Wnt signaling dynamics in head and neck squamous cell cancer tumor‐stroma interactions

Le, Phuong N.; Keysar, Stephen B.; Miller, Bettina; Eagles, Justin R.; Chimed, Tugs-Saikhan; Reisinger, Julie; Gomez, Karina E.; Nieto, Cera; Jackson, Brian E.; Somerset, Hilary; Morton, J. Jason; Wang, Xiaojing; Jimeno, Antonio

doi:10.1002/mc.22937

Cited by 49 publications

(42 citation statements)

References 48 publications

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“…It has been found that Wnt activation was greatest at the boundary between epithelial and stromal compartments, and both cancer cells and cancer-associated fibroblasts mediated reciprocal stimulation by paracrine signals, mainly WNT-3A. In this model, the activation of canonical Wnt signaling induced stemness and increased invasive potential [66]. Several other studies also documented the relationship between Wnt signaling and cell invasion.…”

Section: Functional Significance Of Wnt/β-catenin Pathway Dysregulationmentioning

confidence: 61%

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

Paluszczak

2020

Cells

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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 ...

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Section: Functional Significance Of Wnt/β-catenin Pathway Dysregulationmentioning

confidence: 61%

“…Another study found that a quarter of OSCC showed overexpression of LEF1, which was associated with poor differentiation, lymph node invasion and reduced overall survival [65]. Moreover, transcriptomic analysis of β-catenin target genes confirmed the activation of Wnt signaling in advanced and relapsed HNSCC tumors [66].…”

Section: Introductionmentioning

confidence: 97%

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

Paluszczak

2020

Cells

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“…Alterations in the genes encoding APC have been described in the development of specific colorectal tumors [80]. The involvement of the canonical Wnt pathway in head and neck squamous cell carcinoma (HNSCC) has also been reported in several studies [81]. The Wnt/β-catenin signaling pathway interacts with many other signaling pathways, including NF-κB, Smad3, Notch, forkhead box O (FOXO) and hypoxia-inducing factor-1α (HIF-1α), extending the spectrum of biological functions of this pathway [82].…”

Section: Wnt/beta Catenin Pathwaymentioning

confidence: 95%

Anti-Inflammatory Drugs as Anticancer Agents

Zappavigna

Cossu

Grimaldi

et al. 2020

IJMS

242

171

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Inflammation is strictly associated with cancer and plays a key role in tumor development and progression. Several epidemiological studies have demonstrated that inflammation can predispose to tumors, therefore targeting inflammation and the molecules involved in the inflammatory process could represent a good strategy for cancer prevention and therapy. In the past, several clinical studies have demonstrated that many anti-inflammatory agents, including non-steroidal anti-inflammatory drugs (NSAIDs), are able to interfere with the tumor microenvironment by reducing cell migration and increasing apoptosis and chemo-sensitivity. This review focuses on the link between inflammation and cancer by describing the anti-inflammatory agents used in cancer therapy, and their mechanisms of action, emphasizing the use of novel anti-inflammatory agents with significant anticancer activity.

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“…36 Recent studies have shown that the Wnt inhibitor Ipafricept can suppress the invasiveness, sphere formation and growth of CSCs in head and neck squamous cell carcinoma (HNSCC). 37 Ipafricept is being used in phase I clinical trials for treatment of cancer patients. 38…”

Section: Ipafricept (Omp-54f28)mentioning

confidence: 99%

“…134 One study showed that CAF secretory factors enhance Wnt signalling and that the Wnt inhibitor Ipafricept (OMP-54f28) suppresses proliferation of patientderived xenografts (PDXs) and inhibits CSC tumour initiation by inhibiting Wnt signalling involved in the cancer-TME interaction in head and neck squamous cell carcinoma (HNSCC). 37 Other research on breast cancer indicates that paclitaxel treatment of breast cancer cells leads to relatively high levels of ROR1 expression and that accessory cells in the TME induce activation of the Wnt5a signalling pathway by expressing ROR1, thereby promoting the stemness of breast cancer cells. Furthermore, the humanized anti-ROR1 drug cirmtuzumab inhibits activation of the ROR1 signalling pathway, which hinders the development and metastasis of breast cancer.…”

Section: Targeting the Tumour Microenvironmentmentioning

confidence: 99%

<p>Self-Renewal Signalling Pathway Inhibitors: Perspectives on Therapeutic Approaches for Cancer Stem Cells</p>

Zhu¹,

Shen²,

Chen³

et al. 2020

OTT

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The poor survival and prognosis of individuals with cancer are often attributed to tumour relapse and metastasis, which may be due to the presence of cancer stem cells (CSCs). CSCs have the characteristics of self-renewal, differentiation potential, high carcinogenicity, and drug resistance. In addition, CSCs exhibit many characteristics similar to those of embryonic or tissue stem cells while displaying persistent abnormal activation of self-renewal pathways associated with development and tissue homeostasis, including the Wnt, Notch, Hedgehog (Hh), TGF-β, JAK/STAT3, and NF-κB pathways. Therefore, we can eliminate CSCs by targeting these self-renewal pathways to constrain stem cell replication, survival and differentiation. At the same time, we cannot neglect the ping-pong effect of the tumour microenvironment, which releases cytokines and promotes self-renewal pathways in CSCs. Recently, meaningful progress has been made in the study of inhibitors of self-renewal pathways in tumours. This review primarily summarizes several representative and novel agents targeting these self-renewal signalling pathways and the tumour microenvironment and that represent a promising strategy for treating refractory and recurrent cancer.

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Wnt signaling dynamics in head and neck squamous cell cancer tumor‐stroma interactions

Cited by 49 publications

References 48 publications

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

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

Anti-Inflammatory Drugs as Anticancer Agents

<p>Self-Renewal Signalling Pathway Inhibitors: Perspectives on Therapeutic Approaches for Cancer Stem Cells</p>

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