Abstract
BackgroundThe Discoidin Domain Receptor 1 (DDR1) is one of the two members of a unique family of receptor tyrosine kinase receptors that signal in response to collagen, which has been implicated in cancer progression. Here, we examined the expression of DDR1 in prostate cancer (PCa), and assessed its potential value as a prognostic marker, as a function of grade, stage and other clinicopathologic parameters.MethodsWe investigated the association between the expression level and subcellular localization of DDR1 protein and PCa aggressiveness by immunohistochemistry, using tissue microarrays (TMAs) encompassing 200 cases of PCa with various Gleason scores (GS) and pathologic stages with matched normal tissue, and a highly specific monoclonal antibody.ResultsDDR1 was found to be localized in the membrane, cytoplasm, and nuclear compartments of both normal and cancerous prostate epithelial cells. Analyses of DDR1 expression in low GS (≤ 7[3 + 4]) vs high GS (≥ 7[4 + 3]) tissues showed no differences in nuclear or cytoplasmic DDR1in either cancerous or adjacent normal tissue cores. However, relative to normal-matched tissue, the percentage of cases with higher membranous DDR1 expression was significantly lower in high vs. low GS cancers. Although nuclear localization of DDR1 was consistently detected in our tissue samples and also in cultured human PCa and normal prostate-derived cell lines, its presence in that site could not be associated with disease aggressiveness. No associations between DDR1 expression and overall survival or biochemical recurrence were found in this cohort of patients.ConclusionThe data obtained through multivariate logistic regression model analysis suggest that the level of membranous DDR1 expression status may represent a potential biomarker of utility for better determination of PCa aggressiveness.
Highlights
The Discoidin Domain Receptors (DDRs) belong to the family of receptor tyrosine kinases (RTKs) that signal in response to collagen, the major component of extracellular matrices
We evaluated the expression of Discoidin Domain Receptor 1 (DDR1) in various subcellular fractions in a cohort of prostate cancer (PCa) samples with tumor and adjacent normal epithelium that, to our knowledge, is the largest set of PCa specimens studied for this RTK up to date
DDR1 protein expression can be seen in the cell membrane of some benign glands (Fig. 3A, B), there is a trend towards enhanced membranous DDR1 expression in cancerous glands of lower Gleason scores (GS) cancers (Fig. 3C, D), which is less frequent in cancerous cells of higher GS tumors (Fig. 3E, F)
Summary
The Discoidin Domain Receptors (DDRs) belong to the family of receptor tyrosine kinases (RTKs) that signal in response to collagen, the major component of extracellular matrices. DDR1 is uniquely activated by collagen IV, and DDR1 can mediate the interactions of epithelial cells with the basement membrane. Another feature that sets the DDRs apart from other RTKs is their delayed and long-lasting phosphorylation upon binding to their ligands [2, 7]. The Discoidin Domain Receptor 1 (DDR1) is one of the two members of a unique family of receptor tyrosine kinase receptors that signal in response to collagen, which has been implicated in cancer progression. We examined the expression of DDR1 in prostate cancer (PCa), and assessed its potential value as a prognostic marker, as a function of grade, stage and other clinicopathologic parameters
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