Expression of Proinflammatory and Proangiogenic Cytokines in Patients with Head and Neck Cancer

Expression of Proinflammatory and Proangiogenic Cytokines in Patients with Head and Neck Cancer1

Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland 20892-1419 [Z. C., P. S. M., G. R. T., F. G. O., D. C. D., C. W. S., I. E., N. T. Y., G. S. K., S. R., C. V. W.]; Warren Grant Magnussen Clinical Center, NIH, Bethesda, Maryland 20892-1419 [L. M.]; DuPont-Merck Research and Development, Wilmington, Delaware 19880-0400 [S. M.]; Surgical Pathology Section, Pathology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892-1419 [M. Q.]; and Radiation Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892-1419 [L. L. H.]

Abstract

Altered immune, inflammatory, and angiogenesis responses are observed in patients with head and neck squamous cell carcinoma (HNSCC), and many of these responses have been linked with aggressive malignant behavior and a decrease in prognosis. In this study, we examined the hypothesis that HNSCC cells produce cytokines that regulate immune, inflammatory, and angiogenesis responses. We identified important regulatory cytokines in supernatants of well-defined and freshly cultured HNSCC cell lines by ELISA and determined whether these cytokines are detected in tumor cell lines and tissue specimens by immunohistochemistry. The serum concentration of the cytokines and cytokine-dependent acute phase inflammatory responses (i.e., fibrinogen, C-reactive protein, and erythrocyte sedimentation rate) from patients with HNSCC was determined, and the potential relationship of serum cytokine levels to tumor volume was analyzed. Cytokines interleukin (IL)-1α, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor were detected in similar concentration ranges in the supernatants of a panel of established University of Michigan squamous cell carcinoma (UM-SCC) cell lines and supernatants of freshly isolated primary HNSCC cultures. Evidence for the expression of IL-1α, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor, and VEGF in HNSCC cells within tumor specimens in situ was obtained by immunohistochemistry. In a prospective comparison of the cytokine level and cytokine-inducible acute-phase proteins in serum, we report that cytokines IL-6, IL-8, and VEGF were detected at higher concentrations in the serum of patients with HNSCC compared with patients with laryngeal papilloma or age-matched control subjects (at P < 0.05). The serum concentrations of IL-8 and VEGF were found to be weakly correlated with large primary tumor volume (R² = 0.2 and 0.4, respectively). Elevated IL-1- and IL-6-inducible acute-phase responses were also detected in cancer patients but not in patients with papilloma or control subjects (at P < 0.05). We therefore conclude that cytokines important in proinflammatory and proangiogenic responses are detectable in cell lines, tissue specimens, and serum from patients with HNSCC. These cytokines may increase the pathogenicity of HNSCC and prove useful as biomarkers or targets for therapy.

Footnotes

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↵1 This work was supported by National Institute on Deafness and Other Communications Disorders (NIDCD) Intramural Research Project Z01-DC-00016 and in part by NIDCD-DuPont Merck Cooperative Research and Development Agreement DC 95-01.
↵2 To whom requests for reprints should be addressed, at NIH, Building 10, Room 5D55, MSC-1419, Bethesda, MD 20892-1419.
↵3 The abbreviations used are: HNSCC, head and neck squamous cell carcinoma; IL, interleukin; VEGF, vascular endothelial growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; TNF, tumor necrosis factor; TGF, transforming growth factor; FGF, fibroblast growth factor.
↵4 Z. Chen et al., manuscript in preparation.
↵5 S. H. Hong, F. G. Ondrey, I. M. Avis, Z. Chen, P. F. Cavanaugh, Jr., C. Van Waes, and J. L. Mulshuhe. Effect of cyclooxygenase on the regulation of inflammatory cytokines and growth of human oropharyngeal squamous cell carcinomas, manuscript in preparation.
↵6 G. Thomas, unpublished observations.
↵7 Unpublished observations.
- Accepted March 11, 1999.
- Received November 12, 1998.
- Revision received March 9, 1999.