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Keratinocytes and Head and Neck Squamous Cell Carcinoma Cells Regulate Urokinase-type Plasminogen Activator and Plasminogen Activator Inhibitor-1 in Fibroblasts
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
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2013 (English)In: Anticancer Research, ISSN 0250-7005, Vol. 33, no 8, 3113-3118 p.Article in journal (Refereed) Published
Abstract [en]

Background: To investigate possible differences in the effects of soluble factors from oral squamous cell carcinoma (SCC) cells (UT-SCC-87) and normal oral keratinocytes (NOK) on fibroblast expression of genes involved in tumor stroma turnover. Materials and Methods: Transwell co-cultures with fibroblasts in collagen gels, and SCC cells or NOK in inserts were carried out. Fibroblast gene expression was measured with real-time polymerase chain reaction (PCR). Results: The expression of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) was up-regulated in co-cultures with SCC cells but not with NOK. In contrast, both SCC cells and NOK regulated matrix metalloproteinase-1 (MMP1) and -3, and tissue inhibitor of metalloproteinases-2 (TIMP2) and -3 to a similar extent, while MMP2 and TIMP1 were largely unaffected. Interleukin 1 alpha (IL1 alpha) up-regulated both MMP1 and MMP3 and down-regulated PAI-1, TIMP2 and -3. Conclusion: SCC and NOK regulate fibroblast expression of genes involved in tumor stroma turnover differentially in vitro. These observations may contribute to a better understanding of the mechanisms behind extracellular matrix turnover in tumors.

Place, publisher, year, edition, pages
2013. Vol. 33, no 8, 3113-3118 p.
Keyword [en]
Head and neck cancer, keratinocytes, differential regulation, PAI-1, uPA
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-206561ISI: 000322559300018OAI: oai:DiVA.org:uu-206561DiVA: diva2:644919
Available from: 2013-09-02 Created: 2013-09-02 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, MalinRubin, KristoferGerdin, BengtNowinski, Daniel
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