One of several critical steps resulting in the seeding of tumors to distal sites takes place at the interface between a malignant cell s mobile circulating phase and its ultimate entry into a particular organ. The specific portal of entry of normal lymphocytes from bloodstream into peripheral lymphoid organs was identified as specialized postcapillary venules and named high endothelial venules (HEVs). The lymphocyte cell surface structures mediating adherence to HEVs have been designated lymphocyte homing receptors, or L-selectins, and their complementary carbohydrate ligands on the endothelial surface have been called addressins . Recirculating lymphocytes, but not other blood-borne cells, specifically recognize and migrate through this highly specialized endothelium. Data suggests that these specific adhesion molecules can also direct the traffic of malignant lymphoid cells to the same lymphoid target organs. The investigator has developed and characterized a murine model for lymphocyte tumor metastasis using lymphoid cells transfected with lymphocyte homing receptor, in particular L-selectin and that the mouse and human L-selectins can selectively confer on a non-metastatic cell the ability to disseminate to peripheral lymph nodes. To further probe the biology of this model, the investigator has engineered a genetically altered mouse strain incapable of producing L-selectin. Using Abelson virus transformation, he has derived homozygous L-selectin deficient cell lines from these animals to use as recipients for transfections, thus ensuring that endogenous L-selectin expression is precluded. In addition, he intends to use the L-selectin deficient animals to study lymphocyte metastasis in an environment devoid of L-selectin expression. Transfectants expressing variants and domain deletants of L-selectin will be used in this system to delineate structural features of the molecule important for initiating the adhesion cascade or for other potential roles in the homing process. The investigators have also developed in vitro assays with which they can dynamically monitor the effects of alterations in homing receptor structure on adhesion interactions prior to using the in vivo model. The ability of specific reagents to inhibit this metastasis will be studied in both the in vitro and biological models.
| 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 |
