Expression of receptors tyrosine kinase c-kit and EGF-R in colorectal adenocarcinomas: is there a relationship with epithelial–mesenchymal transition during tumor progression?

Abstract

To the Editor:We read with great interest the contribution by Friederichsand colleagues regarding immunohistochemical detectionof the receptor tyrosine kinases c-kit, EGF-R, and PDGF-Rin colorectal adenocarcinomas [1]. The authors showedEGF-R expression in only 15.3% of cases; emphasized thatactivity of tyrosine kinase inhibitors does not necessarilycorrelate with the tyrosine kinase expression of the tumors;showed that there is no correlation between EGF-R incolorectal cancer, clinical response to anti-EGF-R anti-bodies, and outcome; and that pretreatment selection ofpatients cannot be based on immunohistochemical expres-sion of EGF-R.EGF has recently been identified as a novel inducer ofepithelial–mesenchymal transition (EMT) in human breastcancer [2]. EMT is a process of plasticity by whichepithelial cells lose contact with adjacent cells andbasement membranes, switch patterns of extracellularmatrix protein and intermediate filament expression, andtransdifferentiate into mesenchymal cells. EMT duringtumor progression allows tumor cells to infiltrate surround-ing tissue and to metastatize to distant sites. A key event inEMT is reduction of cell–cell adhesion by transcriptionalrepression of E-cadherin. Loss of E-cadherin expression hasbeen reported in several cancers, including advancedcolorectal carcinomas. EMT hallmarks include reductionof E-cadherin with concomitant production of N-cadherinand acquisition of mesenchymal markers such as vimentinand fibronectin [3, 4]. EMT may influence the response ofcertain tumors to EGF-R-targeted therapies. In nonsmallcell lung cancer cell lines, sensitivity to an EGF-R-targetedmonoclonal antibody (erlotinib) did not correlate with EGF-R levels, but was dependent on EMT status: non-responding nonsmall cell lung carcinomas showed lowlevels of E-cadherin and higher levels of mesenchymalmarkers [5, 6].In the study by Friederichs et al., positive EGF-Rstaining did not show significant correlation with patho-logical parameters, but higher expression of EGF-R inadvanced and metastatic stages in colorectal adenocarcino-mas was reported in other studies.Friederichs et al. concluded that c-kit expression is rarein colorectal carcinomas, and because of the small numberof cases, it is uncertain if c-kit-positive carcinomasrepresent a specific entity or in which way these carcinomasdiffer. The authors suggested that in colorectal cancerwithout c-kit kinase activation, treatment with recentlydeveloped and less selective tyrosine kinase inhibitors mayresult in inhibition of alternative or related tyrosine kinase