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Interleukin-1-mediated effects of normal oral keratinocytes and head and neck squamous carcinoma cells on extracellular matrix related gene expression in fibroblasts
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2012 (English)In: Oral Oncology, ISSN 1368-8375, Vol. 48, no 12, 1236-1241 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: The composition of tumor stroma and the activity of tumor associated fibroblasts are important for tumor growth. Interactions between carcinoma cells and fibroblasts regulate the turnover of extracellular matrix (ECM). Here, the in vitro effects of oral squamous cell carcinoma (SCC) cells (UT-SCC-30 and UT-SCC-87) on fibroblast expression of genes for ECM components and connective tissue growth factor (CTGF/CCN2), were compared to those of normal oral keratinocytes (NOK). Materials and Methods: Cocultures with fibroblasts in collagen gels and keratinocytes with the two cell types separated by a semi permeable membrane were used, and relative gene expression was measured with real-time PCR. Results: All investigated genes were regulated by NOK and the SCCs. The downregulation of pro-collagens alpha 1(I) and alpha 1(III) was more pronounced in cocultures with NOK, while the expression of CCN2 and fibronectin was downregulated by both NOK and the SCCs to a similar extent. UT-SCC-87, but not UT-SCC-30, secreted significantly more IL-1 alpha than NOK. A recombinant interleukin-1 receptor antagonist reversed many of the observed effects on fibroblast gene expression suggesting involvement of IL-1 in cocultures with NOK as well as with SCCs. Conclusion: The observed differential effects on fibroblast gene expression suggest that NOK are more antifibrotic compared to UT-SCC-30 and UT-SCC-87. These findings may contribute to a better understanding of the mechanisms behind ECM turnover in tumors.

Place, publisher, year, edition, pages
2012. Vol. 48, no 12, 1236-1241 p.
Keyword [en]
Cocultures, Extracellular matrix, Interleukin-1 alpha, Tumor stroma
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-188413DOI: 10.1016/j.oraloncology.2012.06.013ISI: 000311151200007OAI: oai:DiVA.org:uu-188413DiVA: diva2:578241
Available from: 2012-12-17 Created: 2012-12-17 Last updated: 2014-06-30Bibliographically approved
In thesis
1. Interactions between Malignant Keratinocytes and Fibroblasts: Studies in Head and Neck Squamous Cell Carcinoma
Open this publication in new window or tab >>Interactions between Malignant Keratinocytes and Fibroblasts: Studies in Head and Neck Squamous Cell Carcinoma
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Carcinoma growth requires a supportive tumor stroma. The concept of reciprocal interactions between tumor and stromal cells has become widely acknowledged and the connective tissue activation seen in the malignant process has been likened to that of a healing wound. Little is, however, known about the specific characteristics of these interactions, distinguishing them from the interplay occurring between epithelial and stromal cells in wound healing. In order to study differences in the humoral effects of malignant and benign epithelial cells on fibroblasts, we used an in vitro coculture model with human oral squamous cell carcinoma cells (SCC) or normal oral keratinocytes (NOK) on one side of a semi-permeable membrane and fibroblasts seeded in gels on the other. Pro-collagens α1(I) and α1(III) were more downregulated in NOK cocultures compared to SCC cocultures. IL-1α was identified as a major keratinocyte-derived soluble factor behind the effects observed. We concluded that SCC are less antifibrotic compared to NOK. There was also a differential expression among enzymes involved in ECM turnover. The urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) were both upregulated by NOK, but not by SCC. Here, rIL-1ra caused further upregulation of PAI-1. Global gene expression in fibroblasts was assessed using Affymetrix™ arrays. In total, 82 transcripts were considered differentially expressed; 52 were up- and 30 were downregulated in SCC compared to NOK cocultures. Among the differentially expressed genes there was an enrichment of genes related to collagens and to a nonspecific, innate-type response. The innate response marker pentraxin (PTX3) was upregulated by keratinocyte-derrived IL-1α in both NOK and SCC cocultures. We observed a considerably higher IL-1α / IL-1ra quotient in SCC cocultures, however, while PTX3 mRNA upregulation was higher in SCC cocultures, there was no difference in the level of PTX3 secreted protein. Taken together, we concluded that NOK and SCC regulate genes important for ECM composition and for the innate immune-response differentially. IL-1α was identified as one important mediator of the observed effects. In general, SCC appeared to be more profibrotic in their effects on fibroblasts. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 48 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 990
coculture, extracellular matrix, interleukin-1 alpha, tumor stroma, differential gene regulation, innate response
National Category
Research subject
Plastic Surgery
urn:nbn:se:uu:diva-221109 (URN)978-91-554-8926-7 (ISBN)
Public defence
2014-05-21, Skoogsalen, Akademiska sjukhuset, Uppsala, 09:15 (Swedish)
Available from: 2014-04-29 Created: 2014-03-25 Last updated: 2014-06-30

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Hakelius, MalinReyhani, VahidRubin, KristoferGerdin, BengtNowinski, Daniel
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