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比（约0.99）。胰腺癌患者的生存时间是在几个月而不是几年中测量的，在诊断之日起，平均生存时间为3-6个月。这种令人沮丧的预后的主要原因是胰腺癌以高频传播，并且由于尚不清楚的原因而对传统的化学治疗和辐射具有抵抗力。我们发现胰腺癌显示的细胞结构结构令人震惊，这让人联想到形态学分化的细胞，这些细胞的性质对化学疗法具有抗性。我们假设该观察结果可能是胰腺癌对治疗的耐药性的关键。该项目的长期目标是更好地了解胰腺癌的侵略性和抗药性性质的机制，以便可以为胰腺癌开发更有效的治疗方法。该提案的目的是确定促侵入性整联蛋白的上调？6？4，它与凋亡耐药性相关，并且在胰腺癌中高度表达，可以促进胰腺腺癌的侵略性和弹性性质。该赠款建议的中心假设是，整联蛋白？6？4及其配体在高频下肿瘤进展早期被上调，并通过促进独特的三维结构来促进胰腺癌细胞的化学治疗性。我们的第一个目的是确定？6？4整联蛋白是否可以介导胰腺癌细胞对传统化学疗法的耐药性。为了正确研究这种现象，我们希望细胞上下文的准确建模将是至关重要的，因此为此开发了三维培养系统。在我们的第二个目标中，我们将定义整联蛋白的阶段？6？4及其配体在人胰腺肿瘤进展中过表达和误态性。由于主要研究者在浸润性癌细胞中整联蛋白的生物学方面具有扎实的背景，因此我们有能力进行拟议的研究。我们拥有参与UTMB胰腺疾病患者诊断和治疗的临床科学家的专业知识和支持。此外，我们还有良好的模型用于研究整联蛋白的模型？6？4在胰腺癌中，其中包括多个胰腺细胞系，整合素的档案组织的免疫组织化学染色以及4个亚基和三维培养物，用于研究细胞卫生结构的影响。最终，我们的研究很重要，因为它们将有助于理解胰腺癌的耐药性，这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：胰腺癌患者的预后不良，由于侵入性和转移的高发病率以及由于胰腺癌细胞的药物耐药性而缺乏有效治疗选择。基于我们对高级癌中整合蛋白生物学的初步数据和知识，该提案的目的是确定促侵入性整合素的上调是否上调？6？4，哪个在胰腺癌中高度表达，可以促进积极的和凋亡/凋亡/凋亡/药物抗药性性质的胰腺癌性质。最终，我们的研究将是重要的，因为它们将有助于理解胰腺癌的耐药性，这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。