Elsevier

Oral Oncology

Volume 49, Issue 4, April 2013, Pages 287-292
Oral Oncology

Review
Epithelial to mesenchymal transition in head and neck squamous cell carcinoma

https://doi.org/10.1016/j.oraloncology.2012.10.009Get rights and content

Summary

Epithelial to mesenchymal transition (EMT) is a dynamic cellular process that is essential for the development of metastatic disease. During EMT, a tumor cell with epithelial characteristics transitions to a tumor cell with mesenchymal characteristics through modulation of cell polarity and adhesion. Two hallmark EMT proteins, E-Cadherin and Vimentin, are tightly controlled during EMT through multiple signal transduction pathways. Epidermal growth factor (EGF) and transforming growth factorβ (TGFβ) promote EMT by regulating a distinct set of transcription factors, including Snail and Twist. Snail, Twist, and Slug are integral to the induction of EMT through direct regulation of genes involved in cellular adhesion, migration, and invasion. This review highlights the current literature on EMT in HNSCC. Understanding the role of EMT will provide insight to the pathogenesis of disease progression and may lead to the development of novel anti-cancer therapeutics for metastatic HNSCC.

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)

  • C. Holz et al.

    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

    (2011)
  • J.H. Lorch et al.

    Epidermal growth factor receptor inhibition promotes desmosome assembly and strengthens intercellular adhesion in squamous cell carcinoma cells

    J Biol Chem

    (2004)
  • J. Dudás et al.

    Fibroblasts produce brain-derived neurotrophic factor and induce mesenchymal transition of oral tumor cells

    Oral Oncol

    (2011)
  • X. Liang et al.

    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

    (2011)
  • J.P. Thiery et al.

    Epithelial–mesenchymal transitions in development and disease

    Cell

    (2009)
  • M. Dohadwala et al.

    The role of ZEB1 in the inflammation-induced promotion of EMT in HNSCC

    Otolaryngol – Head Neck Surg

    (2010)
  • M.L. Gillison

    Human papillomavirus-associated head and neck cancer is a distinct epidemiologic, clinical, and molecular entity

    Semin Oncol

    (2004)
  • F.T. Schneider et al.

    Sonic hedgehog acts as a negative regulator of β-Catenin signaling in the adult tongue epithelium

    Am J Pathol

    (2010)
  • American Cancer Society. Cancer Facts & Figures 2011. Atlanta: American Cancer Society;...
  • P. Boyle et al.

    International agency for research on cancer. World cancer report

    (2008)
  • Glisson B, Cango M, Feigenberg S. Head and neck tumors. In: Pazdur R, Wagman L, Camphausen K, Hoskins W, editors....
  • C.H. Chung et al.

    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

    (2006)
  • J.P. Thiery

    Epithelial–mesenchymal transitions in tumour progression

    Nat Rev Cancer

    (2002)
  • R. Kalluri et al.

    The basics of epithelial–mesenchymal transition

    J Clin Invest

    (2009)
  • M. Zeisberg et al.

    Biomarkers for epithelial–mesenchymal transitions

    J Clin Invest

    (2009)
  • J.E. Eriksson et al.

    Introducing intermediate filaments: from discovery to disease

    J Clin Invest

    (2009)
  • S. Islam et al.

    Expression of N-Cadherin by human squamous carcinoma cells induces a scattered fibroblastic phenotype with disrupted cell–cell adhesion

    J Cell Biol

    (1996)
  • R.B. Hazan et al.

    Exogenous expression of N-Cadherin in breast cancer cells induces cell migration, invasion, and metastasis

    J Cell Biol

    (2000)
  • X. Wan et al.

    Inhibition of Aurora-A suppresses epithelial–mesenchymal transition and invasion by downregulating MAPK in nasopharyngeal carcinoma cells

    Carcinogenesis

    (2008)
  • Y. Kudo et al.

    Invasion and metastasis of oral cancer cells require methylation of E-Cadherin and/or degradation of membranous β-catenin

    Clin Cancer Res

    (2004)
  • G. Tamura et al.

    E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas

    JNCI J Natl Cancer Inst

    (2000)
  • K. Yoshiura et al.

    Silencing of the E-Cadherin invasion-suppressor gene by CpG methylation in human carcinomas

    Proc Natl Acad Sci

    (1995)
  • K. Bauer et al.

    P-Cadherin induces an epithelial-like phenotype in oral squamous cell carcinoma by GSK-3beta-mediated Snail phosphorylation

    Carcinogenesis

    (2009)
  • R. Bauer et al.

    Truncated P-Cadherin is produced in oral squamous cell carcinoma

    FEBS J

    (2008)
  • A. Kovacs et al.

    Expression of P-Cadherin, but not E-Cadherin or N-Cadherin, relates to pathological and functional differentiation of breast carcinomas

    Mol Pathol

    (2003)
  • P. Nguyan et al.

    N-Cadherin expression is involved in malignant behavior of head and neck cancer in relation to epithelial–mesenchymal transition

    Histol Histopathol

    (2011)
  • P.T. Nguyen et al.

    N-Cadherin expression is correlated with metastasis of spindle cell carcinoma of head and neck region

    J Oral Pathol Med

    (2010)
  • N. Zidar et al.

    Cadherin–catenin complex and transcription factor Snail-1 in spindle cell carcinoma of the head and neck

    Virchows Archiv

    (2008)
  • Cited by (0)

    This work was supported in part by National Institutes of Health (R01CA135096) and American Cancer Society (RSG0821901).

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