Brachyury identifies a class of enteroendocrine cells in normal human intestinal crypts and colorectal cancer

Abstract

Normal homeostasis of adult intestinal epithelium and repair following tissue damage is maintained by a balance of stem and differentiated cells, many of which are still only poorly characterised. Enteroendocrine cells of the gut are a small population of differentiated, secretory cells that are critical for integrating nutrient sensing with metabolic responses, dispersed amongst other epithelial cells. Recent evidence suggests that sub-sets of secretory enteroendocrine cells can act as reserve stem cells. Given the link between cells with stem-like properties and cancer, it is important that we identify factors that might provide a bridge between the two. Here, we identify a sub-set of chromogranin A-positive enteroendocrine cells that are positive for the developmental and cancer-associated transcription factor Brachyury in normal human small intestinal and colonic crypts. Whilst chromogranin A-positive enteroendocrine cells are also Brachyury-positive in colorectal tumours, expression of Brachyury becomes more diffuse in these samples, suggesting a more widespread function in cancer. The finding of the developmental transcription factor Brachyury in normal adult human intestinal crypts may extend the functional complexity of enteroendocrine cells and serves as a platform for assessment of the molecular processes of intestinal homeostasis that underpins our understanding of human health, cancer and aging.

Aging effects on intestinal homeostasis associated with expansion and dysfunction of intestinal epithelial stem cells

“…The Sox9-EGFP mouse model offers the opportunity to study and isolate progenitor cells (Sox9-EGFP Sublow ) and Sox9-EGFP High cells that contain EEC cells and an activatable reserve stem cell population [ 25 ]. A recent study suggested that subsets of secretory EEC cells can act as reserve stem cells in humans [ 45 ]. Interestingly, we observed an increased proportion of Sox9-EGFP High cells in S phase of the cell cycle in old mice, yet no expansion in cell number.…”

Brachyury oncogene is a prognostic factor in high‐risk testicular germ cell tumors

“…Importantly, in these tumors, Brachyury has been reported as an independent biomarker of poor prognosis (Kilic et al ., ; Haro et al ., ; Palena et al ., ; Pinto et al ., , ,b). Brachyury acts as a key player in the epithelial–mesenchymal transition (EMT) and metastasis formation (Fernando et al ., ; Imajyo et al ., ; Shimoda et al ., ; Du et al ., ; Palena et al ., ; Pinto et al ., ; Shao et al ., ; Xu et al ., ), also playing an important role in promoting stem cell properties (Sarkar et al ., ; Shimoda et al ., ; Jezkova et al ., ; Pinto et al ., ,b) and resistance to cytotoxic‐based therapy (Fernando et al ., ; Roselli et al ., ; Pinto et al ., ,b). Based on Brachyury oncogenic behavior, an anti‐Brachyury vaccine (GI‐6301) was developed and is currently in Phase II clinical trial (http://www.clinicaltrials.gov, 2015 – NCT02383498) for patients with chordoma (Heery et al ., ).…”

Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer

“…Post-developmentally, brachyury is expressed in the testes and some thyroid tissues, but is undetectable in all other non-neoplastic adult tissues (Edwards et al, 1996; Hamilton et al, 2015). Interestingly, recent studies have reported the expression of brachyury in several epithelial cancers where it promotes growth, confers resistance to chemo- and radiotherapy, and drives epithelial-to-mesenchymal transition (EMT) (Cho et al, 2010; Fernando et al, 2010; Haro et al, 2013; Huang et al, 2013; Imajyo et al, 2012; Jezkova et al, 2016; Kobayashi et al, 2014; Larocca et al, 2013; Li et al, 2016; Miettinen et al, 2015; Palena et al, 2014; Park et al, 2008; Pinto et al, 2015; Pinto et al, 2014; Pires and Aaronson, 2014; Roselli et al, 2012; Sarkar et al, 2012; Shao et al, 2015; Shimoda et al, 2012; Vujovic et al, 2006; Xu et al, 2015; Yoshihama et al, 2016); however, the mechanistic details of how brachyury mediates these features of tumor progression have not been fully elucidated. Furthermore, the lack of brachyury expression in most adult non-neoplastic tissues and exclusive tumor-specific expression underscores its value as a potential diagnostic and therapeutic target in cancer.…”