EXPRESSION AND SHEDDING OF ICAM-1 IN BLADDER-CANCER AND ITS IMMUNOTHERAPY

Intercellular adhesion molecule-1 (ICAM-1) is one of 3 major ligands for the beta2 integrin leucocyte function-associated antigen-1 (LFA-1). Several reports have emerged describing soluble forms of ICAM-1 in association with normal and pathological states (eg., malignancy). In this study we have identified the secretion of soluble ICAM-1 in tissue culture supernatants from bladder tumour monolayers and in the urine of patients receiving intravesical BCG immunotherapy for superficial bladder cancer. In vitro, small amounts of sICAM-1 were detected in the tissue culture supernatants of bladder cancer cells, known to constitutively express ICAM- 1. Following stimulation with interferon gamma, the levels of sICAM-1 increased inversely to the levels of cell surface ICAM-1, suggesting shedding. Induction and augmentation of cell surface ICAM-1 required de novo mRNA and protein synthesis. However, treatment with cycloheximide, after stimulation with IFN-gamma, resulted in increased levels of membrane associated ICAM-1. Correspondingly, the level of sICAM-1 in the supernatant was low in comparison with controls, suggesting that cycloheximide acted via stabilization of membrane ICAM-1 or via prevention of some enzymatic cleavage event. In vivo, sICAM-1 can be detected at high levels in patients' urine following immunotherapy of bladder cancer with intravesically administered BCG organisms. Production of sICAM-1 is transient and occurs only in the first 12 hr following instillation. Furthermore, production of sICAM-1 is heterogeneous as some patients fail to produce any at all. If the source of sICAM-1 is the bladder tumour per se, then its detection in urine could indicate a response of the tumour to immunotherapy and indeed may prove a useful indicator of clinical response. (C) 1993 Wiley-Liss, Inc.