Epithelial-to-Mesenchymal Transition in Metastasis: Focus on Laryngeal Carcinoma

Abstract

In epithelial neoplasms, such as laryngeal carcinoma, the survival indexes deteriorate abruptly when the tumor becomes metastatic. A molecular phenomenon that normally appears during embryogenesis, epithelial-to-mesenchymal transition (EMT), is reactivated at the initial stage of metastasis when tumor cells invade the adjacent stroma. The hallmarks of this phenomenon are the abolishment of the epithelial and acquisition of mesenchymal traits by tumor cells which enhance their migratory capacity. EMT signaling is mediated by complex molecular pathways that regulate the expression of crucial molecules contributing to the tumor’s metastatic potential. Effectors of EMT include loss of adhesion, cytoskeleton remodeling, evasion of apoptosis and immune surveillance, upregulation of metalloproteinases, neovascularization, acquisition of stem-cell properties, and the activation of tumor stroma. However, the current approach to EMT involves a holistic model that incorporates the acquisition of potentials beyond mesenchymal transition. As EMT is inevitably associated with a reverse mesenchymal-to-epithelial transition (MET), a model of partial EMT is currently accepted, signifying the cell plasticity associated with invasion and metastasis. In this review, we identify the cumulative evidence which suggests that various aspects of EMT theory apply to laryngeal carcinoma, a tumor of significant morbidity and mortality, introducing novel molecular targets with prognostic and therapeutic potential.

Transcriptional subtypes of glottic cancer characterized by differential activation of canonical oncogenic programming

“…Though EMT programming is an active area of oncology research, the survival implications of EMT in laryngeal cancer are well-documented in the extant literature; tumor cells acquire migratory and metastatic capacity, and via a spectrum of parallel effects (e.g., upregulation of metalloproteinases, immune tolerance, neovascularization, and acquisition of stemness), demonstrate increased invasiveness, and more aggressive and metastatic potential. 28 In fact, studies investigating immunohistochemical markers in glottic and supraglottic squamous cell carcinoma have correlated both partial-EMT and EMT with worse overall and diseasefree survival. 29 Moreover, EMT programming has been associated with higher risk of PNI, a disease parameter correlated with State 2 membership and with poorer prognosis among patients with head and neck cancer.…”

“…Samples in State 2 most closely resembled F0, the transcriptional milieu of which represented EMT (Figure 2), with multiple associated oncogenic signaling networks (TGF‐β and PI3K/AKT/mTOR) coordinately upregulated, as well. Though EMT programming is an active area of oncology research, the survival implications of EMT in laryngeal cancer are well‐documented in the extant literature; tumor cells acquire migratory and metastatic capacity, and via a spectrum of parallel effects (e.g., upregulation of metalloproteinases, immune tolerance, neovascularization, and acquisition of stemness), demonstrate increased invasiveness, and more aggressive and metastatic potential 28 . In fact, studies investigating immunohistochemical markers in glottic and supraglottic squamous cell carcinoma have correlated both partial‐EMT and EMT with worse overall and disease‐free survival 29 .…”

Pan-cancer analysis identifies NT5E as a novel prognostic biomarker on cancer-associated fibroblasts associated with unique tumor microenvironment

“…Similarly, in pancreas, prostate and bladder cancer, NT5E has also been validated to correlate with tumor development and invasion ( Yang et al, 2013 ; Mandapathil et al, 2018 ; Koivisto et al, 2019 ; Zhou et al, 2019 ; Chen et al, 2022 ). In detail, for gastric cancer patients, CD73 may serve as a regulator in RICS/RhoA-LIMK-cofilin signaling pathway by its extracellular function in adenosinergic pathway, and then promote β-catenin-induced epithelial-mesenchymal transition (EMT) process, which is correlated with metastasis property of tumor cells ( Xu et al, 2020 ; Goulioumis and Gyftopoulos, 2022 ). In our study, the enrichment analyses also indicated that NT5E may be related to EMT and metastasis during HNSC progression.…”