AbstractsMedical & Health Science

Matrix metalloproteinases and toll-like receptors in early-stage oral tongue squamous cell carcinoma

by Laura K. Mäkinen

Institution: University of Helsinki
Department: Institute of Clinical Medicine; Department of Otorhinolaryngology - Head and Neck Surgery, and Department of Pathology, Helsinki University Hospital, and Doctoral Programme in Clinical Research, University of Helsinki
Year: 2015
Keywords: lääketiede
Record ID: 1141213
Full text PDF: http://hdl.handle.net/10138/154663


Predicting the clinical course of an early-stage oral tongue squamous cell carcinoma (OTSCC) is challenging, as even small tumors can behave aggressively. OTSCC often metastasizes to the cervical lymph nodes, and the presence of lymph node metastasis at the time of diagnosis is considered the most important tumor-related prognostic factor in OTSCC. The mechanisms of this disease progression are poorly understood. Despite slight improvement in the prognosis of OTSCC in recent decades, the outcome of these patients is still modest. Therefore, a deeper understanding of the phenomena behind tumor progression would enable medical professionals to evaluate the aggressiveness of the disease and to adjust its treatment more effectively. The extracellular matrix and basement membrane must be broken down before a tumor can invade surrounding tissues and further spread into blood and lymph vessels. This is a process that involves various proteolytic enzymes, the most important of which are matrix metalloproteinases (MMPs). Over 25 structurally related, but genetically distinct, human MMPs have been identified and characterized: collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and other MMPs. Toll-like receptors (TLRs) are pattern-recognition molecules involved in innate immunity that are also expressed in many types of cancer. TLRs apparently play a pivotal role in malignant disease: they are related to tumor progression and, conversely, to cancer inhibition. Their expression pattern and role in oral cancer, however, remains unclear. In this thesis we studied the expression of MMPs 2, 7, 8, 9, 13, and 25 and TLRs 2, 4, 5, 7, and 9 in early-stage OTSCC. The study comprised 73 consecutive clinically T1N0M0 and T2N0M0 OTSCC patients treated at the Helsinki University Hospital, Helsinki, Finland in 1992-2002. We prepared tissue array blocks from primary tumors and immunostained them. We also used whole section slides from patients with metastasized or recurrent disease. We compared immunoexpression of MMPs and TLRs to tumor and patient characteristics as well as to patient outcomes. We also used Western immunoblot to examine TLR-2 and -4 expression in the highly invasive and aggressive HSC-3 OTSCC cell line. In addition, we studied the effect of TLR-2 and -4 antagonist GIT27 (4,5-dihydro-5-isoxasoleacetic acid) on the invasion of the HSC-3 cell line in myoma organotypic invasion assay. OTSCC tumors expressed both MMPs and TLRs. Nuclear expression of MMP-13, but not cytoplasmic expression of MMP-2, -8, and -9, associated with deeper invasion and advanced tumor size. Furthermore, high nuclear MMP-13 expression predicted poor disease-specific survival. High MMP-7 protein expression associated with the presence of occult cervical metastases, increased invasion depth, and higher tumor grade, and also predicted poor outcome. Immunostaining of MMP-25 failed to correlate with any clinical parameters. High TLR-2, -4, and -9 expression correlated with deeper tumor invasion. Cytoplasmic expression of TLR-2…