ER stress and the unfolded protein response in gastrointestinal stem cells and carcinogenesis

Endoplasmic reticulum (ER) stress and the adaptive response that follows, termed the unfolded protein response (UPR), are crucial molecular mechanisms to maintain cellular integrity by safeguarding proper protein synthesis. Next to being important in protein homeostasis, the UPR is intricate in cell fate decisions such as proliferation, differentiation, and stemness. In the intestine, stem cells are critical in governing epithelial homeostasis and they are the cell of origin of gastrointestinal malignancies. In this review, we will discuss the role of ER stress and the UPR in the gastrointestinal tract, focusing on stem cells and carcinogenesis. Insights in mechanisms that connect ER stress and UPR with stemness and carcinogenesis may broaden our understanding in the development of cancer throughout the gastrointestinal tract and how we can exploit these mechanisms to target these malignancies. •In the gastrointestinal tract, UPR signaling is intricately involved in stem cell fate decisions.•The UPR is a critical tenet for cellular physiology and plays an important role in colorectal tumorigenesis.•Understanding the interplay between carcinogenesis and the UPR is used to identify novel cancer treatment.