Maintenance of the integrity of the interaction between normal lymphocytes and HEV throughout ontogeny and phylogeny of lymphoid-organogenesis argues strongly that this system is vital to the development of immunocompetence. It is the vascular barrier that must be breached in the course of normal extravasation of hematolymphoid cells in order to access antigen and antigen-presenting cells in lymphoid organs and/or in tissues, and to wall-off and/or eliminate foreign insult in those tissues. This cellular traffic is responsible for desired and undesired inflammation to proceed when normal cells are involved, and it is likely that similar mechanisms operate through which neoplastic counterparts spread from one tissue to another. It is this subject we hope to investigate in this proposal. In the past five years I have been engaged in the molecular description, characterization, cloning, and functional attributes of the lymph node homing receptor (mLHR, LECCAM-1) in mouse and man (hLHR, LAM-1, Leu-8). Molecular cloning and predicted amino acid sequence revealed a novel makeup of a tandem collection of protein domains, shared by two addition cell surface adhesion molecules localized to induced endothelium and/or platelets. All share functions critical to interactions between circulating cells and the vasculature. It is now clear that members of this new class of adhesion molecule, designated selectins, are a distinct family, clustering on the distal arm of chromosome 1 in mouse and man. This supports the existence of a new gene family of adhesion molecules, guiding and targeting cells to sites throughout the organism. We intend to investigate the influence of LHR expression on tumor dissemination and localization in an in vivo murine model. To this end murine lymphoid cell lines with no homing or HEV adhesion properties have been transfected with the human and mouse LHR cDNA, and injected into syngeneic and Thy-1 congenic mice to assess the influence of this receptor on tumor metastasis. This transfection system is designed to allow further manipulation and fine molecular mapping of the cDNA in order to dissect functional domains and structural requirements of the protein by deletion, site directed mutagenesis, and chimeric molecule mapping for lymphocyte homing and metastasis. Development of reagents to inhibit metastasis based on antibodies, fragments of the molecule, or the sugar specificity of this special lectin molecule is an approachable therapeutic avenue. Natural extensions of this inquiry will be to examine the influence of the receptor on metastasis in non-lymphoid malignancies, and to search for additional members of the selectin family in a variety of human tumors.
| DeGrendele, H C; Estess, P; Siegelman, M H (1997) Requirement for CD44 in activated T cell extravasation into an inflammatory site. Science 278:672-5 |
