Affiliations: Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road, NW Washington, DC 20007, USA | Cancer Genetics, DVAMC and LCC, Georgetown University, Washington, DC, USA
Abstract: WNT signaling plays a key role in the developing embryo and in the maintenance of a stem/progenitor cell compartment in adult tissues. However, WNT signaling is also believed to play an important role in carcinogenesis. WNT signaling may be activated directly through WNT ligand overexpression, or more often through mutations downstream in the WNT signaling cascade. The common endpoint is an inappropriate expansion of a stem cell compartment and proliferation of more differentiated daughter cells which ultimately acquire additional mutations leading to the development of a malignant, invasive cancer cell. It is likely that WNT signaling is at the core of many human cancers, but no definitive biomarker of WNT activity has been established. Furthermore, while therapies targeting WNT-responsive gene products such as COX-2 and VEGF have been developed, no therapy directly targeting WNT signaling itself has yet made it into the clinic. We present here a brief summary of the WNT signaling cascade, and focus particularly on markers of WNT activity that have diagnostic, prognostic, or therapeutic relevance. Finally, we propose the development of novel ligands of the steroid hormone family of nuclear receptors to be used as therapies that specifically target and inhibit WNT/β-catenin/TCF-mediated transcriptional activity.
