VEGF Promotes Pancreatic Tumor Cell Arrest in the Liver

描述(申请人提供)：肝转移是胰腺癌血行播散的主要形式，也是癌症相关死亡的主要原因。为分析肿瘤细胞向肝脏血行转移的机制而建立的动物模型描述了一种非常低效的过程，即大多数通过门静脉栓塞到肝窦的细胞不会发展为转移肿瘤。然而，这些模型并没有解决由遥远的原发肿瘤产生的体液细胞因子的潜在影响。在所有胰腺癌患者中，全身肿瘤来源的血管内皮生长因子(VEGF)水平几乎是正常水平的五倍，水平升高预示着癌症相关死亡。这一建议的中心假设是，肿瘤来源的血管内皮生长因子影响宿主肝窦内皮细胞的变化，最终提高肝脏血道转移的发展效率。为了确定肿瘤来源的血管内皮生长因子在胰腺癌肝转移中的作用，我们将探讨以下目标。目的1.观察重组血管内皮细胞生长因子和肿瘤源性血管内皮细胞生长因子对小鼠肝窦内皮细胞的影响。目的2.研究阻断全身或肿瘤来源的血管内皮细胞生长因子对小鼠早期肝脏微转移形成的影响。 这种合作努力的独特能力将允许对这一假设进行检验。首先，结合灵敏的结构和功能成像能力的原位胰腺小鼠模型允许评估宿主肝脏的时间变化。其次，针对肿瘤来源的血管内皮生长因子和血管内皮生长因子激活的内皮细胞的新抗体已经被提出，并被证明可以控制胰腺肿瘤异种移植瘤的生长，并与胰腺肿瘤中血管内皮生长因子激活的血管结合；这些试剂可以识别血管内皮生长因子诱导的变化。 这项实验室工作代表着两位研究人员之间的合作，一位在胰腺癌转移方面具有临床和研究专长的内科科学家，以及一位在血管生物学和肿瘤血管生成方面具有专长的研究科学家，他们都致力于胰腺癌肿瘤-宿主相互作用的研究。

DESCRIPTION (provided by applicant): Hepatic metastases represent the dominant form of hematogenous spread of pancreatic cancer and a primary cause of cancer-related death. Animal models developed to dissect the mechanisms surrounding hematogenous metastasis of tumor cells to the liver describe a very inefficient process in which most cells that embolize to hepatic sinusoids via the portal vein do not develop into metastatic tumors. However, these models do not address the potential impact of humoral cytokines produced by a remote primary tumor. Systemic levels of tumor-derived vascular endothelial growth factor (VEGF) are nearly five-times normal in all patients with pancreatic adenocarcinomas, and elevated levels predict cancer-related death. The central hypothesis of this proposal is that tumor-derived VEGF affects changes in host liver sinusoidal endothelial cells (SEC) that ultimately increase the efficiency of hematogenous metastasis development in the liver. To determine the function of tumor-derived VEGF in the metastasis of pancreatic cancer to the liver the following aims will be addressed. Aim 1. Identify in vivo changes in liver sinusoidal endothelial cells in mice after exposure to systemic recombinant VEGF or tumor-derived VEGF. Aim 2. Determine the efficiency of early hepatic micrometastasis development in mice with and without blockade of systemic or tumor-derived VEGF. Unique capabilities of this collaborative effort will allow the examination of this hypothesis. First, an orthotopic pancreatic mouse model coupled with sensitive structural and functional imaging capabilities allows for evaluation of temporal changes in the host liver. Second, novel antibodies against tumor-derived VEGF and VEGF-activated endothelial cells have been raised and shown to control the growth of pancreatic tumor xenografts and bind to VEGF-activated blood vessels in pancreatic tumors; these reagents allow identification of VEGF-induced changes. This laboratory effort represents a partnership between two investigators, a physician scientist with clinical and research expertise in metastasis of pancreatic cancer and a research scientist with expertise in vascular biology and tumor angiogenesis, both committed to the study of tumor-host interactions in pancreatic adenocarcinoma.