Clone wars: From molecules to cell competition in intestinal stem cell homeostasis and disease

Abstract

Cancer: Tumors gain competitive edge over intestinal stem cells Stem cells in the gut rapidly renew themselves through processes that cancer cells co-opt to trigger tumor development. Gabriele Colozza from the Institute of Molecular Biotechnology in Vienna, Austria, and colleagues review how a network of critical molecular signals and competition for limited space help to regulate the dynamics of stem cells in the intestines. The correct balance between self-renewal and differentiation is tightly controlled by the so-called Wnt signaling pathway and its inhibitors. Competition between dividing cells in the intestinal crypts, the locations between finger-like protrusions in the gut where stem cells are found, provides another protective mechanism against runaway stem cell growth. However, intestinal cancer cells, thanks to their activating mutations, bypass these safeguards to gain a survival advantage. Drugs that target these 'super-competitive' behaviors could therefore help combat tumor proliferation. The small intestine is among the fastest self-renewing tissues in adult mammals. This rapid turnover is fueled by the intestinal stem cells residing in the intestinal crypt. Wnt signaling plays a pivotal role in regulating intestinal stem cell renewal and differentiation, and the dysregulation of this pathway leads to cancer formation. Several studies demonstrate that intestinal stem cells follow neutral drift dynamics, as they divide symmetrically to generate other equipotent stem cells. Competition for niche space and extrinsic signals in the intestinal crypt is the governing mechanism that regulates stemness versus cell differentiation, but the underlying molecular mechanisms are still poorly understood, and it is not yet clear how this process changes during disease. In this review, we highlight the mechanisms that regulate stem cell homeostasis in the small intestine, focusing on Wnt signaling and its regulation by RNF43 and ZNRF3, key inhibitors of the Wnt pathway. Furthermore, we summarize the evidence supporting the current model of intestinal stem cell regulation, highlighting the principles of neutral drift at the basis of intestinal stem cell homeostasis. Finally, we discuss recent studies showing how cancer cells bypass this mechanism to gain a competitive advantage against neighboring normal cells.