The molecular pathogenesis of head and neck squamous cell carcinoma
S. Michael Rothenberg, Leif W. Ellisen
S. Michael Rothenberg, Leif W. Ellisen
Published June 1, 2012
Citation Information: J Clin Invest. 2012;122(6):1951-1957. https://doi.org/10.1172/JCI59889.
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Science in Medicine

The molecular pathogenesis of head and neck squamous cell carcinoma

Abstract

Squamous cell carcinoma of the head and neck (HNSCC) is a relatively common human cancer characterized by high morbidity, high mortality, and few therapeutic options outside of surgery, standard cytotoxic chemotherapy, and radiation. Although the most important risk factors are tobacco use and alcohol consumption, the disease is also linked to infection with high-risk types of human papilloma viruses (HPVs). Recent genetic analyses have yielded new insights into the molecular pathogenesis of this disease. Overall, while somatic activating mutations within classical oncogenes including PIK3CA and RAS occur in HNSCC, they are relatively uncommon. Instead genetic data point to a contribution of multiple tumor suppressor pathways, including p53, Rb/INK4/ARF, and Notch, in tumor initiation, progression, and maintenance. The increasingly refined knowledge of HNSCC genetics, combined with ever-more-sophisticated animal models and newer drug targeting strategies, should promote novel therapeutic approaches and improved disease outcomes.

Authors

S. Michael Rothenberg, Leif W. Ellisen

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Figure 1

Hallmarks of head and neck squamous tumorigenesis.

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Hallmarks of head and neck squamous tumorigenesis. (A) The normal proces...
(A) The normal process of squamous morphogenesis in the adult mucosa is controlled in part by TP63 and NOTCH1. The former is expressed in keratinocytes of the basal layer, where it maintains their proliferative potential and controls expression of basal markers (e.g., keratins 5/14 [K5/14]); expression of the latter results in terminal differentiation into cells of the spinous (K1/10) and granular layers. Rare stem cells in the basal layer (light blue) undergo terminal differentiation through asymmetric cell division. Abnormal proliferation is prevented primarily by differentiation-associated cell cycle exit and by apoptosis. (B) Pathways altered in HNSCC pathogenesis identified in whole-exome sequencing studies. Red: putative and established tumor suppressors; green: oncogenes; brown: other relevant genes/proteins; blue: viral proteins. Loss of TP53 and CDKN2A, amplification of CCND1, and loss of TGFBR2/SMAD4 permit abnormal proliferation and decrease apoptosis. However, abnormal cell cycling may still be restrained by intact differentiation and apoptotic programs. Loss of NOTCH1 and/or abnormal expression of TP63, together with alterations in “survival” genes (e.g., CASP8, PIK3CA, EGFR), may remove additional barriers to tumor cell proliferation and survival. Loss of cell adhesion genes (e.g., FAT1) could permit release of cells from the mucosal lining, while invasion through the basement membrane is promoted by TGFB1 (and SMAD3). (C) Schematic of HNSCC hallmarks. The precise order of acquisition of distinct alterations is not clear. In addition, several genes (e.g., TP53, TP63, NOTCH1) may contribute to more than one hallmark.