Nonmalignant oral keratinocytes from patients with head and neck squamous cell carcinoma show enhanced metabolism of retinoic acid.
OBJECTIVE
Retinoids show promise in the treatment of various (pre)malignancies, including head and neck squamous cell carcinoma (HNSCC). It has been shown that metabolic pathways of retinoids are important in their anticancer effect and that these pathways may change during HNSCC carcinogenesis. We have previously reported that HNSCC cells have a 17-fold greater turnover rate of retinoic acid (RA) than normal oral keratinocytes from noncancer controls, and that the formation of polar metabolites such as 4-oxo-RA and 4-hydroxy-RA is only seen in HNSCC cell lines. We aimed to establish whether this altered retinoid metabolism is an intrinsic characteristic of HNSCC patients.


METHODS
The normal mucosa of cancer and noncancer patients was the source of keratinocyte cultures. The cells were exposed to RA for various time periods, and the levels of various retinoids were measured in the culture medium and cell pellets with reverse-phase liquid chromatography.


RESULTS
Cells from cancer patients were morphologically normal and showed no genetic aberrations (i.e. loss of heterozygosity). The RA turnover rate in normal oral keratinocytes of cancer patients was 15 times higher (p = 0.003) than that in normal oral keratinocytes of noncancer controls, with average turnover rates of 218.6 and 14.8 pmol/mg protein/h, respectively. Specific profiles of RA metabolites were similar.


CONCLUSIONS
The observed higher RA metabolism in noncancer cells of HNSCC patients suggests that individuals with a relatively high RA turnover have an increased risk of developing HNSCC.
Klaassen
Ingeborg
I
Section of Tumor Biology, Department of Otolaryngology/Head and Neck Surgery, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
Cloos
Jacqueline
J
Smeets
Serge J
SJ
Brakenhoff
Ruud H
RH
Tabor
Maarten P
MP
Snow
Gordon B
GB
Braakhuis
Boudewijn J M
BJ
D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009055:Mouth / Q000473:pathology; D014212:Tretinoin / Q000378:metabolism*
D014212:Tretinoin