AKR1B1 Expression in the Colorectal Tumor Microenvironment Contributes Towards Its Prognostic Significance

BackgroundAKR1B1, a member of the aldo-keto reductase enzyme family involved in the polyol pathway of aldehyde metabolism, is aberrantly expressed in colorectal cancer (CRC). Our previous studies demonstrated that AKR1B1 knockdown reduced the motility and proliferation of CRC cell lines, and its elevated expression was correlated with increased mesenchymal marker expression, inflammation, and poor prognosis in CRC patient cohorts. However, whether stromal cells also express AKR1B1 and whether stromal expression can affect clinical outcomes has not been examined.ObjectivesTo evaluate the expression of AKR1B1 within the tumor microenvironment (TME) of CRC, with a paticular focus on stromal cells, and to assess its association with clinical outcomes.MethodsWe assessed AKR1B1 expression in colorectal tumors utilizing publicly available transcriptomic data from CRC tumors. Single-cell RNA-sequencing data from CRC samples were analyzed to determine cell type-specific expression. Immunohistochemistry based assessment of AKR1B1 expression was performed in Turkish and Serbian cohorts. Co-localization of AKR1B1 and CD163 (M2 macrophage marker) was evaluated by immunoflourescence.ResultsAKR1B1 was expressed in both the epithelial and stromal components of colorectal tumors, with higher expression observed in the stroma. Single-cell transcriptomic analysis revealed AKR1B1 expression in myeloid cells, T and NK cells, B cells, dendritic cells, fibroblasts, and epithelial cells. Notably, AKR1B1-expressing macrophages were predominantly of the M2 phenotype, and AKR1B1 expression and M2 marker expression showed strong positive correlation in bulk transcriptomic data. Immunofluorescence confirmed the colocalization of CD163 and AKR1B1 in stromal macrophages. Moreover, immunohistochemical analysis of AKR1B1 expression in tumor stroma from a cohort of Turkish patients revealed that its expression was associated with favorable overall survival, particularly in tumors with higher stromal infiltration.ConclusionsOverall, our findings underscore the significant influence of the TME composition on the relationship between AKR1B1 expression and clinical outcomes.