Title

Fibrin induces interleukin-8 expression from human oral squamous cell carcinoma cells

Date of Completion

January 2001

Keywords

Biology, Cell|Health Sciences, Oncology

Degree

Ph.D.

Abstract

Angiogenesis, the formation of new blood vessels, is vital for tumor growth and metastasis. Interleukin-8 (IL-8) is a potent angiogenic factor responsible for most of the angiogenic activity induced by human oral squamous cell carcinoma (HOSCC) cells. Interestingly, fibrin induces IL-8 expression from human vascular endothelial cells and fibroblasts. Since fibrin has been implicated in tumor progression, we hypothesized that fibrin is present in the tumor microenvironment and directly induces expression of protumorigenic factors, such as IL-8, from tumor cells. ^ We began to test this hypothesis by studying the presence of fibrin in association with IL-8 expressing HOSCC cells in vivo. The presence of fibrin and IL-8 was studied in 19 sections from 8 patient's head and neck tumors (including six HOSCC) by immunohistochemistry using a monoclonal antibody specific for fibrin. Fibrin was seen in 100% of tumor sections studied, surrounding islands of IL-8 positive tumor cells, in contact with tumor cells and prominent at the invasive edges of the tumor. ^ We next examined the ability of fibrin to stimulate IL-8 expression from HOSCC cells in vitro. A physiologically relevant concentration of in situ polymerized fibrin, but not fibrinogen, was found to cause a specific, dose and time dependent stimulation of IL-8 expression from oral and pharyngeal tumor cells but not from a non-tumorigenic oral cell line. Further studies demonstrated that fibrin-derived liquid expressates and preformed fibrin clots were also able to induce IL-8 expression from the oral tumor cells. ^ Finally, we investigated the identity of the fibrin-derived factor(s) involved in this response. We found that a monoclonal antibody against the N terminal region of the β chain of human fibrin (Bβ15–42) was able to inhibit 67% of fibrin-derived expressate induced IL-8 expression. A peptide (GHRP) representing the sequence at the N terminus of this region was able to induce a dose-dependent stimulation of IL-8 expression, further confirming the role of this region. ^ Thus, these studies directly support our hypothesis that fibrin is present in the tumor microenvironment and induces protumorigenic factor expression from tumor cells. Future studies may lead to the design of peptide antagonists with important therapeutic potential. ^

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