Cancer Stem Cells (CSC) Responses and Toll-Like Receptors (TLRs) and p53 Signaling Pathway: Effects of Bacillus Calmette-Guerin (BCG) and P-MAPA Immunotherapies in Non-Muscle Invasive Bladder Cancer (NMIBC)
Wagner J Favaro, Athanase Billis, Fabio RF Seiva, Iseu S Nunes, Nelson Duran. University of Campinas (UNICAMP), Campinas, Sao Paulo, Brazil; Farmabrasilis, Campinas, Sao Paulo, Brazil; Universidade Federal do ABC, Santo Andre, Sao Paulo, Brazil
Background: The role of TLRs in cancer is a matter of debate because conflicting data argue for TLRs being negative or positive regulators of cancer. P-MAPA is an acronym for Protein Aggregate Magnesium-Ammonium Phospholinoleate-Palmitoleate Anhydride having significant in vivo antitumor. Thus, the aims of the hereby study were to characterize the effects of TLRs and p53 on CSCs in the NMIBC of rats submitted to BCG and P-MAPA, and to relate the distribution of these cells with P-MAPA and BCG immunotherapy.
Design: Forty female Fisher 344, 7 week old, rats were anesthetized and received 1.5 mg/kg dose of n-methyl-n-nitrosourea (MNU), intravesically every other week for 8 weeks. After MNU treatment, the 30 rats were divided into 3 groups: The MNU (Cancer) group received 0.30 ml dose of 0.9% physiological saline for 6 weeks; The P-MAPA group received 5mg/kg dose of P-MAPA intravesically for 6 weeks; The BCG group received 106 CFU dose of BCG for 6 weeks. After 16 weeks, all bladders were collected for immunological and Western Blotting analysis for CD44, CD133, CD117, ABCG2, p53, TLR 2 and 4.
Results: The p53 and TLRs 2 and 4 protein levels were significantly higher in the P-MAPA group and decreased in the BCG and MNU groups. CSCs were ABCG2/CD44/CD133+, which were more often in the MNU group and decreased in the BCG and P-MAPA groups. Also, normal urothelial stem cells (USCs) CD44/CD133/CD117/p53+ were increased in the P-MAPA group in relation to the other treatment groups.
Conclusions: The P-MAPA immunotherapy showed stimulatory effect on TLRs and p53 that correlated with the decreased of cancer state. Also, TLRs showed responses p53-mediated. The BCG and P-MAPA immunotherapies upregulated the occurrence of normal USCs and CSCs in the NMIBC. The CSCs were especially sensitive to decreased p53 and TLRs immunoreactivities. P-MAPA immunotherapy was more sensitive in restoring balance between normal USCs and CSCs. Finally, these results pointed out a common control mechanism for urothelial carcinogenesis, which involved TLRs and p53 signaling pathway and CSCs regulation.
Category: Genitourinary (including renal tumors)
Monday, March 4, 2013 1:00 PM
Poster Session II # 181, Monday Afternoon