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Expression and shedding of ICAM-1 in bladder cancer and its immunotherapy
A M Jackson1, A B Alexandrov, S C Gribben
1Department of Surgery (WGH), University of Edinburgh Medical School, UK.
Insights
Researchers found soluble intercellular adhesion molecule-1 (ICAM-1) in bladder cancer cell cultures and patient urine after BCG immunotherapy. This soluble ICAM-1 may indicate a tumor response to treatment.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Intercellular adhesion molecule-1 (ICAM-1) is a key ligand for leucocyte function-associated antigen-1 (LFA-1).
- Soluble forms of ICAM-1 (sICAM-1) have been observed in various physiological and pathological conditions, including malignancy.
Purpose of the Study:
- To investigate the secretion of sICAM-1 from bladder tumor cells in vitro.
- To determine the presence and dynamics of sICAM-1 in urine of patients undergoing intravesical BCG immunotherapy for superficial bladder cancer.
Main Methods:
- Cultured bladder tumor cells and measured sICAM-1 in supernatants.
- Stimulated cells with interferon-gamma (IFN-γ) and cycloheximide to assess ICAM-1 expression and shedding.
- Quantified urinary sICAM-1 levels in patients before and after BCG immunotherapy.
Main Results:
- sICAM-1 was detected in bladder cancer cell culture supernatants, increasing with IFN-γ stimulation and inversely correlating with cell surface ICAM-1.
- Cycloheximide treatment appeared to stabilize membrane ICAM-1, reducing sICAM-1 secretion.
- Elevated urinary sICAM-1 levels were observed transiently (within 12 hours) post-BCG immunotherapy, with heterogeneous patient responses.
Conclusions:
- Bladder tumor cells secrete sICAM-1, with shedding potentially regulated by cellular processes.
- Urinary sICAM-1 detection following BCG immunotherapy may originate from the bladder tumor.
- Urinary sICAM-1 could serve as a potential biomarker for monitoring therapeutic response in superficial bladder cancer.
Abstract:
Intercellular adhesion molecule-1 (ICAM-1) is one of 3 major ligands for the beta 2 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 (e.g., 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 sheeding. 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 installation. 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.