Experimental Models for Testing Novel Targets for Pancreatic Cancer Cell Invasion

描述（由申请人提供）：胰腺癌是所有腹内恶性肿瘤中生存率最低的。由于无法在早期阶段发现它，在做出诊断时，疾病往往已经发展到很远的阶段。迫切需要更好地了解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。恶性肿瘤与高凝状态和血栓栓塞并发症的高风险相关。癌症中血液凝固的激活是一个复杂的现象，涉及许多不同的止血系统途径。在这项探索性资助中，我们将使用我们实验室开发的一种新型体外人类血管段灌注模型来研究胰腺肿瘤转移的过程，以测试化合物在阻止肿瘤细胞侵入血管壁的初始步骤中的功效。人脐静脉段将灌注含有胰腺癌细胞的自体富血小板血浆。附着或侵入血管节段将通过显微镜观察来量化。为了验证体外血管段模型的发现，我们将利用小鼠体内自发性胰腺转移模型。待研究的试验药物是低分子量肝素化合物（LMWH），在化疗药物吉西他滨存在或不存在的情况下使用，以确定它们是否能增强该药物的抗转移活性。具体来说，要测试的药物是市售的低分子肝素（Tinzaparin）和非抗凝低分子肝素（NACH）。这种NACH的全身抗凝作用有限，止血作用有限。血管段模型中药物限制肿瘤细胞侵袭的功效与体内模型中随后对转移的保护之间的相关性将证实该模型在预测肿瘤细胞转移行为和筛选化合物以防止肿瘤细胞侵袭作为肿瘤转移的先决条件方面的价值。对癌症患者的癌症和血栓形成的改善管理是至关重要的。这项探索性资助采用创新的方法，将适用于各种肿瘤类型，重点是筛选和评估LMWHs单独或联合化疗药物治疗转移性胰腺癌的有效治疗方法。癌症患者通常表现出与血液凝固相关的过程异常，这可能会使肿瘤生长恶化并导致癌症的转移性扩散。使用低分子肝素化合物（LMWH）治疗在一些患者中具有显著的生存优势，但有时会导致出血次数增加。这项探索性资助采用创新的方法，专注于筛选和评估LMWHs（一种对出血影响有限的药物）单独或联合化疗药物治疗转移性胰腺癌的有效治疗方法。

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.