Identification of a region of the fibrin molecule involved in upregulation of interleukin-8 expression from human oral squamous cell carcinoma cells.
A number of studies have implicated the fibrin-coagulation-fibrinolysis system in human tumour progression. Interleukin-8 (IL-8) mediates most of the angiogenic activity induced by human oral squamous cell carcinoma (OSCC) cells. We have recently demonstrated that: (1) fibrin is present in association with IL-8 expressing human OSCC cells in vivo and (2) in situ fibrin polymerisation induces a specific, dose and time-dependent upregulation of IL-8 expression from human OSCC cells in vitro. Our present studies extend this observation by demonstrating that in addition to fibrin formed in situ, both fibrin-derived liquid expressates (soluble fibrin) and preformed fibrin clots induced an over eight-fold stimulation of IL-8 expression from human OSCC cells as compared to media controls. IL-8 upregulation by soluble fibrin was dose-dependent. A monoclonal antibody against the N terminal region of the beta chain of human fibrin (Bbeta15-42) inhibited 67% of soluble fibrin-induced IL-8 expression from human OSCC cells. A peptide (GHRP), representing the sequence at the N terminus of this region, induced a dose-dependent stimulation of IL-8 expression, further confirming the role of this region. These studies directly support our hypothesis that fibrin induces protumourigenic factor expression from tumour cells, thus promoting tumour progression. Future studies to further characterise the role of the Bbeta15-42 region in tumour cell activation may lead to the design of peptide antagonists with important therapeutic potential.
Lalla
Rajesh V
RV
Department of Oral Diagnosis, Division of Oral Medicine, University of Connecticut School of Dental Medicine, Farmington, CT 06030, USA. lalla@nso2.uchc.edu
Tanzer
Marvin L
ML
Kreutzer
Donald L
DL
D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005337:Fibrin / Q000737:chemistry / Q000494:pharmacology*; D005338:Fibrin Fibrinogen Degradation Products / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D046911:Macromolecular Substances; D008297:Male; D009062:Mouth Neoplasms / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects*
D005338:Fibrin Fibrinogen Degradation Products; D016209:Interleukin-8; D046911:Macromolecular Substances; D009842:Oligopeptides; D010446:Peptide Fragments; C033786:fibrinogen Bbeta (15-42); C048770:glycyl-histidyl-arginyl-proline; D005337:Fibrin