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Effects of cytokines on matrix metalloproteinase expression in squamous cell carcinoma in vitro
Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
Departments of Otorhinolaryngology—Head and Neck Surgery and Medical Biochemistry, University Hospital and University of Turku, Turku, Finland.
Department of Medical Oncology, University Hospital, Linköping, Sweden.
2007 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 125, no 7, 765-773 p.Article in journal (Refereed) Published
Abstract [en]

Objective: MMPs play an important role in enhanced intra-tumoral proteolytic activity, promoting angiogenesis and invasion by acting on extracellular matrix substances. Cytokines secreted by tumour-infiltrating immune cells, fibroblasts and tumour cells can modulate MMP expression and secretion by cancer cells. The objective of this study was to investigate the effects of IL-6, soluble IL-6 receptor (sIL-6R), HGF, TNF- and IL-8 on MMP-1, -2 and -9 expression by two oral squamous cell carcinoma cell lines (UT-SCC-20A and -24A).

Material and methods: ELISA was used to analyse secretion of total MMP protein and gelatin zymography was used for activity analysis.

Results: IL-6 had a moderate stimulatory effect on MMP-1 secretion in both cell lines, whereas sIL-6R had no effect. When these cytokines were added together, a dose-dependent, synergistic stimulatory effect was observed. HGF also upregulated MMP-1 secretion, especially in one cell line (UT-SCC-24A), and a synergistic effect was observed when HGF was added to IL-6 in both cell lines. MMP-9 secretion by UT-SCC-24A was increased when stimulated with HGF and IL-6 combined with sIL-6R, whereas no effect was found in the other cell line. TNF- stimulated MMP-9 secretion in both cell lines, but only stimulated MMP-1 secretion in one (UT-SCC-24A). The zymographic results were consistent with the ELISA results, indicating an upregulation of active enzyme when a stimulatory effect on protein expression was detected.

Conclusions: The intra-tumoral cytokines IL-6, hepatocyte growth factor (HGF) and tumour necrosis factor- (TNF-) stimulate oral cancer cells to enhanced secretion of matrix metalloproteinase (MMP)-1 and -9. These results contribute to an understanding of the extracellular events necessary for tumour progression.

Place, publisher, year, edition, pages
2007. Vol. 125, no 7, 765-773 p.
Keyword [en]
Cytokine, matrix metalloproteinase, oral cancer, squamous cell carcinoma
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-12807DOI: 10.1080/00016480510027484OAI: oai:DiVA.org:liu-12807DiVA: diva2:17092
Available from: 2007-11-28 Created: 2007-11-28 Last updated: 2017-12-14
In thesis
1. Head and Neck Cancer: Factors Affecting Tumour Growth
Open this publication in new window or tab >>Head and Neck Cancer: Factors Affecting Tumour Growth
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Head and neck cancer is the fifth most common cancer worldwide with an estimated annual global incidence of over 500 000 cases. These malignant tumours develop in the mucosal linings of the upper respiratory tract or in the salivary glands. The most common sites are in the oral cavity and larynx. Treatment modalities comprising surgery and chemoradiotherapy have improved significantly during the last 20 years, but not the long-term survival of patients. The aim of this thesis was to study the different factors affecting tumour growth in head and neck cancer that may have clinical implications in the future. Factors involving apoptosis, cell cycle activity, inflammation, and enzyme activity were of special interest.

The results of the thesis indicate that patients with malignant salivary gland tumours having the lowest level of actively replicating cells have the best prognosis. The largest amount of replicating cells in tongue cancer specimens was found in the peripheral areas of tumour nests. Metallothionein, a protein that can hinder apoptosis, was found in excess in the same areas, whereas apoptosis activity was considerably lower. Taken together, these results indicate that the most aggressive cancer cells are found in the peripheral areas of tumours where apoptosis may be hindered.

The expression of the death receptor Fas was higher in tongue cancer specimens than in normal mucosa. The expression of this receptor was studied further in two cell lines established from oral cancers. When a low dose of cisplatin was added to cell cultures, the Fas expression was enhanced in both cell lines and, furthermore, the Fas-induced apoptosis was increased in one of the cell lines. The results show that a common chemotherapeutic drug given in a low, less toxic dose may enhance receptor-mediated apoptosis of cancer cells.

Malignant solid tumours are often distinguished by an increased proteolytic activity resulting in invasive growth, neo-angiogenesis, and metastases. This activity is conducted by enzymes that are secreted from tumour cells, or from normal cells in the tumour microenvironment. The regulation of enzyme secretion may be mediated by cytokines, small signalling molecules also present in cancer tissue. The results of this thesis show that two cytokines can synergistically induce enzyme secretion (matrix metalloproteinase-1 and -9) from oral cancer cells. Cytokine tumour necrosis factor-alpha and hepatocyte growth factor added alone to cell cultures strongly stimulated secretion of these enzymes. Thus, the tested cytokines, which are commonly secreted by fibroblasts and immune cells, may promote tumour growth.

This thesis has contributed to an increased understanding of factors affecting tumour growth in head and neck cancer. The upcoming cancer therapies will be based on the increasing knowledge of these and other aberrant cellular mechanisms that may vary between different cancer forms.

Place, publisher, year, edition, pages
Institutionen för klinisk och experimentell medicin, 2007. 54 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1032
Keyword
Head and neck cancer, Chemoradiotherapy, Tumour, Malignant salivary, Metallothionein, Neo-angiogenesis, Metastases, Cytokine tumour necrosis factor-alpha, hepatocyte growth factor
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-10348 (URN)978-91-85895-31-1 (ISBN)
Public defence
2007-12-07, S. Entrén (Ingång 1), Universitetssjukhuset, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2007-11-28 Created: 2007-11-28 Last updated: 2017-08-30

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Sundelin, KaarinaRoberg, Karin

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Oto-Rhiono-Laryngology and Head & Neck Surgery Faculty of Health SciencesDepartment of ENT - Head and Neck Surgery UHL
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