pancreatic cancer growth and spread. Our central hypothesis is that APP and APLP2 stimulate the proliferation and metastasis of pancreatic cancer cells. To accomplish this objective, our Aims are, first, to ascertain mechanisms mediated by APP and APLP2 that facilitate pancreatic cancer cell growth. Our working hypothesis for this aim is that secreted APLP2 and APP trigger the proliferation of pancreatic cancer cells via a NF-¿B pathway. The second aim is to determine mechanisms mediated by APP and APLP2 that increase the spread of pancreatic cancer cells. The working hypothesis that will be tested in this aim is that transmembrane APP and APLP2 are key regulators of the adhesion and dissemination of pancreatic cancer cells. Our results from these studies will provide a novel perspective on the regulation of cellular growth and motility, with relevance to normal and cancer cells and particularly to pancreatic cancer cells. Furthermore, results from this study are expected to support the use of novel treatments for pancreatic cancer that target APP and APLP2.