PMID- 35939229
OWN - NLM
STAT- MEDLINE
DCOM- 20221007
LR  - 20221011
IS  - 1573-2584 (Electronic)
IS  - 0301-1623 (Linking)
VI  - 54
IP  - 11
DP  - 2022 Nov
TI  - Castration immunoregulates toll-like receptor-4 in male bladder cancer.
PG  - 2845-2853
LID - 10.1007/s11255-022-03336-9 [doi]
AB  - PURPOSE: Among diverse Pattern Recognition Receptors (PRRs), Toll-like receptor-4 
      (TLR-4) is a key urothelial trigger for innate immune response impacting 
      urothelial bladder carcinoma (BC). Androgen activation promotes immunotolerance, 
      playing an immunoregulatory role by unknown mechanisms. We explored the 
      castration impact on urothelial TLR-4 modulation in carcinogenesis and 
      immunotherapeutic scenario. METHODS: Intact (SHAM) versus castrated male 
      Fisher-344 rats were evaluated in 2 scenarios: (A) Carcinogenesis: After 
      randomization to SHAM (n = 5) and Castration (n = 5), carcinogenesis was induced 
      by four intravesical doses of 1.5 mg/kg n-methyl-n-nitrosourea (MNU) every 
      15 days. (B) Treatment: After ultrasonographic confirmed MNU-induced papillary BC 
      on week 8, rats were randomized to SHAM (n = 5) and Castration (n = 5) and 
      offered 6 weekly intravesical treatment of 10(6) CFU of bacillus Calmette Guerin 
      (BCG) in 0.2 ml saline. After 15 weeks the urinary bladders underwent 
      histopathology. Urothelial cell proliferation was measured by Ki-67 
      immunohistochemistry (IHC), and TLR-4 expression was quantified by IHC and WB. 
      RESULTS: Castration induced higher TLR-4 urothelial expression (p = 0.007) and 
      anticarcinogenic effect with fewer urothelial tumors (60 vs. 80%) and lower 
      urothelial cell proliferation compared to intact animals (p = 0.008). In the 
      intravesical BCG treatment setting, castration has potentialized the BCG 
      activation of TLR-4 (p = 0.007) with no residual in situ carcinoma compared to 
      intact animals, suggesting the potential to amplify the BCG immune response. 
      CONCLUSION: To our knowledge, this is the first description of TLR-4 urothelial 
      expression hormonal modulation. The described castration-mediated 
      immunomodulation will help to improve the knowledge of urothelial cancer gender 
      diversities and PRRs modulations with treatment implications.
CI  - (c) 2022. The Author(s), under exclusive licence to Springer Nature B.V.
FAU - Reis, Leonardo Oliveira
AU  - Reis LO
AUID- ORCID: 0000-0003-2092-414X
AD  - UroScience, School of Medical Sciences, State University of Campinas, UNICAMP, 
      Campinas, SP, Brazil. reisleo.l@gmail.com.
AD  - Pontifical Catholic University of Campinas, PUC-Campinas, Sao Paulo, Brazil. 
      reisleo.l@gmail.com.
FAU - Salustiano, Ana Clara Ciglioni
AU  - Salustiano ACC
AD  - UroScience, School of Medical Sciences, State University of Campinas, UNICAMP, 
      Campinas, SP, Brazil.
FAU - Capibaribe, Diego Moreira
AU  - Capibaribe DM
AD  - UroScience, School of Medical Sciences, State University of Campinas, UNICAMP, 
      Campinas, SP, Brazil.
FAU - Kiehl, Isis Gallani Avansini
AU  - Kiehl IGA
AD  - UroScience, School of Medical Sciences, State University of Campinas, UNICAMP, 
      Campinas, SP, Brazil.
FAU - Denardi, Fernandes
AU  - Denardi F
AD  - UroScience, School of Medical Sciences, State University of Campinas, UNICAMP, 
      Campinas, SP, Brazil.
LA  - eng
GR  - 304747/2018-1/Instituto Nacional de Ciencia e Tecnologia em Nanomateriais de 
      Carbono/
PT  - Journal Article
PT  - Randomized Controlled Trial, Veterinary
DEP - 20220808
PL  - Netherlands
TA  - Int Urol Nephrol
JT  - International urology and nephrology
JID - 0262521
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Androgens)
RN  - 0 (Anticarcinogenic Agents)
RN  - 0 (BCG Vaccine)
RN  - 0 (Ki-67 Antigen)
RN  - 0 (Toll-Like Receptor 4)
RN  - 684-93-5 (Methylnitrosourea)
SB  - IM
MH  - Adjuvants, Immunologic
MH  - Administration, Intravesical
MH  - Androgens
MH  - Animals
MH  - Anticarcinogenic Agents
MH  - BCG Vaccine/therapeutic use
MH  - Carcinogenesis/chemically induced
MH  - Carcinoma, Transitional Cell/pathology
MH  - *Castration
MH  - Ki-67 Antigen
MH  - Male
MH  - Methylnitrosourea/toxicity
MH  - Rats
MH  - Toll-Like Receptor 4
MH  - *Urinary Bladder Neoplasms/pathology
OTO - NOTNLM
OT  - Bacillus Calmette-Guerin
OT  - Castration
OT  - DAMP-Damage-Associated Molecular Patterns
OT  - Immunomodulation
OT  - Male
OT  - PRR
OT  - Pattern Recognition Receptors
OT  - Toll-like receptor
OT  - Urothelial carcinoma
EDAT- 2022/08/09 06:00
MHDA- 2022/10/12 06:00
CRDT- 2022/08/08 11:20
PHST- 2022/04/07 00:00 [received]
PHST- 2022/07/30 00:00 [accepted]
PHST- 2022/08/09 06:00 [pubmed]
PHST- 2022/10/12 06:00 [medline]
PHST- 2022/08/08 11:20 [entrez]
AID - 10.1007/s11255-022-03336-9 [pii]
AID - 10.1007/s11255-022-03336-9 [doi]
PST - ppublish
SO  - Int Urol Nephrol. 2022 Nov;54(11):2845-2853. doi: 10.1007/s11255-022-03336-9. 
      Epub 2022 Aug 8.