Robust expressions of stem cell markers, including leucine-rich repeat-containing G protein- coupled receptor 5, in association with early embryonic expression patterns of niche factors in untreated and chemoradiation-treated rectal cancer

Abstract

Abstract Purpose This study aimed to ascertain the involvement of cancer stem cells (CSCs) in therapy resistance by estimating CSC markers, niche factors, and WNT/β-catenin-relating molecules in untreated and chemoradiation-treated (CRT) rectal cancer. Methods Expression ratios of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR), proto-oncogene and polycomb ring finger 1 (BMI1), yes-associated transcriptional regulator (YAP) and its paralog TAZ (hereafter; YAP/TAZ), and nuclear β-catenin were compared in untreated and CRT rectal cancer using in situ hybridization and immunostainings. Niche factors and WNT/β-catenin-relating molecules were also immunohistochemically compared in human rectal cancer specimens and with early embryonic intestine. Results The mean ratios were 15% and 14% in LGR5; 30% and 33% in BMI1; 2.7% and 7.6% in YAP/TAZ; 38% and 32% in nuclear β-catenin in untreated and CRT rectal cancer, respectively, suggesting their robust expressions after CRT. LGR5 and nuclear β-catenin expression was significantly correlated in the CRT cohort. High mobility group AT-hook 1, but not c-MYC and SRY-box transcription factor 9, was significantly upregulated in CRT tumors. WNT2B and GREM1 were uniformly expressed with similarity to the pattern of early embryonic intestine, whereas WNT3A and HES1 expressions were limited. Additionally, stromal GLI1 and YAP/TAZ were more expressed in the CRT cohort. Conclusions Stem cell markers of LGR5 and BMI1 as well as nuclear YAP/TAZ, a marker of stem cell regeneration, were robustly expressed in untreated and CRT rectal cancer. WNT2B and GREM1 were aberrantly and uniformly expressed in untreated and CRT rectal cancer with similarity to the early embryonic expression pattern.