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Normal oral keratinocytes and head and neck squamous carcinoma cells induce an innate response 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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0003-2789-6276
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
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2016 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 36, no 5, p. 2131-2137Article in journal (Other academic) Published
Abstract [en]

Background: Tumor stroma is similar to the connective tissue of chronic inflammation. The extracellular matrix of tumors is formed by cancer-associated fibroblasts that also modulate the inflammatory response. Materials and Methods: We studied the ability of oral keratinocytes (NOK) and oral squamous cell carcinoma cells (SCC) to induce an innate immune response in fibroblasts. Co-cultures with fibroblasts in collagen gels and keratinocytes in inserts were used. Pentraxin 3 (PTX3) was used as an indicator of an innate immune response. Results: SCC and NOK up-regulated fibroblast mRNA expression and protein release of PTX3. mRNA levels were more pronounced in cultures with malignant cells. The induction of PTX3 was abrogated by an interleukin-1 receptor antagonist Conclusion: Keratinocytes have the capacity to induce an interleukin-1-dependent innate immune response by fibroblasts in vitro. This could be important for subsequent fibroblast modulation of the inflammatory reaction in non-malignant and malignant disease processes.

Place, publisher, year, edition, pages
2016. Vol. 36, no 5, p. 2131-2137
Keywords [en]
co-culture, pentraxin-3, extracellular matrix, interleukin-1 alpha, tumor stroma
National Category
Surgery Cancer and Oncology
Research subject
Plastic Surgery
Identifiers
URN: urn:nbn:se:uu:diva-221123ISI: 000375456200010PubMedID: 27127114OAI: oai:DiVA.org:uu-221123DiVA, id: diva2:708072
Available from: 2014-03-26 Created: 2014-03-25 Last updated: 2017-12-05Bibliographically 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. p. 48
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 990
Keywords
coculture, extracellular matrix, interleukin-1 alpha, tumor stroma, differential gene regulation, innate response
National Category
Surgery
Research subject
Plastic Surgery
Identifiers
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)
Opponent
Supervisors
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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