ADHESION MOLECULES IN NO MODULATED TUMORIGENESIS

描述（申请人描述）： NO调节的粘附分子 肿瘤发生 控制肿瘤转移是癌症的一个重大变化 今天的治疗 这个项目的目的是检验假设， 一氧化氮（NO）对粘附分子的调节在肿瘤中起作用 进展和转移。 许多研究表明，过度- 表达粘附分子，如E-和P-选择，特别是 CD 44亚型与肿瘤发生的关系。 肿瘤细胞可能表达选择性 配体如唾液酸刘易斯X，其结合内皮细胞上的P-或E-选择， 细胞并且被认为增强肿瘤细胞与血管内皮的粘附， 导致外渗，以及细胞在远离血管的部位生长。 原发性肿瘤 CD 44是基质糖胺聚糖的受体， 透明质酸（HA）是透明质酸（HA）的主要来源，在细胞降解HA中起关键作用。 HA降解释放的寡聚体可刺激血管生成， 在来自肿瘤细胞的传代中观察到HA的显著增加， 从原发状态到转移状态 据推测， CD 44/HA相互作用可能促进细胞粘附和迁移 在细胞入侵中起重要作用。 诱导型NO基因缺陷的小鼠表现出 减少小鼠乳腺肿瘤模型中的肿瘤发展和转移。 粘附分子在NO调控肿瘤发生、发展及预后中的作用 转移将通过以下三个具体目标进行：1）确定 一氧化氮对选择性表达和CD 44粘附的影响 肿瘤发生系统。 2)为了检查选择和 CD 44粘附系统在NO介导的肿瘤转移中的作用 3)确定 内皮NO在肿瘤进展和转移中的作用。 多焦点 高频率转移到肺的乳腺肿瘤形成于 表达多瘤病毒（PyV）中T抗原的转基因小鼠在 小鼠乳腺肿瘤病毒长末端的转录调控 重复（LTR）。 携带MMTV/PyV中间T抗原基因的小鼠， 与缺乏诱导型一氧化氮基因NOS 2或 L-精氨酸转运蛋白CAT 2将用于这些研究。 激光- 捕获解剖显微镜将能够检查粘附分子 在肿瘤进展的特定阶段和特定部位的表达 在病变中。 内皮细胞上的粘附分子被调节， 我们将确定内皮NOS是否在激活中起作用。 在肿瘤发生和发展中的作用。 这些研究将有助于确定 这些 一氧化氮介导的粘附分子改变在 肿瘤发生，并可能导致改善治疗癌症患者。

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.