The Significance of the Dysregulation of Canonical Wnt Signaling in Head and Neck Squamous Cell Carcinomas

Abstract

The knowledge about the molecular alterations which are found in head and neck squamous cell carcinomas (HNSCC) has much increased in recent years. However, we are still awaiting the translation of this knowledge to new diagnostic and therapeutic options. Among the many molecular changes that are detected in head and neck cancer, the abnormalities in several signaling pathways, which regulate cell proliferation, cell death and stemness, seem to be especially promising with regard to the development of targeted therapies. Canonical Wnt signaling is a pathway engaged in the formation of head and neck tissues, however it is not active in adult somatic mucosal cells. The aim of this review paper is to bring together significant data related to the current knowledge on the mechanisms and functional significance of the dysregulation of the Wnt/β-catenin pathway in head and neck tumors. Research evidence related to the role of Wnt signaling activation in the stimulation of cell proliferation, migration and inhibition of apoptosis in HNSCC is presented. Moreover, its role in promoting stemness traits in head and neck cancer stem-like cells is described. Evidence corroborating the hypothesis that the Wnt signaling pathway is a very promising target of novel therapeutic interventions in HNSCC is also discussed.Cells 2020, 9, 723 2 of 20 blocking the interaction between PD-1 receptor and PD-L1, may be beneficial in patients with advanced, metastatic or recurrent HNSCC [7]. However, other therapeutic options are also necessary for the better clinical management of HNSCC patients. To that end, molecular alterations observed in HNSCC need to be studied in detail, in order to point to promising drug targets. Mechanisms of Wnt/β-Catenin Pathway Activation in HNSCCRecent genomic analyses have shown the prevalence of genetic driver alterations in HNSCC, which most frequently affect genes associated with receptor tyrosine kinase (e.g., EGFR, MET, KIT), PI3K, p53, Notch or Hippo signaling pathways. On the other hand, genetic alterations in genes related to canonical Wnt signaling were rarely detected in HNSCC [8,9]. In contrast to colorectal cancers, which show molecular alterations driving Wnt signaling activation in around 90% of cases [9], HNSCC were shown to lack CTNNB1 mutations and APC mutations were present infrequently [10][11][12][13][14][15][16]. The mutations of FAT1 tumor suppressor, which encodes a protocadherin protein that binds and inactivates β-catenin, were detected in some cases of HNSCC [17]. However, the activation of the Wnt/β-catenin pathway in HNSCC seems to be more prevalent than it is suggested by genetic findings, due to cross-talk with other molecular alterations, which can lead to pathway cross-activation. Indeed, it has been shown that β-catenin can be activated via enhanced EGFR or PI3K signaling, which belong to the most frequently dysregulated signaling pathways in HNSCC. In this regard, elevated EGFR expression was associated with delocalized β-catenin expression [13]. In another study, the nuclear ...

Impact of Tenascin-C on Radiotherapy in a Novel Syngeneic Oral Squamous Cell Carcinoma Model With Spontaneous Dissemination to the Lymph Nodes

“…We observed several immune modulating molecules such as Cd274, Ctla4 and Irf7 to be expressed by the cultured OSCC13 cells, mimicking HNSCC, 4NQO-induced tumors and the 4MOSC1-4 cells [ Supplementary Table S3 ( 18 , 24 , 33 )]. Moreover, many molecules involved in the TGFβ (46 genes) and Wnt signaling pathways (68 genes) were significantly expressed suggesting intrinsic activation of these pathways again recapitulating features of human HNSCC [ Figure 1E and Supplementary Table S3 ( 34 , 35 )]. Altogether, we propose that the OSCC13 cells could be a relevant novel cellular model that recapitulates properties of human tobacco smoking associated HNSCC.…”

Salivary miR-30c-5p as Potential Biomarker for Detection of Oral Squamous Cell Carcinoma

“…miR-30c and miR-181a synergistically modulate the p53–p21 pathway in diabetes-induced cardiac hypertrophy. Although there is no direct evidence of genetic alteration in the Wnt pathway in head and neck tumors, several works demonstrated that this pathway might be over-induced as a results of trans activation of EGFR and PI3K signaling [ 26 ]. In that context, the inhibitory effect of miR-30c-5p on the p53 and Wnt pathways could represents an important event during the onset and development of OSCC.…”

Upper Aerodigestive Tract Squamous Cell Carcinomas Show Distinct Overall DNA Methylation Profiles and Different Molecular Mechanisms behind WNT Signaling Disruption

“…One of the differentially affected pathways was the WNT signaling pathway. The WNT signaling pathway activation has been recurrently reported in UADT tumors from preneoplastic lesions to more advanced tumors, being associated with patients’ outcome [ 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ]. This pathway is crucial for the development of the epithelial linings, but in adult epithelial cells it becomes silent, and its reactivation seems to play a driver role in neoplastic transformation [ 71 , 73 , 74 ].…”