Integrin Contributions to Pancreatic Cancer

整合素对胰腺癌的贡献

• 批准号: 7845314
• 负责人: KATHLEEN L. O'CONNOR
• 金额: $ 13.55万
• 依托单位: UNIVERSITY OF KENTUCKY
• 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 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845314
• 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）：胰腺癌在所有癌症中的死亡率与发病率之比最高（约为0.99）。胰腺癌患者的生存时间是以月而不是年来衡量的，其中平均生存时间是从诊断时起的3-6个月。这种令人沮丧的预后的主要原因来自于胰腺癌以高频率传播并且由于尚不清楚的原因而对传统化疗和放射具有抗性的事实。我们发现胰腺癌显示的细胞结构令人联想到形态分化的细胞，其本质上对化疗具有抗性。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，以便为胰腺癌开发更有效的治疗方法。这项建议的目的是确定是否上调的促侵入整合素？六个？4与细胞凋亡抵抗相关，在胰腺癌中高度表达，可能有助于胰腺癌的侵袭性和弹性。这项拨款建议的中心假设是，整合素？六个？4及其配体在肿瘤进展早期以高频率上调，并通过促进独特的三维结构来促进胰腺癌细胞的化疗抗性。我们的第一个目标是确定如果？六个？4整合素介导胰腺癌细胞对传统化疗药物的耐药。为了正确地研究这种现象，我们期望细胞背景的准确建模将是至关重要的，因此为此目的开发了三维培养系统。在我们的第二个目标，我们将定义的阶段，整合素？六个？4及其配体在人胰腺肿瘤进展中过表达和错误定位。我们有能力进行这项研究，因为主要研究者在侵袭性癌细胞中整合素的生物学方面有坚实的背景。我们拥有临床科学家的专业知识和支持，他们在UTMB参与胰腺疾病患者的诊断和治疗。此外，我们有完善的模型研究整合素？六个？4在胰腺癌，其中包括多种胰腺细胞系，免疫组化染色的档案组织的整合素？4亚基，和三维文化研究细胞结构的影响。最终，我们的研究是重要的，因为它们将有助于了解胰腺癌的耐药性，最终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：由于侵袭和转移的高发生率以及由于胰腺癌细胞的耐药性而缺乏有效的治疗选择，胰腺癌患者的预后不良。基于我们对晚期癌症中整合素生物学的初步数据和知识，本提案的目的是确定促侵袭性整合素的上调是否与癌症的发生有关。六个？4，其在胰腺癌中高度表达，可以有助于胰腺癌的侵袭性和凋亡/耐药性质。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。