COST Action CA17118 TRANSCOLONCAN Torino Meeting, 7 - 09 March 2022, pp.27
Evaluation of AKR1B1 expression in the CRC tumor microenvironment
AKR1B1 is a member of the aldo-keto reductase family of enzymes that participate in the polyol pathway of aldehyde metabolism and is aberrantly expressed in colon cancer. We previously showed that high expression of AKR1B1 was associated with enhanced motility, inflammation and poor clinical outcome in colon cancer patients (1,2). As the expression of this gene is also strongly and positively correlated with mesenchymal marker expression and a high AKR1B1 expression is associated with a CMS4 (consensus molecular subtypes) subtype which is rich in stroma (2), in this study, we aimed to explore the specific cell types that express AKR1B1 in the tumor microenvironment, and evaluate whether the expression of AKR1B1 in the tumor microenvironment contributes towards the prognostic predictions observed. Bioinformatic analyses of publically available transcriptomic data of colon tumors showed that the expression of AKR1B1 was significantly higher in the stromal compartment compared to the epithelial compartment of CRC tumor tissues. Utilizing ESTIMATE, that enables assessment of immune/stromal cell fractions of tumors based on transcriptomic data, we showed that AKR1B1 was positively correlated with both immune and stromal fractions (r>0.50, p<0.001). To specify immune cell types that were more likely to express AKR1B1, we used CIBERSORT algorithm that enables assessment of 22 distinct immune cell type fractions. Our results showed that tumors with higher macrophage fractions had higher AKR1B1 expression. As the prognostic relationship of AKR1B1 was dramatically different when tumors were stratified based on stromal and immune cell fractions in silico, we overall conclude that AKR1B1 is expressed by cells in the tumor microenvironment and this may majorly contribute towards its prognostic role.
Keywords: Colorectal Cancer (CRC), Aldo-keto reductases, AKR1B1, stroma, tumor microenvironment
1. Taskoparan B, Seza EG, Demirkol S, Tuncer S, Stefek M, Gure AO, Banerjee S. Opposing roles of the aldo-keto reductases AKR1B1 and AKR1B10 in colorectal cancer. Cell Oncol (Dordr). 2017 Dec;40(6):563-578. doi: 10.1007/s13402-017-0351-7.
2. Demirkol Canli S, Seza EG, Sheraj I, Gomceli I, Turhan N, Carberry S, Prehn JHM, Gure AO, Banerjee
S: Evaluation of an aldo-keto reductase gene signature with prognostic significance in colon cancer via
activation of epithelial to mesenchymal transition and the p70S6K pathway. Carcinogenesis 2020. Sep
24;41(9):1219-1228. doi: 10.1093/carcin/bgaa072.