Integrin Contributions to Pancreatic Cancer

整合素对胰腺癌的贡献

• 批准号: 7470886
• 负责人: KATHLEEN L. O'CONNOR
• 金额: $ 20.39万
• 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 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470886
• 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; Condition; Data; Development; Diagnosis; Dimensions; Drug resistance; Ductal; ECM receptor; Employee Strikes; Environment; Epithelium; Event; Excision; Frequencies; Goals; Head; Hemidesmosomes; Human; In Vitro; Incidence; Integrins; Invasive; 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; Protein Overexpression; Public Health; Purpose; 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; concept; human NTN1 protein; indexing; innovation; killings; laminin-5; mortality; netrin-1; outcome forecast; pancreatic neoplasm; 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）：在所有癌症中，胰腺癌的死亡率与发病率最高（约 0.99）。胰腺癌患者的生存时间以月而不是年为单位，平均生存时间为从诊断之日起 3-6 个月。这种预后不良的主要原因是胰腺癌播散频率高，并且对传统化疗和放疗产生耐药性，原因尚不清楚。我们发现令人震惊的是，胰腺癌表现出的细胞结构让人想起形态分化的细胞，这些细胞本质上对化疗有抵抗力。我们假设这一观察结果可能是胰腺癌对治疗产生耐药性的关键。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胰腺癌治疗方法。该提案的目的是确定促侵袭性整合素α6β4（与细胞凋亡抵抗相关并在胰腺癌中高表达）的上调是否有助于胰腺癌的侵袭性和弹性。该资助提案的中心假设是，整合素α6β4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来促进胰腺癌细胞的化疗耐药性。我们的第一个目标是确定?6?4 整合素是否可以介导胰腺癌细胞对传统化疗的耐药性。为了正确研究这种现象，我们预计细胞环境的准确建模至关重要，因此为此目的开发了三维培养系统。在我们的第二个目标中，我们将定义整合素α6β4及其配体在人类胰腺肿瘤进展中过度表达和错误定位的阶段。我们有能力开展这项拟议的研究，因为主要研究者在侵袭性癌细胞整合素生物学方面拥有扎实的背景。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，我们还拥有用于研究胰腺癌中整合素α6β4的成熟模型，其中包括多种胰腺细胞系、对档案组织进行整合素α4亚基的免疫组织化学染色，以及用于研究细胞结构影响的三维培养物。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，最终使我们能够降低胰腺癌患者的发病率和死亡率。 公共健康相关性：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，胰腺癌患者的预后持续不佳。根据我们对晚期癌症整合素生物学的初步数据和知识，本提案的目的是确定在胰腺癌中高度表达的促侵袭性整合素α6β4的上调是否有助于侵袭性和侵袭性。胰腺癌的细胞凋亡/耐药性。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。