VEGF Promotes Pancreatic Tumor Cell Arrest in the Liver

描述（由申请人提供）：肝转移是胰腺癌血行扩散的主要形式，也是癌症相关死亡的主要原因。为了剖析肿瘤细胞向肝脏的血液转移机制而建立的动物模型描述了一个非常低效的过程，在这个过程中，大多数通过门静脉栓塞到肝窦的细胞不会发展成转移性肿瘤。然而，这些模型并没有解决由远处原发肿瘤产生的体液细胞因子的潜在影响。在所有胰腺腺癌患者中，全身肿瘤源性血管内皮生长因子（VEGF）水平几乎是正常水平的5倍，VEGF水平升高预示着癌症相关的死亡。该建议的中心假设是，肿瘤来源的VEGF影响宿主肝窦内皮细胞（SEC）的变化，最终增加肝脏血液转移发展的效率。为了确定肿瘤来源的VEGF在胰腺癌转移到肝脏中的功能，以下目标将被解决。目的1。确定小鼠暴露于系统性重组VEGF或肿瘤来源的VEGF后肝窦内皮细胞的体内变化。目标2。测定有和没有全身性或肿瘤源性VEGF阻断的小鼠早期肝微转移发展的效率。

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.