TrkB-Targeted Therapy for Mucoepidermoid Carcinoma
Vivian P. Wagner,
Manoela D. Martins,
Esra Amoura,
Virgilio G. Zanella,
Rafael Roesler,
Caroline B. de Farias,
Colin D. Bingle,
Pablo A. Vargas,
Lynne Bingle
Affiliations
Vivian P. Wagner
Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba 13414-903, Brazil
Manoela D. Martins
Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba 13414-903, Brazil
Esra Amoura
Oral and Maxillofacial Pathology, Department of Clinical Dentistry, University of Sheffield, Sheffield S10 2TA, UK
Virgilio G. Zanella
Department of Pathology, School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre 90035-003, Brazil
Rafael Roesler
Cancer and Neurobiology Laboratory, Experimental Research Center, Porto Alegre Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre 90035-903, Brazil
Caroline B. de Farias
Cancer and Neurobiology Laboratory, Experimental Research Center, Porto Alegre Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre 90035-903, Brazil
Colin D. Bingle
Academic Unit of Respiratory Medicine, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2RX, UK
Pablo A. Vargas
Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba 13414-903, Brazil
Lynne Bingle
Oral and Maxillofacial Pathology, Department of Clinical Dentistry, University of Sheffield, Sheffield S10 2TA, UK
The brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (TrkB) pathway was previously associated with key oncogenic outcomes in a number of adenocarcinomas. The aim of our study was to determine the role of this pathway in mucoepidermoid carcinoma (MEC). Three MEC cell lines (UM-HMC-2, H253 and H292) were exposed to Cisplatin, the TrkB inhibitor, ANA-12 and a combination of these drugs. Ultrastructural changes were assessed through transmission electron microscopy; scratch and Transwell assays were used to assess migration and invasion; and a clonogenic assay and spheroid-forming assay allowed assessment of survival and percentage of cancer stem cells (CSC). Changes in cell ultrastructure demonstrated Cisplatin cytotoxicity, while the effects of ANA-12 were less pronounced. Both drugs, used individually and in combination, delayed MEC cell migration, invasion and survival. ANA-12 significantly reduced the number of CSC, but the Cisplatin effect was greater, almost eliminating this cell population in all MEC cell lines. Interestingly, the spheroid forming capacity recovered, following the combination therapy, as compared to Cisplatin alone. Our studies allowed us to conclude that the TrkB inhibition, efficiently impaired MEC cell migration, invasion and survival in vitro, however, the decrease in CSC number, following the combined treatment of ANA-12 and Cisplatin, was less than that seen with Cisplatin alone; this represents a limiting factor.
