Abstract
Aims Tumour buds in colorectal cancer represent an aggressive subgroup of non‐proliferating and non‐apoptotic tumour cells. We hypothesize that the survival of tumour buds is dependent upon anoikis resistance. The role of tyrosine kinase receptor B (TrkB), a promoter of epithelial–mesenchymal transition and anoikis resistance, in facilitating budding was investigated.
Methods and results Tyrosine kinase receptor B immunohistochemistry was performed on a multiple‐punch tissue microarray of 211 colorectal cancer resections. Membranous/cytoplasmic and nuclear expression was evaluated in tumour and buds. Tumour budding was assessed on corresponding whole tissue slides. Relationship to Ki‐67 and caspase‐3 was investigated. Analysis of Kirsten Ras (KRAS), proto‐oncogene B‐RAF (BRAF) and cytosine–phosphate–guanosine island methylator phenotype (CIMP) was performed. Membranous/cytoplasmic and nuclear TrkB were strongly, inversely correlated (P < 0.0001; r = −0.41). Membranous/cytoplasmic TrkB was overexpressed in buds compared to the main tumour body (P < 0.0001), associated with larger tumours (P = 0.0236), high‐grade budding (P = 0.0011) and KRAS mutation (P = 0.0008). Nuclear TrkB was absent in buds (P <0.0001) and in high‐grade budding cancers (P =0.0073). Among patients with membranous/cytoplasmic TrkB‐positive buds, high tumour membranous/cytoplasmic TrkB expression was a significant, independent adverse prognostic factor [P = 0.033; 1.79, 95% confidence interval (CI) 1.05–3.05]. Inverse correlations between membranous/cytoplasmic TrkB and Ki‐67 (r = −0.41; P < 0.0001) and caspase‐3 (r =−0.19; P < 0.05) were observed.
Conclusions Membranous/cytoplasmic TrkB may promote an epithelial–mesenchymal transition (EMT)‐like phenotype with high‐grade budding and maintain viability of buds themselves.
Dawson, Heather