Experimental Models for Testing Novel Targets for Pancreatic Cancer Cell Invasion

测试胰腺癌细胞侵袭新靶点的实验模型

基本信息

批准号：
7596380
负责人：
SHAKER A MOUSA
金额：
$ 20.1万
依托单位：
ALBANY COLLEGE OF PHARMACY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7596380
关键词：
Adenocarcinoma Adhesions Adverse effects Aggressive behavior Angiogenesis Inhibition Anticoagulants Autologous Behavior Benign Bleeding time procedure Blood Circulation Blood Clot Blood Platelets Blood Vessels Blood coagulation Cancer Model Cancer Patient Cells Clinical Complex Cytoplasmic Tail Diagnosis Disease Distant Ductal Endothelium Evaluation Event Experimental Models Exposure to Extravasation Factor VIIa Generations Grant Growth Hematogenous Hemorrhage Hemostatic Agents Hemostatic function Heparin Human In Vitro Intra-abdominal Laboratories Lead Legal patent Low-Molecular-Weight Heparin Malignant Neoplasms Malignant neoplasm of pancreas Metastatic to Microscopic Modeling Molecular Monitor Mus Neoplasm Metastasis Outcome Pancreas Pathologic Neovascularization Pathway interactions Patients Penetration Perfusion Physiological Plasma Process Production Proteins Relative (related person)Research Screening procedure Secondary to Signal Transduction Site Staging Survival Rate System TFPI Testing Thrombin Thromboplastin Thrombosis Time Tissue Stains Tissues Tumor Angiogenesis Tumor Cell Invasion Umbilical vein Vascular Endothelium Vascularization Work abstracting cancer cell cell type chemotherapeutic agent conventional therapy effective therapy extracellular gemcitabine high risk implantation improved in vitro Model in vivo in vivo Model inhibitor/antagonist innovation malignant phenotype mouse model neoplastic cell novel outcome forecast overexpression pancreatic neoplasm prevent tinzaparin treatment effect tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer has the poorest survival of any intra-abdominal malignancy. Because of the inability to detect it at an early stage, the disease is often far advanced by the time the diagnosis is made. Better understanding of the cellular and molecular mechanisms involved in pancreatic tumor growth and metastasis is urgently needed to promote treatment of this disease. Malignancy is associated with a hypercoagulable state and high risk for thromboembolic complications. Activation of blood coagulation in cancer is a complex phenomenon, involving many different pathways of the hemostatic system. In this Exploratory Grant we will study the process of pancreatic tumor metastasis using a novel in vitro human vessel segment perfusion model developed in our laboratory to test compounds for efficacy in preventing the initial steps of tumor cell invasion into the vascular wall. Human umbilical vein segments will be perfused with autologous platelet-rich plasma containing pancreatic cancer cells. Attachment or invasion into the vessel segments will be quantified by microscopic observation. To validate the findings from the in vitro vessel segment model we will utilize an in vivo mouse model of spontaneous pancreatic metastasis. Test agents to be investigated are low molecular weight heparin compounds (LMWH), utilized in the presence or absence of chemotherapeutic agent Gemcitabine, to determine if they can enhance the anti-metastatic activities of this agent. Specifically, agents to be tested are commercially available LMWH Tinzaparin and non-anticoagulant LMWH (NACH). This NACH has limited to no systemic anticoagulant effects and limited effects on hemostasis. Correlations between the efficacies of agents in the vessel segments model to limit tumor cell invasion with subsequent protection against metastasis in the in vivo model would confirm the value of this model for predicting metastatic behavior of tumor cells and for screening compounds to prevent tumor cell invasion as a pre-requisite for tumor metastasis. There is crucial need for an improved management of both cancer and thrombosis in cancer patients. This exploratory grant utilizes innovative approaches that will be applicable to various tumor types by focusing on the screening and the evaluation of an effective treatment with LMWHs, alone or in combination with chemotherapeutic agents in the treatment of metastatic pancreatic cancer. Cancer patients often show abnormalities in processes associated with blood clotting that can worsen tumor growth and lead to metastatic spread of the cancer. Treatment with low molecular weight heparin compounds (LMWH) is associated with significant survival advantage in some patients but sometimes causes increases in bleeding times. This exploratory grant utilizes innovative approaches by focusing on the screening and the evaluation of an effective treatment with LMWHs (one, with limited effects on bleeding), alone or in combination with chemotherapeutic agents for the treatment of metastatic pancreatic cancer.

描述（由申请人提供）：胰腺癌的生存最差。由于无法在早期阶段检测到它，因此在诊断时，这种疾病通常会远远出现。迫切需要更好地了解参与胰腺肿瘤生长和转移的细胞和分子机制，以促进该疾病的治疗。恶性肿瘤与血栓栓塞并发症的高凝状态和高风险有关。癌症血液凝血的激活是一种复杂的现象，涉及止血系统的许多不同途径。在这项探索性赠款中，我们将使用一种在我们的实验室中开发的新型体外人体血管灌注模型来研究胰腺肿瘤转移的过程，以测试化合物，以防止肿瘤细胞入侵血管壁的初始步骤。人脐静脉片段将用含有胰腺癌细胞的富含血小板的血浆来灌注。将通过微观观察来定量附着或侵袭血管段。为了验证体外容器段模型的发现，我们将利用自发胰腺转移的体内小鼠模型。要研究的测试剂是在存在或不存在化学治疗剂吉西他滨的情况下使用的低分子量肝素化合物（LMWH），以确定它们是否可以增强该药物的抗转移活性。具体而言，要测试的代理是市售的LMWH tinzaparin和非抗癌LMWH（NACH）。该NACH仅限于全身性抗凝作用，对止血作用有限。在体内模型中限制肿瘤细胞侵袭并随后对转移的保护的血管片段模型中药物的效率之间的相关性将证实该模型对于预测肿瘤细胞转移性行为的价值，以及用于筛选化合物以防止肿瘤细胞入侵作为肿瘤转移的前提。癌症患者对癌症和血栓形成的治疗至关重要。这项探索性赠款利用了创新方法，通过专注于筛查和评估LMWHS的有效治疗，单独或与化学治疗剂相结合，以治疗转移性胰腺癌。癌症患者经常表现出与血液凝结相关的过程异常，这可能会使肿瘤生长恶化并导致癌症的转移性传播。低分子量肝素化合物（LMWH）的治疗与某些患者的生存优势相关，但有时会导致出血时间增加。这项探索性赠款通过专注于筛查和评估LMWHS的有效治疗（一种，对出血的影响有限），或与化学治疗剂结合使用，以治疗转移性胰腺癌。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Suppression of pancreatic cancer by sulfated non-anticoagulant low molecular weight heparin.

DOI：
10.1016/j.canlet.2014.04.016
发表时间：
2014-08-01
期刊：
CANCER LETTERS
影响因子：
9.7
作者：
Sudha, Thangirala;Yalcin, Murat;Lin, Hung-Yun;Elmetwally, Ahmed M.;Nazeer, Tipu;Arumugam, Thiruvengadam;Phillips, Patricia;Mousa, Shaker A.
通讯作者：
Mousa, Shaker A.