Drug discovery approaches to target Wnt signaling in cancer stem cells

Abstract

Cancer stem cells (CSCs) represent a unique subset of cells within a tumor that possess self-renewal capacity and pluripotency, and can drive tumor initiation and maintenance. First identified in hematological malignancies, CSCs are now thought to play an important role in a wide variety of solid tumors such as NSCLC, breast and colorectal cancer. The role of CSCs in driving tumor formation illustrates the dysregulation of differentiation in tumorigenesis. The Wnt, Notch and Hedgehog (HH) pathways are developmental pathways that are commonly activated in many types of cancer. While substantial progress has been made in developing therapeutics targeting Notch and HH, the Wnt pathway has remained an elusive therapeutic target. This review will focus on the clinical relevance of the Wnt pathway in CSCs and tumor cell biology, as well as points of therapeutic intervention and recent advances in targeting Wnt/β-catenin signaling.

Figure 1. Cancer stem cell properties and therapeutic resistance

An illustration of a solid tumor depicts the cellular milieu, comprised of differentiated tumor bulk, a small number of CSCs, and tumor vasculature. The CSC niche provides cues that direct CSCs to undergo self-renewal to maintain the CSC sub-population, or differentiation to generate the tumor bulk. Conventional chemotherapeutic approaches target the tumor bulk, but due to their inherent chemoresistance, CSCs remain largely unaffected and potentially lead to tumor repopulation and/or metastasis. CSC directed therapeutics that target critical regulatory pathways in CSCs, such as Wnt, Notch and HH, have the potential to inhibit tumor repopulation and metastasis, resulting in tumor degeneration.

Figure 2. Canonical Wnt signaling and dysregulation in cancer

The Wnt signaling pathway is comprised of extracellular, cytoplasmic and nuclear signaling events that are amenable to therapeutic intervention. Dysregulation at these stages are common in numerous cancers, captured in the white boxes. Upon entering the nucleus and interacting with TCF/LEF and various co-activators, β-catenin drives transcription of programs critical for CSCs, tumor cells and EMT.