Downregulation of EGFR in hypoxic, diffusion-limited areas of squamous cell carcinomas of the head and neck.
BACKGROUND
The receptor for the epidermal growth factor (EGFR) is widely considered to be one of the central drivers of oncogenesis in squamous cell carcinomas of the head and neck region (HNSCC). Inhibition of EGFR using monoclonal antibodies is established both in the curative and the palliative setting in this disease. HNSCCs are known to contain abundant hypoxic tissue areas and hypoxia has been shown to be involved in the (down)regulation of EGFR membrane expression.


METHODS
A novel method for multiplex immunofluorescence and single-cell segmentation (via DAPI-stained nuclei) was established, to study the expression of EGFR, the endogenous hypoxia marker CA IX, and intratumoural diffusion distances from microvessels (using CD34 staining) in 58 human HNSCCs and 9 normal/cancer adjacent tissues.


RESULTS
EGFR was found to be significantly downregulated with increasing distance from tumour microvessels, whereas the opposite was true for CA IX. Larger diffusion-limited areas were correlated with higher expression of CA IX.


CONCLUSIONS
The hypoxic tumour microenvironment may have a major role in mediating resistance against anti-EGFR strategies by downregulating EGFR molecules on tumour cells.
Department of Radiation Oncology and Radiotherapy, University Medical Center, Mainz 55131, Germany.
Arnulf
A
Mayer
Department of Radiation Oncology and Radiotherapy, University Medical Center, Mainz 55131, Germany.
Sebastian
S
Zahnreich
Department of Otolaryngology, Head and Neck Surgery, University Medical Center, Mainz 55131, Germany.
Jürgen
J
Brieger
Department of Radiation Oncology and Radiotherapy, University Medical Center, Mainz 55131, Germany.
Peter
P
Vaupel
Department of Radiation Oncology and Radiotherapy, University Medical Center, Mainz 55131, Germany.
Heinz
H
Schmidberger
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000071231:Carbonic Anhydrase IX / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D055806:Microvessels / Q000378:metabolism; D008875:Middle Aged; D000077195:Squamous Cell Carcinoma of Head and Neck
D066246:ErbB Receptors; D000071231:Carbonic Anhydrase IX