Abstract
Recent studies showed the potential linkage of estrogen/estrogen receptor signaling with bladder tumorigenesis, yet detailed mechanisms remain elusive. Here we found a new potential therapy with the combination of Bacillus Calmette-Guerin (BCG) and the anti-estrogen ICI 182,780 led to better suppression of bladder cancer (BCa) than BCG alone. Mechanism dissection found ICI 182,780 could promote BCG attachment/internalization to the BCa cells through increased integrin-α5β1 expression and IL-6 release, which may enhance BCG-induced suppression of BCa cell growth via recruiting more monocytes/macrophages to BCa cells and increased TNF-α release. Consistently, in vivo studies found ICI 182,780 could potentiate the anti-BCa effects of BCG in the carcinogen-induced mouse BCa models. Together, these in vitro and in vivo results suggest that combining BCG with anti-estrogen may become a new therapeutic approach with better efficacy to suppress BCa progression and recurrence.
Keywords:
Bacillus Calmette-Guérin; bladder cancer; estrogen; estrogen receptor alpha.
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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BCG Vaccine / administration & dosage
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BCG Vaccine / therapeutic use*
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Butylhydroxybutylnitrosamine
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Movement / genetics
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Drug Synergism
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Estradiol / administration & dosage
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Estradiol / analogs & derivatives*
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Estradiol / therapeutic use
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Estrogen Receptor Antagonists / administration & dosage
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Estrogen Receptor Antagonists / therapeutic use
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Estrogen Receptor alpha / antagonists & inhibitors*
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Estrogen Receptor alpha / metabolism
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Female
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Fulvestrant
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Humans
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Integrin alpha5beta1 / genetics
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Integrin alpha5beta1 / metabolism
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Macrophages / drug effects
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Macrophages / metabolism
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Mice
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Neoplasms, Experimental / chemically induced
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / metabolism
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Treatment Outcome
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Tumor Necrosis Factor-alpha / metabolism
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Urinary Bladder Neoplasms / drug therapy*
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Urinary Bladder Neoplasms / genetics
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Urinary Bladder Neoplasms / metabolism
Substances
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BCG Vaccine
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Estrogen Receptor Antagonists
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Estrogen Receptor alpha
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Integrin alpha5beta1
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Interleukin-6
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Tumor Necrosis Factor-alpha
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Fulvestrant
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Butylhydroxybutylnitrosamine
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Estradiol