Cross Talks Among Notch, Wnt, and Hedgehog Signaling Pathways Regulate Stem Cell Characteristics

Abstract

The use of stem cells as medicines is a promising area of research as they may help the body to replace damaged or lost tissue in a host of diseases including cancer. The integration of intrinsic and extrinsic signals is required to preserve the self-renewal and tissue regenerative capacity of adult stem cells, while protecting them from malignant conversion or loss of proliferative potential by death, differentiation or senescence. It is now clear that malignant tumors are heterogeneous and contain diverse subpopulations of cells with unique characteristics including the ability to initiate a tumor and metastasize. This phenomenon might be explained by the so-called cancer stem cell (CSC) theory. Recent technological developments have allowed a deeper understanding and characterization of CSCs. The CSCs share some of the common signaling pathways of self-renewal with that of normal stem cells or progenitor cells. Signaling pathways such as Notch, Sonic hedgehog and Wnt play major roles in stem cell self-renewal and metastasis. These pathways cross-talk and allow stem cells to balance their regenerative potential and the initiation of terminal differentiation programs, ensuring appropriate tissue homeostasis. Understanding the signaling circuitries regulating stem cell fate decisions might provide insights into cancer initiation and progression that involve the progressive loss of tissue-specific adult stem cells. Efficacious therapeutic approaches targeting the CSC population should be explored to overcome therapeutic failure and improve patient outcomes. This review will focus on the signaling pathways required for regulation of CSCs, and development of therapeutic approaches to target specifically CSCs.