Intestinal stem cell injury and protection during cancer therapy

Abstract

Radiation and chemotherapy remain the most effective and widely used cancer treatments. These treatments cause DNA damage and selectively target rapidly proliferating cells such as cancer cells, as well as inevitably cause damage to normal tissues, particularly those undergoing rapid self renewal. The side effects associated with radiation and chemotherapy are most pronounced in the hematopoietic (HP) system and gastrointestinal (GI) tract. These tissues are fast renewing and have a well-defined stem cell compartment that plays an essential role in homeostasis, and in treatment-induced acute injury that is dose limiting. Using recently defined intestinal stem cell markers and mouse models, a great deal of insight has been gained in the biology of intestinal stem cells (ISCs), which will undoubtedly help further mechanistic understanding of their injury. This review will cover historic discoveries and recent advances in the identification and characterization of intestinal stem cells, their responses to genotoxic stress, and a new crypt and intestinal stem cell culture system. The discussion will include key pathways regulating intestinal crypt and stem cell injury and regeneration caused by cancer treatments, and strategies for their protection. The focus will be on the acute phase of cell killing in mouse radiation models, where our understanding of the mechanisms in relation to intestinal stem cells is most advanced and interventions appear most effective.

Keywords: DNA repair; Radiation; apoptosis; chemotherapy; intestinal stem cells (ISCs).

Figure 1

Radiation-induced ISC responses. High dose radiation induces rapid apoptosis in the CBCs (green) and TA (yellow) cells, which triggers activation of quiescent ISCs and progenitors (purple and enlarged after IR) for crypt regeneration. The CBCs and some other cells express Lgr5. Fully recovered crypts generally resume the CBC/Paneth cell (pink) pattern.

Figure 2

Exploring the p53 and NF-κB pathways for ISC protection. Radiation activates the p53 and NF-κB pathways in ISCs. p53-dependent PUMA induction leads to rapid apoptosis of ISCs, while p53-dependent p21 induction suppresses genome instability and mitotic death via DNA repair. Blocking apoptosis, inducing quiescence or NF-κB activation transiently improves ISC survival and regeneration. A potential cross talk between these two pathways for ISC protection is worth exploring. Promising agents in development include growth factors, small molecule inhibitors of GSK (GSKi), PUMA (PUMAi), CDK (CDKi) and TLR agonists.