Abstract
Previous reports have shown that fresh tissues and cell lines from patients with squamous cell carcinoma of the head and neck (SCCHN) overexpress transforming growth factor alpha (TGF-α) and its receptor, the epidermal growth factor receptor (EGFR) at both the mRNA and protein levels. Protein localization studies confirm that TGF-α and EGFR are produced by the same epithelial cells in tissues from head and neck cancer patients further supporting an autocrine growth pathway. Using three strategies, we examined the hypothesis that downmodulation of EGFR would reduce the proliferation of SCCHN cells. We targeted EGFR mRNA using antisense oligonucleotides and the mature EGFR protein at two sites, the ligand-binding domain and the kinase domain, and determined the effects of this targeting on SCCHN proliferation. Treatment of several SCCHN cell lines with a pair of antisense oligodeoxynucleotides directed against the translation start site and first intron-exon splice junction of the human EGFR gene resulted in decreased EGFR protein production and inhibited growth by 86% compared to a 13% reduction in cells treated with sense oligonucleotides (P = 0.03). Growth inhibition was specific for carcinoma cells since the same EGFR antisense oligonucleotides had no effect on the proliferation of normal mucosa cells harvested from non-cancer patients. Two monoclonal antibodies which block ligand binding to EGFR (MAbs 425 and 528) inhibited the growth of several SCCHN cell lines by up to 97% which suggests that EGFR is participating in an autocrine pathway in SCCHN that is, at least in part, external. An EGFR-specific tyrosine kinase inhibitor (PD 153035) was found to inhibit EGFR phosphorylation in SCCHN cell lines and to reduce growth by 68% although it had no effect on the growth rate of normal mucosal epithelial cells. These experiments indicate that EGFR gene expression and function is critical for SCCHN cell growth but not for growth of normal mucosa cells and therefore may serve as a tumor-specific target for preventive and therapeutic strategies in head and neck cancer.
| Original language | English |
|---|---|
| Pages (from-to) | 409-416 |
| Number of pages | 8 |
| Journal | Oncogene |
| Volume | 15 |
| Issue number | 4 |
| DOIs | |
| State | Published - 24 Jul 1997 |
| Externally published | Yes |
Bibliographical note
Funding Information:We are grateful to Dr Susanne M Gollin for providing us with head and neck cancer cell lines UPCI:SCC066 and UPCI:SCC104, to Dr Thomas Carey for providing the cell line 22B and Dr Reuben Lotan for the gift of the cell line 1483. We are also grateful to Dr David Fry for providing us with the EGFR kinase inhibitor PD-153035 and Dr Uli Rodeck for the gift of MAb 425. Supported in part by grants 1 K11 CA01760-01 from the National Cancer Institute, American Cancer Society grant DHP-111, the John R McCune Charitable Trust Foundation and the Mary Hillman Jennings Foundation.
Funding
We are grateful to Dr Susanne M Gollin for providing us with head and neck cancer cell lines UPCI:SCC066 and UPCI:SCC104, to Dr Thomas Carey for providing the cell line 22B and Dr Reuben Lotan for the gift of the cell line 1483. We are also grateful to Dr David Fry for providing us with the EGFR kinase inhibitor PD-153035 and Dr Uli Rodeck for the gift of MAb 425. Supported in part by grants 1 K11 CA01760-01 from the National Cancer Institute, American Cancer Society grant DHP-111, the John R McCune Charitable Trust Foundation and the Mary Hillman Jennings Foundation.
| Funders | Funder number |
|---|---|
| John R McCune Charitable Trust Foundation | |
| Mary Hillman Jennings Foundation | |
| American Cancer Society | DHP-111 |
| National Cancer Institute | K11CA001760 |
Keywords
- Epidermal growth factor receptor
- Head and neck cancer
