Integrin Contributions to Pancreatic Cancer

描述(申请人提供)：胰腺癌是所有癌症中死亡与发病率比最高的(约0.99)。胰腺癌患者的生存时间以月为单位，而不是以年为单位，后者的平均生存时间是从确诊之日起3-6个月。这种令人沮丧的预后的主要原因是胰腺癌的扩散频率很高，并且对传统的化疗和放射治疗具有抵抗力，原因尚不清楚。我们发现令人惊讶的是，胰腺癌显示的细胞结构使人想起形态分化的细胞，而分化的细胞本质上对化疗具有抵抗力。我们推测，这一观察结果可能是胰腺癌耐药的关键。该项目的长期目标是更好地了解胰腺癌侵袭性和耐药性的机制，以便开发更有效的胰腺癌治疗方法。本研究的目的是确定在胰腺癌中高表达的、与细胞凋亡抵抗相关的侵袭前整合素？6？4的上调是否有助于胰腺癌的侵袭性和韧性。这项拨款提案的中心假设是整合素？6？4及其配体在肿瘤进展的早期高频上调，并通过促进独特的三维结构促进胰腺癌细胞的化疗耐药。我们的第一个目标是确定？6？4整合素是否能够介导胰腺癌细胞对传统化疗药物的耐药性。为了正确地研究这一现象，我们预计对细胞环境的准确建模将是至关重要的，因此为此目的开发了一种三维培养系统。在我们的第二个目标中，我们将定义整合素？6？4及其配体在人类胰腺肿瘤进展中过度表达和错位定位的阶段。由于首席研究员在侵袭性癌细胞中整合素的生物学方面有扎实的背景，我们有很好的条件开展这项拟议的研究。我们拥有临床科学家的专业知识和支持，他们参与了UTMB胰腺疾病患者的诊断和治疗。此外，我们还建立了研究整合素？6？4在胰腺癌中的成熟模型，包括多个胰腺细胞系、整合素亚单位的免疫组织化学染色以及用于研究细胞构筑效应的三维培养。最终，我们的研究具有重要意义，因为它们将有助于了解胰腺癌的耐药性，最终将使我们能够降低胰腺癌患者的发病率和死亡率。公共卫生相关性：胰腺癌患者预后较差的原因是侵袭和转移的高发生率，以及由于胰腺癌细胞的抗药性而缺乏有效的治疗选择。基于我们对晚期癌症中整合素生物学的初步数据和知识，本研究的目的是确定在胰腺癌中高表达的前侵袭性整合素？6？4的上调是否与胰腺癌的侵袭性和细胞凋亡/耐药特性有关。最终，我们的研究将具有重要意义，因为它们将有助于了解胰腺癌的耐药性，最终将使我们能够通过开发更有效的治疗方法来降低胰腺癌患者的发病率和死亡率。

DESCRIPTION (provided by applicant): Pancreatic cancer has the highest death to incidence ratio (approximately 0.99) of all cancers. Survival time for pancreatic cancer patients is measured in months, rather than years, where the mean survival time is 3-6 months from the time of diagnosis. The major reasons for this dismal prognosis come from the fact that pancreatic cancers disseminate at a high frequency and are resistant to traditional chemotherapeutics and radiation for reasons that are unclear. We find it striking that pancreatic carcinomas display cytoarchitecture that is reminiscent of morphologically differentiated cells, which by their nature are resistant to chemotherapies. We postulate that this observation may hold the key to the resistance of pancreatic cancers to treatment. The long- term goal of this project is to better understand the mechanisms governing the aggressive and drug-resistant nature of pancreatic carcinomas so that more effective treatments can be developed for pancreatic cancer. The objective of this proposal is to determine if upregulation of the pro-invasive integrin ?6?4, which is associated with apoptosis resistance and is highly expressed in pancreatic carcinomas, can contribute to the aggressive and resilient nature of pancreatic adenocarcinomas. The central hypothesis of this grant proposal is that the integrin ?6?4 and its ligands are upregulated early in tumor progression at high frequency and promote the chemotherapeutic resistance of pancreatic cancer cells by facilitating a unique three-dimensional architecture. Our first aim is to determine if the ?6?4 integrin can mediate resistance of pancreatic carcinoma cells to traditional chemotherapies. To study this phenomenon properly, we expect that the accurate modeling of the context of the cells will be critical and thus have developed a three-dimensional culture system for this purpose. In our second aim, we will define the stage at which integrin ?6?4 and its ligands are overexpressed and mislocalized in human pancreatic tumor progression. We are well positioned to undertake the proposed research since the principal investigator has a solid background in the biology of integrins in invasive carcinoma cells. We have the expertise and support of clinical scientists who are involved in the diagnosis and treatment of patients with pancreatic disease at UTMB. In addition, we have well-developed models for studying integrin ?6?4 in pancreatic cancer, which includes multiple pancreatic cell lines, immunohistochemical staining of archival tissues for integrin ?4 subunit, and three-dimensional cultures for studying the effects of cytoarchitecture. Ultimately, our studies are significant because they will contribute to the understanding of drug resistance in pancreatic cancer that, in time, will allow us to decrease the morbidity and mortality of pancreatic cancer patients. PUBLIC HEALTH RELEVANCE: The poor prognosis for pancreatic cancer patients persists due to a high incidence of invasion and metastasis and a lack of effective treatment options due to the drug-resistant nature of pancreatic cancer cells. Based on our preliminary data and knowledge of the biology of integrins in advanced cancers, objective of this proposal is to determine if upregulation of the pro-invasive integrin ?6?4, which is highly expressed in pancreatic carcinomas, can contribute to the aggressive and apoptosis/drug-resistant nature of pancreatic carcinomas. Ultimately, our studies will be significant because they will contribute to the understanding of drug resistance in pancreatic cancer that, in time, will allow us to decrease the morbidity and mortality of pancreatic cancer patients through the development of more effective treatments.