ReviewEpithelial to mesenchymal transition in head and neck squamous cell carcinoma☆
Introduction
In 2011, it is estimated there will be over 11,460 deaths from head and neck squamous cell carcinoma cancers (HNSCC) in the United States and over 300,000 deaths worldwide.1, [2] Most HNSCC patients present with stage III/IV disease and have a 5-year survival rate below 40%.3 HNSCC patients with metastatic disease have extremely poor prognosis and a survival rate of less than 10%.3 Gene expression profiling studies have identified gene signatures associated with NF-κB activation, epithelial to mesenchymal transition (EMT), and cell adhesion deregulation as prominent genetic alterations in HNSCC development and/or progression.4 EMT is a complex and reversible biological process, where an epithelial tumor cell alters its polar, adhesive phenotype to a mesenchymal phenotype characterized by an increase in cell migration and invasion potential, cytoskeleton remodeling, and resistance to apoptosis (Fig. 1).[5], [6] In 2009, Kalluri and Weinberg designated EMT in cancer as type 3.6 This classification recognizes the fluidity and idiosyncrasies of EMT in cancer in comparison to the more characterized fibroblast formation (type 2 EMT) and developmental process transitions (type 1 EMT).6 A recent study reported that primary HNSCC tumors expressing a hallmark EMT signature, low E-Cadherin and high Vimentin, has a twofold increase in the satellite’s average distance compared to primary HNSCC tumors without an EMT signature.7 Therefore, a clear understanding of the EMT process is essential to identify novel druggable targets for the development of therapeutic approaches to prevent disease progression and metastasis in HNSCC.
Section snippets
Cytoskeletal, extracellular matrix, and adhesion molecules in EMT
Rearrangement of stress fibers, modulation of adhesion molecules and extracellular proteins are key events in EMT for tumor cells (Fig. 2).8 Epithelial cells are characterized by stable cell–cell contacts and the formation of adherents junctions.5 These junctions and contacts are predominantly E-Cadherin-dependent and connect to actin filaments through α- or β-catenin.5 Loss of E-Cadherin and relocalization of β-catenin from the membrane to the nucleus is frequently observed in tumor cells
Transcriptional factors in EMT
The transcription factors Slug, Snail, and Twist are known to bind to the E-box regulatory regions of E-Cadherin.[30], [31], [32] All three are the most recognized transcription factors associated with EMT, mainly due to their repression of E-Cadherin.[6], [8] In salivary adenoid cystic carcinoma, Slug expression correlated with advanced stage, invasion, recurrence, and distant metastasis.33 A intriguing study showed that Slug controls group migration and not individual tumor cell migration in
Growth factor and receptor signaling in EMT
Transforming growth factorβ1 (TGFβ1) is increased in HNSCC and exposure to TGFβ is sufficient to induce a mesenchymal morphology in HNSCC cell lines (Fig. 4A).[44], [45] There is evidence to propose a novel EMT mechanism in which TGFβ1 upregulates matrix metalloprotease 9 (MMP9) through Snail/Ets-1-dependent transcriptional regulation.44 MMPs are gelatinases that are capable of degrading the extracellular matrix components, as well as, regulating pathways and growth factors from the
Hypoxia and inflammation in EMT
Hypoxia, or oxygen deprivation, occurs in tumors due to inadequate vasculature to allow sufficient oxygen diffusion.66 HIF-1α, a key hypoxia-regulated gene, is an important contributor to metastasis and has been shown to induce EMT.67 HNSCC cells with high HIF-1α was demonstrated to exhibit the hallmark EMT phenotype and modulate the expression of EMT-associated genes.67 HIF-1α was shown to bind to the HRE proximal promoter element of Twist to enhance Twist expression.67 Co-expression of
Conclusion
HNSCC patients with distant metastasis have a mortality rate of approximately 90%.3 EMT is a cellular process that is intimately linked to metastasis and understanding EMT biology will be essential to improve patient outcome. Downregulation of E-Cadherin, upregulation of Vimentin, relocalization of β-catenin, and rearrangement of the cytoskeleton are some of the most critical cellular events during EMT. Extensive research has focused on elucidating the signal transduction pathways co-opted by
Conflict of Interest Statement
No conflicts of interest exist.
References (77)
- et al.
Significance of tumor satellite variables in reflecting the epithelial–mesenchymal transition of tongue cancer
Oral Oncol
(2011) - et al.
Expression of E-Cadherin and Vimentin correlates with metastasis formation in head and neck squamous cell carcinoma patients
Radiother Oncol
(2011) - et al.
Down-regulation of microRNAs of the miR-200 family and miR-205, and an altered expression of classic and desmosomal Cadherins in spindle cell carcinoma of the head and neck – hallmark of epithelial–mesenchymal transition
Hum Pathol
(2011) - et al.
Basement membranes: molecular organization and function in development and disease
Curr Opin Cell Biol
(1989) - et al.
The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer
J Biol Chem
(2002) - et al.
Twist is a transcriptional repressor of E-Cadherin gene expression in breast cancer
Biochem Biophys Res Commun
(2008) - et al.
Expression of c-kit and Slug correlates with invasion and metastasis of salivary adenoid cystic carcinoma
Oral Oncol
(2010) - et al.
The epithelial–mesenchymal transition generates cells with properties of stem cells
Cell
(2008) - et al.
TGF-β1 induced MMP-9 expression in HNSCC cell lines via Smad/MLCK pathway
Biochem Biophys Res Commun
(2008) - et al.
Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers
Drug Resist Updates
(2008)
Epithelial–mesenchymal-transition induced by EGFR activation interferes with cell migration and response to irradiation and cetuximab in head and neck cancer cells
Radiother Oncol
Epidermal growth factor receptor inhibition promotes desmosome assembly and strengthens intercellular adhesion in squamous cell carcinoma cells
J Biol Chem
Fibroblasts produce brain-derived neurotrophic factor and induce mesenchymal transition of oral tumor cells
Oral Oncol
Hypoxia-inducible factor-1 alpha, in association with TWIST2 and SNIP1, is a critical prognostic factor in patients with tongue squamous cell carcinoma
Oral Oncol
Epithelial–mesenchymal transitions in development and disease
Cell
The role of ZEB1 in the inflammation-induced promotion of EMT in HNSCC
Otolaryngol – Head Neck Surg
Human papillomavirus-associated head and neck cancer is a distinct epidemiologic, clinical, and molecular entity
Semin Oncol
Sonic hedgehog acts as a negative regulator of β-Catenin signaling in the adult tongue epithelium
Am J Pathol
International agency for research on cancer. World cancer report
Gene expression profiles identify epithelial-to-mesenchymal transition and activation of nuclear Factor-B signaling as characteristics of a high-risk head and neck squamous cell carcinoma
Cancer Res
Epithelial–mesenchymal transitions in tumour progression
Nat Rev Cancer
The basics of epithelial–mesenchymal transition
J Clin Invest
Biomarkers for epithelial–mesenchymal transitions
J Clin Invest
Introducing intermediate filaments: from discovery to disease
J Clin Invest
Expression of N-Cadherin by human squamous carcinoma cells induces a scattered fibroblastic phenotype with disrupted cell–cell adhesion
J Cell Biol
Exogenous expression of N-Cadherin in breast cancer cells induces cell migration, invasion, and metastasis
J Cell Biol
Inhibition of Aurora-A suppresses epithelial–mesenchymal transition and invasion by downregulating MAPK in nasopharyngeal carcinoma cells
Carcinogenesis
Invasion and metastasis of oral cancer cells require methylation of E-Cadherin and/or degradation of membranous β-catenin
Clin Cancer Res
E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas
JNCI J Natl Cancer Inst
Silencing of the E-Cadherin invasion-suppressor gene by CpG methylation in human carcinomas
Proc Natl Acad Sci
P-Cadherin induces an epithelial-like phenotype in oral squamous cell carcinoma by GSK-3beta-mediated Snail phosphorylation
Carcinogenesis
Truncated P-Cadherin is produced in oral squamous cell carcinoma
FEBS J
Expression of P-Cadherin, but not E-Cadherin or N-Cadherin, relates to pathological and functional differentiation of breast carcinomas
Mol Pathol
N-Cadherin expression is involved in malignant behavior of head and neck cancer in relation to epithelial–mesenchymal transition
Histol Histopathol
N-Cadherin expression is correlated with metastasis of spindle cell carcinoma of head and neck region
J Oral Pathol Med
Cadherin–catenin complex and transcription factor Snail-1 in spindle cell carcinoma of the head and neck
Virchows Archiv
Cited by (0)
- ☆
This work was supported in part by National Institutes of Health (R01CA135096) and American Cancer Society (RSG0821901).