Abstract
Clinical data indicates that T cells can be recruited to bladder cancer (BCa), yet the impact of T cells on BCa progression remains unclear. In the present study, we found that T cells were recruited more to BCa tissues than to the surrounding normal bladder tissues. Results from an in vitro co-culture system also found that BCa recruited more CD4+ T cells than did normal bladder cells. The recruiting of T cells to BCa tissues may increase the proliferation and invasion of BCa cells. Mechanistic studies revealed that infiltrating T cells stimulate BCa estrogen receptor beta (ERβ) signaling and consequently increase the expression of MET proto-oncogene, receptor tyrosine kinase (c-MET), through either direct binding to its promoter or via modulation of IL-1 expression. Interruption of ERβ/c-MET or ERβ/IL-1/c-MET signaling via ERβ-shRNA, IL-1 antagonist, or the c-MET inhibitor, SU11274, could partially reverse the T cell-enhanced BCa cell invasion and proliferation. Finally, the mouse BCa model with xenografted BCa 5637 cells with T (HH) cells confirmed the results of in vitro co-culture studies showing that infiltrating T cells could promote BCa metastasis via modulation of the ERβ/c-MET or ERβ/IL-1/c-MET signaling pathways. These findings may provide a new therapeutic approach to better combat BCa progression via targeting these newly identified signaling pathways.
Keywords:
Bladder cancer; Estrogen receptor; Tumor microenvironment; c-MET.
Copyright © 2018 Elsevier B.V. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / metabolism*
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Cystectomy
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Disease Progression
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Estrogen Receptor beta / antagonists & inhibitors
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Estrogen Receptor beta / metabolism*
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics
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Humans
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Indoles / pharmacology
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Interleukin-1 / antagonists & inhibitors
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Interleukin-1 / metabolism*
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Male
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Mice
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Mice, Nude
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Neoplasm Invasiveness / pathology
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Neoplasm Invasiveness / prevention & control
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Piperazines / pharmacology
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Mas
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Proto-Oncogene Proteins c-met / antagonists & inhibitors
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Proto-Oncogene Proteins c-met / genetics*
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Proto-Oncogene Proteins c-met / metabolism
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Pyrazoles / pharmacology
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Pyrimidines / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Sulfonamides / pharmacology
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Up-Regulation / drug effects
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Urinary Bladder / cytology
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Urinary Bladder / pathology
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Urinary Bladder / surgery
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Urinary Bladder Neoplasms / pathology*
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Urinary Bladder Neoplasms / surgery
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Xenograft Model Antitumor Assays
Substances
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((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide)
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4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol
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ESR2 protein, human
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Estrogen Receptor beta
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Indoles
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Interleukin-1
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MAS1 protein, human
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Piperazines
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Proto-Oncogene Mas
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Pyrazoles
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Pyrimidines
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Sulfonamides
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MET protein, human
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Proto-Oncogene Proteins c-met