UC San Diego

Hematogenous metastasis is the passage of malignant cells from a primary solid tumor into the vasculature, where they interact with leukocytes and platelets before their extravasation into a distant tissue, forming metastatic foci. This dissertation focuses on two proteins known to be involved in this process, P-selectin and L-selectin. P- selectin is expressed on activated platelets and endothelium, whereas L-selectin is constitutively expressed on most leukocytes. The role of P-selectin in metastasis has been previously studied. P-selectin mediates platelet interactions with tumor cells, potentially shielding them from immune cell surveillance in the vasculature. The role of L-selectin in metastasis was not previously known. Chapter II of this dissertation describes the findings that L-selectin affects tumor cell survival in the vasculature, and that there is a temporal appearance of putative endothelial, Fucosyltransferase-7- dependent ligands that appear in the lungs following tumor cell injection. Work shown in Appendix I supports this supposition, as it demonstrates that leukocyte selectin ligands are not involved in experimental metastasis. While many investigators are developing specific inhibitors of selectin-ligand binding, with the hope of attenuating metastasis, our lab had previously discovered that the clinical anticoagulant heparin also has the ability to inhibit P- and L-selectin. An independent body of work had indicated that heparin might block metastasis. However, most prior experimental evaluations of heparin and metastasis were done at very high doses that were not clinically-relevant, and not all currently available heparins had been tested for selectin inhibition. Chapter III details studies demonstrating that not all heparins can inhibit selectins in vitro, and that only those heparins with selectin-inhibitory activity are capable of inhibiting metastasis in vivo, at clinically-relevant doses. Additionally, it is shown that the higher molecular weight fragments of a heparin contain the bulk of the selectin-inhibitory activity. The roles of P- and L- selectin and their ligands in tumor progression are explored in this dissertation. Mechanistic studies of the exact role of L-selectin have been performed, and the clinical potential for inhibiting metastasis by inhibiting selectins is demonstrated. This knowledge can be used to further the treatment of not only metastasis, but other selectin-mediated pathologies as well