Journal
CANCER LETTERS
Volume 430, Issue -, Pages 215-223Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2018.03.045
Keywords
Bladder cancer; Estrogen receptor; c-MET; Tumor microenvironment
Categories
Funding
- University of Rochester CTSI [UL1 TR000042]
- National Natural Science Foundation of China [81702502]
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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 (ER beta) 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 ER beta/c-MET or ER beta/IL-1/c-MET signaling via ER beta-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 ER beta/c-MET or ER beta/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. (C) 2018 Elsevier B.V. All rights reserved.
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