Progression of squamous cell carcinoma of the head and neck is associated with down-regulation of the opioid growth factor receptor

Opioid growth factor (OGF) is a native opioid peptide ([Met5]-enkephalin) that interacts with the OGF receptor (OGFr). OGF serves as a tonically active negative growth factor in neoplasia, and the OGF-OGFr axis contributes to the maintenance of an equilibrium in cell proliferation by targeting the cyclin-dependent inhibitory kinase pathway. To inquire whether the expression of OGFr is related to tumor progression, cell lines of human squamous cell carcinoma of the head and neck (SCCHN) were transplanted into nude mice, and small, medium, and large tumors were assessed for OGFr by receptor binding assays and quantitative immunohistochemistry, and for gene expression of OGFr mRNA. Large tumors had a reduction of 3- to 7-fold in OGFr binding sites relative to small tumors, and medium size tumors showed a progressive diminishment in OGF receptors that ranged between that of small and large neoplasias. Tumors with xenografts of three different cell lines of SCCHN, representing poorly- and well-differentiated cancers, exhibited similar results. Quantitative densitometric immunohistochemistry revealed data comparable to receptor binding assays. Receptor affinity and the gene expression of OGFr mRNA were unchanged in tumors of different sizes. These data demonstrate that OGFr is reduced in SCCHN with tumor progression and that translation/posttranslation of OGFr protein, but not transcriptional levels of the OGFr gene, is (are) involved. The attenuated levels of OGFr binding capacity may serve as a marker of SCCHN. These subnormal levels of OGFr may diminish the efficacy of the OGF-OGFr axis in maintaining cell proliferative activity, and contribute to more active cell replication. Gene therapy to reinstate more OGFr, and thus enhance OGFr function, could serve as a useful treatment for inhibiting tumor progression.