Integrin Contributions to Pancreatic Cancer

整合素对胰腺癌的贡献

• 批准号: 7609159
• 负责人: KATHLEEN L. O'CONNOR
• 金额: $ 3.43万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-08 至 2009-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609159
• 关键词: Advanced Malignant Neoplasm; Affect; Antigens; Apical; Apoptosis; Apoptotic; Appearance; Applications Grants; Architecture; Basement membrane; Biological Models; Biology; Blocking Antibodies; Breast; Cancer Patient; Carcinoma; Cell Line; Cells; Cellular biology; Cessation of life; Clinical; Data; Development; Diagnosis; Dimensions; Drug resistance; Ductal; ECM receptor; Employee Strikes; Environment; Epithelium; Event; Excision; Frequencies; Goals; Head; Hemidesmosomes; Human; In Vitro; Incidence; Integrins; Knowledge; Laminin; Left; Ligands; Ligation; Localized Disease; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of pancreas; Mean Survival Times; Measures; Mediating; Modeling; Morbidity - disease rate; Nature; Neoplasm Metastasis; Operative Surgical Procedures; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Diseases; Pancreatic carcinoma; Pathologist; Patients; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Principal Investigator; Property; Radiation; Research; Resistance; Sampling; Scientist; Signal Transduction; Small Interfering RNA; Solid; Staging; Staining method; Stains; Study models; Surface; Surgeon; System; Testing; Time; Tissues; Tumor Cell Invasion; Up-Regulation; Work; base; cancer cell; chemotherapy; effective therapy; human NTN1 protein; indexing; innovation; killings; laminin-5; mortality; netrin-1; outcome forecast; overexpression; pancreatic neoplasm; public health relevance; receptor; response; tumor; tumor progression; two-dimensional

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.

描述（由申请人提供）：胰腺癌是所有癌症中死亡率和发病率最高的（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，从诊断开始，平均生存时间为3-6个月。这种惨淡预后的主要原因是胰腺癌传播频率高，对传统化疗和放疗有耐药性，原因尚不清楚。我们发现令人震惊的是，胰腺癌显示的细胞结构与形态分化细胞相似，而形态分化细胞本质上对化疗具有耐药性。我们假设这一观察结果可能是胰腺癌对治疗抵抗的关键。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，以便开发出更有效的治疗胰腺癌的方法。本提案的目的是确定促侵入性整合素的上调是否会影响4，它与细胞凋亡抵抗相关，在胰腺癌中高度表达，可以促进胰腺腺癌的侵袭性和弹性。这项拨款提案的中心假设是整合素？4及其配体在肿瘤进展早期高频上调，并通过促进独特的三维结构促进胰腺癌细胞的化疗耐药。我们的首要目标是确定？6？整合素可介导胰腺癌细胞对传统化疗的耐药性。为了正确地研究这一现象，我们期望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个三维培养系统。在我们的第二个目标中，我们将定义integrin ?6？4及其配体在人类胰腺肿瘤进展中过度表达和错定位。由于首席研究员在浸润性癌细胞中整合素的生物学方面有扎实的背景，因此我们很适合进行拟议的研究。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，我们有完善的模型来研究整合素？4在胰腺癌，其中包括多个胰腺细胞系，免疫组化染色档案组织整合素？4个亚基，以及用于研究细胞结构影响的三维培养。最终，我们的研究意义重大，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：胰腺癌患者预后不良的情况持续存在，这是由于胰腺癌侵袭和转移的高发生率，以及由于胰腺癌细胞的耐药性质而缺乏有效的治疗选择。基于我们的初步数据和对晚期癌症中整合素生物学的了解，本提案的目的是确定促侵袭性整合素的上调是否会影响晚期癌症的预后。4，在胰腺癌中高表达，可以促进胰腺癌的侵袭性和凋亡/耐药性质。最终，我们的研究将是重要的，因为它们将有助于了解胰腺癌的耐药性，及时，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。