): 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.
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