Comprehending the crosstalk between Notch, Wnt and Hedgehog signaling pathways in oral squamous cell carcinoma - clinical implications

Abstract

Background: Oral squamous cell carcinoma (OSCC) is a malignant oral cavity neoplasm that affects many people, especially in developing countries. Despite several advances that have been made in diagnosis and treatment, the morbidity and mortality rates due to OSCC remain high. Accumulating evidence indicates that aberrant activation of cellular signaling pathways, such as the Notch, Wnt and Hedgehog pathways, occurs during the development and metastasis of OSCC. In this review, we have articulated the roles of the Notch, Wnt and Hedgehog signaling pathways in OSCC and their crosstalk during tumor development and progression. We have also examined possible interactions and associations between these pathways and treatment regimens that could be employed to effectively tackle OSCC and/or prevent its recurrence.

Conclusions: Activation of the Notch signaling pathway upregulates the expression of several genes, including c-Myc, β-catenin, NF-κB and Shh. Associations between the Notch signaling pathway and other pathways have been shown to enhance OSCC tumor aggressiveness. Crosstalk between these pathways supports the maintenance of cancer stem cells (CSCs) and regulates OSCC cell motility. Thus, application of compounds that block these pathways may be a valid strategy to treat OSCC. Such compounds have already been employed in other types of cancer and could be repurposed for OSCC.

Keywords: Crosstalk; Hedgehog signaling; Notch signaling; OSCC; Oral squamous cell carcinoma; Therapeutic regimens; Wnt signaling.