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Progression of Head and Neck Cancer in an In Vitro Model
George H. Yoo, MD;
James Washington, BS;
Marie Piechocki, PhD;
John Ensley, MD;
Terry Shibuya, MD;
Dolphine Oda, DDS, MSc;
Wei-Zen Wei, PhD
Arch Otolaryngol Head Neck Surg. 2000;126:1313-1318.
Objective To identify alterations in angiogenesis and cell cycle regulation as preneoplastic cells progress to cancer in an in vitro model of head and neck tumor progression.
Methods Immortal human gingival keratinocyte (IHGK) cells (preneoplastic) were derived from normal oral keratinocytes and were immortalized with human papillomavirus 16. Transformation of IHGK cells with a carcinogen (NNK, 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone) gave rise to IHGKN cells. We determined the growth rates, cell cycle phase, expression of cell cycle regulators, and expression of vascular endothelial growth factor along with the organotypic features of these cells and compared them with characteristics of head and neck cancer cells.
Results IHGK and IHGKN cells grown in raft culture were morphologically similar to severe dysplasia and carcinoma, respectively. The proportion of cells in G0/G1 was similar between IHGK and IHGKN. However, the proportion of IHGK cells was 35% greater in S phase as compared with the IHGKN cells, while a greater percentage (40%) of IHGKN cells were in G2/M. The expression of the other cell cycle regulators tested was unchanged. IHGK cells secreted less vascular endothelial growth factor on day 1 when compared with IHGKN (50.6 vs 245.6 pg/mL), along with a lower overall production rate (79% vs 133%).
Conclusions Transformation of IHGK cells resulted in the activation of vascular endothelial growth factor associated with angiogenesis. Inactivation of the G1 cell cycle regulation occurred during immortalization and before transformation, and was sustained after carcinogen exposure. These alterations correspond to changes observed in patients with head and neck squamous cell carcinoma. This model can be useful in testing novel therapeutic and preventive strategies.
From the Department of Otolaryngology–Head and Neck Surgery, Wayne State University, Detroit, Mich (Drs Yoo, Piechocki, and Shibuya and Mr Washington); Departments of Medical Oncology (Dr Ensley) and Immunology (Drs Piechocki and Wei), Wayne State University and Karmanos Cancer Institute, Detroit; and Department of Oral and Maxillofacial Surgery, University of Washington, Seattle (Dr Oda).
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