Identification of the putative intestinal stem cell marker doublecortin and CaM kinase‐like‐1 in Barrett's esophagus and esophageal adenocarcinoma

Abstract

Background In Barrett’s esophagus (BE), the normal esophageal squamous epithelium is replaced by specialized metaplastic columnar epithelium. BE is a premalignant lesion which can progress to esophageal adenocarcinoma (EAC). Currently there are no early molecular indicators that would predict progression from BE to EAC. As the only permanent residents of the epithelium, stem cells have been implicated in this metaplastic progression. Aim To determine the expression of DCAMKL-1 and other putative gastrointestinal stem cell markers in normal esophageal mucosa (NEM), BE and EAC. Methods Human NEM, BE, EAC and multi-tissue microarrays were analyzed for DCAMKL-1 and immunohistochemically scored based on staining intensity and tissue involvement, with epithelia and stroma scored separately. Total RNA isolated from BE and paired NEM was subjected to real-time RT-PCR analysis for DCAMKL-1, LGR5 and Musashi-1 mRNA expression. Results DCAMKL-1 is minimally expressed in squamous NEM, but increased in BE (with and without dysplasia) and EAC tissues. In EAC, we found increased stromal DCAMKL-1 staining compared to adjacent epithelia. Within the sub-mucosa of dysplastic BE tissues, an increase in endothelial cell expression of DCAMKL-1 was observed. Finally, an upregulation of DCAMKL-1, LGR5 and Musashi-1 mRNA was seen in BE compared to squamous NEM. Conclusions Here we report progressive increase of DCAMKL-1 expression in BE from dysplasia to EAC. Furthermore, there was an increase in putative stem cell markers DCAMKL-1, LGR5 and Msi-1 mRNA. These data taken together suggest that regulation of resident stem cells may play an important role in progression of BE to EAC.

Long-lived intestinal tuft cells serve as colon cancer–initiating cells

“…Upon isolation, intestinal DCLK1 + cells formed primitive epithelial spheres (24). Moreover, DCLK1 + tuft cells are substantially increased in a number of models of inflammation-induced carcinogenesis, arguing for a possible role in malignant transformation (26)(27)(28). Recently, Nakanishi and colleagues described the generation of a Dclk1-CreERT 2 knockin mouse that allowed formal lineage tracing.…”

Expression of doublecortin and CaM kinase‑like‑1 protein in serrated neoplasia of the colorectum

“…Previous reports have suggested that DCLK1 may mark cancer stem cells in gastrointestinal and other cancers (10,24), while others have identified DCLK1 upregulation in several types of cancer, including esophageal, stomach, colorectal, pancreatic and liver cancer (8,(13)(14)(15)(16)(17)(18). In addition, increased DCLK1 expression has been identified in Barrett's esophagus, a premalignant lesion that can progress to esophageal adenocarcinoma, and may be regarded as an early molecular predictor of tumor progression (18). Although DCLK1 has been demonstrated to be upregulated in human colorectal adenoma and cancer (13), studies on the expression of DCLK1 in serrated tumor tissue are lacking.…”

“…Although the precise tumor-promoting mechanism of DCLK1 is yet to be determined, it has been demonstrated that reduced DCLK1 expression correlates with increased expression of tumor suppressor microRNAs (miRs), including miR-145, miR-200 and let-7a (11,12). Indeed, DCLK1 has been indicated to function as an oncogene in several types of tumor, including CRC (13)(14)(15), pancreatic cancer (8), hepatocellular carcinoma (16), gastric cancer (17) and Barrett's adenocarcinoma (18).…”

Barrett esophagus

“…72 In our L2-IL-1b mouse model and in human BE, we found an accumulation of Dclk1+ cells, and this was confirmed in a study by another group, which reported a progressive increase of Dclk1 expression in BE from dysplasia to EAC. 73 Dclk1+ cells are highly abundant in the gastric cardia, particularly in areas immediately adjacent to the SCJ. segment can be clonally derived, with rapid spread of mutations through the epithelium.…”