A Mechanistic Overview of Taste Bud Maintenance and Impairment in Cancer Therapies

Abstract

Since the early 20th century, progress in cancer therapies has significantly improved disease prognosis. Nonetheless, cancer treatments are often associated with side effects that can negatively affect patient well-being and disrupt the course of treatment. Among the main side effects, taste impairment is associated with depression, malnutrition, and morbid weight loss. Although relatively common, taste disruption associated with cancer therapies remains poorly understood. Here, we review the current knowledge related to the molecular mechanisms underlying taste maintenance and disruption in the context of cancer therapies.

Keywords: Hedgehog signaling; Notch signaling; Wnt signaling; chemotherapy; organoids; radiotherapy.

Figure 1.

Anatomy of the tongue and taste cell renewal. (A) Taste buds (yellow) are embedded in taste papillae in the tongue epithelium. The number of taste buds in fungiform papillae, which are located in the anterior two-thirds of the tongue, is species-dependent; rodent fungiform papillae each contain a single taste bud while multiple taste buds can be found in a human fungiform papilla. Hundreds of taste buds line the trenches (epithelial invaginations) of foliate and circumvallate papillae in the posterior tongue. In human circumvallate papillae, taste buds are mostly found in the inner wall of the trench. Foliate papillae lie laterally while circumvallate papillae are organized in a central V-shaped formation. Rodents possess only a single circumvallate papilla. (B) Taste buds are made of 50–100 cells that are continually replaced throughout life. Progenitor cells (dark blue) reside along the basement membrane outside taste buds and actively divide to self-renew and produce taste cells and non-taste keratinocytes (light gray) that surround taste buds. Following mitosis, taste-fated lingual progenitors enter taste buds and specify into post-mitotic SHH⁺ taste precursor cells (magenta). Precursor cells then differentiate into most prevalent Type I glial-like cells (tangerine), Type II sweet/bitter/umami receptor cells (green), and least common Type III sour receptor cells (yellow). (C) Fate decision is regulated by the Wnt pathway, Hedgehog, and Notch signaling. The Wnt/β-catenin pathway controls all steps of taste and non-taste cell renewal, while SHH instructs progenitors to differentiate into taste cells. Notch signaling represses Type II cell fate via HES1 and transcriptionally represses ASCL1 to control Type III taste cell differentiation. Illustrations are modified from Servier Medical Art licensed under a Creative Commons Attribution 3.0 Unported License (https://smart.servier.com/).

Figure 2.

Signaling pathways targeted in cancer therapies. Hedgehog, Wnt/β-catenin, and Notch signaling are developmental pathways that are activated in multiple forms of cancer, rendering them promising therapeutic targets. (A) Hedgehog signaling pathway. In the absence of SHH, PTCH receptor inhibits SMO. SUFU sequesters GLI1 in the cytoplasm resulting in inactive Hh signaling. SHH binding to PTCH receptor ① lifts its inhibition of SMO ②. Activated SMO sequesters SUFU ③, resulting in translocation of GLI1 to the nucleus ④ and transcription of target genes. Targeted cancer therapeutics include Robotnikin that binds and inhibits SHH, SMO inhibitors Vismodegib and Sonidegib, and GLI1 inhibitor arsenic trioxide. (B) Wnt/β-catenin signaling pathway. PORCN palmitoylates WNTs in the endoplasmic reticulum of signal-sending cells ①. Secreted WNTs bind to FZD/LRP receptor complex on the surface of signal-receiving cells ②, resulting in dismantling of the degradation complex and release of β-catenin rather than its degradation ③. β-catenin then translocated to the nucleus and binds to T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors to induce the transcription of target genes ④. Anticancer drug LGK974 averts the activation of WNTs via inhibition of PORCN, while WNT inhibitors prevent binding to the receptors and vantictumab inhibits FZD proteins. (C) Notch signaling pathway. Interaction of delta-like (DLL) and jagged (JAG) ligands present on the surface of signal-sending cells with NOTCH receptors anchored in the membrane of signal-receiving cells ① results in extracellular S2 site cleavage by ADAM metalloproteases ②. Subsequent intramembrane S3 site cleavage by γ-secretases releases Notch intracellular domain (NICD) ③ that translocates to the nucleus and activates the transcription of target genes ④. Anticancer therapeutics have been developed to inhibit Notch ligands and receptors, as well as γ-secretases. Illustrations are modified from Servier Medical Art licensed under a Creative Commons Attribution 3.0 Unported License (https://smart.servier.com/).