Tyrosine kinase receptor B (TrkB) expression in colorectal cancers highlights anoikis resistance as a survival mechanism of tumour budding cells.
OBJECTIVE
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.


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.
Department of Clinical Pathology, Institute of Pathology, University of Bern, Bern, Switzerland; Translational Research Unit, Institute of Pathology, University of Bern, Bern, Switzerland.
Heather
H
Dawson
Sandra
S
Grundmann
Viktor H
VH
Koelzer
José A
JA
Galván
Richard
R
Kirsch
Eva
E
Karamitopoulou
Alessandro
A
Lugli
Daniel
D
Inderbitzin
Inti
I
Zlobec
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D023102:Anoikis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D020813:Receptor, trkB; D012189:Retrospective Studies; D046888:Tissue Array Analysis; D018631:ras Proteins / Q000378:metabolism
C117307:KRAS protein, human; D019394:Ki-67 Antigen; C000715470:MAS1 protein, human; D008562:Membrane Glycoproteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human; D053148:Caspase 3; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
anoikis; colorectal cancer; epithelial-mesenchymal transition; tumour budding; tyrosine kinase receptor B