ADHESION MOLECULES IN NO MODULATED TUMORIGENESIS

描述(申请人描述)：非调制状态下的黏附分子 肿瘤发生学。控制肿瘤转移是癌症的重大变化 今天的治疗。这个项目的目标是检验这样一个假设 一氧化氮(NO)对黏附分子的调节在肿瘤中的作用 进展和转移。许多研究已经将这种过度的 黏附分子如E-和P-选择素和特异性的表达 CD44亚型与肿瘤发生肿瘤细胞可能表达选择性 与内皮上的P-或E-选择素结合的配体，如唾液酸化的Lewis X 细胞，并被认为能增强肿瘤细胞与血管内皮细胞的黏附， 导致细胞渗出，并在远离血管的部位生长 原发肿瘤。CD44是基质糖胺聚糖的受体， 透明质酸(HA)，在细胞对透明质酸的降解中起着关键作用。 透明质酸降解释放的寡糖可以刺激血管生成和 从肿瘤细胞传代中观察到透明质酸显著增加。 从原发状态转变为转移状态。人们一直假设， CD44/HA相互作用可能促进细胞黏附和迁移事件 在细胞侵袭中起重要作用。缺乏诱导性NO基因的小鼠表现出 在小鼠乳腺肿瘤模型中减少肿瘤的发展和转移。 黏附分子在NO调控肿瘤发生发展中的作用 转移将通过以下三个具体目标来进行：1)确定 一氧化氮对选择素和CD44黏附分子表达的影响 肿瘤发生中的系统。2)考察选拔和管理的作用 CD44黏附系统在NO介导的肿瘤转移中的作用3)确定 内皮一氧化氮在肿瘤进展和转移中的作用。多焦点 高频率转移到肺部的乳腺肿瘤形成于 表达多瘤病毒中T抗原的转基因小鼠 小鼠乳腺肿瘤病毒(MMTV)长末端转录调控 重复(Ltr)。携带MMTV/PYV中T抗原基因的小鼠 与诱导型一氧化氮合酶基因缺陷的小鼠杂交，NOS2或 L-精氨酸转运蛋白CAT2将被用于这些研究。激光- 捕获解剖显微镜将使黏附分子的检查成为可能 肿瘤进展的特定阶段和特定部位的表达 在皮损内。内皮细胞上的黏附分子在 对激活的反应，我们将确定内皮一氧化氮合酶是否在 在肿瘤发生和发展中的作用。这些研究将有助于确定 一氧化氮在血管内皮细胞黏附分子改变中的重要性 肿瘤的发生，并可能导致癌症患者治疗的改进。

DESCRIPTION (Applicant's Description): Adhesion Molecules in NO Modulated Tumorigenesis. Controlling tumor metastasis is a major change in cancer therapy today. The objective of this project is to test the hypothesis that modulation of adhesion molecules by nitric oxide (NO) plays a role in tumor progression and metastasis. Numerous studies have correlated the over- expression of adhesion molecules such as E- and P-selecting and particular isoforms of CD44 with tumorigenesis. Tumor cells may express selecting ligands such as sialyl Lewis X which bind to P- or E- selecting on endothelial cells and are thought to enhance tumor cell adhesion to vascular endothelium, resulting in extravasation, and growth of cells at sites distant from the primary tumor. CD44 is a receptor for the matrix glycosaminoglycan, hyaluronan (HA) and plays a key role in the degradation of HA by cells. Oligosaccharides released by HA degradation can stimulate angiogenesis and a marked increase in HA has been observed in the passage of tumor cells from the primary state to the metastatic state. It has been hypothesized that the CD44/HA interaction may act to promote cell adhesion and migration events important in cell invasion. Mice deficient in the inducible NO gene show a reduction in tumor development and metastasis in a mouse mammary tumor model. The role of adhesion molecules in NO modulated tumor, development and metastasis will be pursued by following three specific aims: 1) To determine the effect of nitric oxide on the expression of selecting and CD44 adhesion systems in tumorigenesis. 2) To examine the function of the selecting and CD44 adhesion systems in NO mediated tumor metastasis. 3) To determine the role of endothelial NO in tumor progression and metastasis. Multifocal mammary tumors that metastasize with high frequency to the lung are formed in transgenic mice expressing the polyomavirus (PyV) middle T antigen under transcriptional control of the murine mammary tumor virus (MMTV) long terminal repeat (LTR). Mice carrying the MMTV/PyV middle T antigen gene which have been crossed with mice deficient in the inducible nitric oxide gene, NOS2 or the L-arginine transporter, CAT2 will be utilized in these studies. Laser- capture dissection microscopy will enable examination of adhesion molecule expression at specific stages of tumor progression and at specific sites within the lesions. Adhesion molecules on endothelial cells are modulated in response to activation and we will determine whether endothelial NOS plays a role in tumor development and progression. These studies will help to define t h e importance of NO mediated alterations in adhesion molecules in tumorigenesis and may lead to improved therapy for cancer patients.