STUDY LIMITATIONS AND FUTURE DIRECTIONS

The patient material of the study was small and collected retrospectively, thus a possibility of selection bias was present. The study was single centered and all the clinical data were not available to the researchers.

We were not able to study the activation of the metalloproteinases in vitro, which makes LW GLI¿FXOW WR XQGHUVWDQG WKH HIIHFWV RI 003V LQ WXPRU PLFURHQYLURQPHQWV7KH VDPH problem is evident in almost all of our papers. As immunohistochemistry was almost the only method used, validation of the results with other methods was not undertaken. We GLGQRWVWXG\WKHHIIHFWRIWKH7/5DJRQLVWÀDJHOOLQRQWKHDFWLYDWLRQRI1)ț%RUWKH induction of cytokine production.

,ZRXOGSURSRVHWZRSDWKVIRUWKHIXWXUHVWXG\RI26&&DQG&6&&7KH¿UVWSDWKZRXOG be a multicenter clinicopathological study on HRA models and survival. The second path would be collecting individual tumors and studying mutations and the invasion capabilities of each tumor in vitro.

CONCLUSIONS

Taken together OSCC and CSCC are epithelial cancers which progress and invade in similar steps. As described previously, OSCC has a poorer prognosis than CSCC, thus single or more likely multiple differences should be found between these tumors. These differences, if present, are situated in the tumor cells, in the tumor stromal cells, in the communication between tumor cells and stromal cells or in the communication within tumor cells or stromal cells. In our study, OSCCs and CSCCs expressed the following histological, epithelial and stromal markers differently:

OSCC had poorer WPOI than CSCC, but stromal LHR and CAFs were similarly expressed in OSCC and CSCC but did not predict OSCC or CSCC behavior.

E-cadherin and Snail were similarly expressed in OSCC and CSCC tumors. In both OSCC and CSCC, E-cadherin expression in the tumor epithelium decreased in the invasive fronts. E-cadherin and Snail expression could not explain the different behaviors of these tumors in our study.

Syndecan-1 expression decreased similarly in the invasive fronts of OSCC and CSCC possibly the result. Syndecan-1 expression in stromal tissue of tumors with LQYDVLRQGHSWKVRYHUPPZDVKLJKHULQ26&&WKDQLQ&6&&:HSURSRVHWKDW soluble syndecan-1 expression might induce this invasion.

MMP-7 was expressed mainly in the invasive fronts of OSCC and CSCC and the expression was stronger in OSCC. MMP-8 and -9 were absent from the tumor HSLWKHOLXP DQG ZHUH PDLQO\ LQ SHULWXPRUDO LQÀDPPDWRU\ FHOOV DQG LQ 26&& peritumoral MMP-9 was more abundant than it was in CSCC.

TLR-5 was more strongly expressed in OSCC than in CSCC. In in vitro studies, 7/5OLJDQGÀDJHOOLQZDVDEOHWRLQGXFHWKHSUROLIHUDWLRQPLJUDWLRQDQGLQYDVLRQ of less aggressive oral and cutaneous cell lines. Flagellin had no effect on the most aggressive oral cancer cell line.

ACKNOWLEDGMENT

This PhD thesis project was done during the years 2009-2015 at the University of Helsinki. The research and experiments were performed at the Department of Oral and Maxillofacial Diseases, Department of Pathology, University of Helsinki and at the 0HGLFDO5HVHDUFK&HQWHU2XOX8QLYHUVLW\RI2XOX7KLVVWXG\ZDV¿QDQFLDOO\VXSSRUWHG by Helsinki University Central Hospital Research Funds, the Dental Society of Apollonia and the University of Helsinki.

My respect and my gratitude belong to my supervisors Docent Jaana Hagström and Prof. Timo Sorsa. Docent Hagström has been guiding me through all of my years at the university. She supervised my D.D.S thesis and encouraged me to continue with the research. I really admire the passion and the determination that Jaana posses. I met Prof. Sorsa in early 2009 when we discussed a possible PhD-thesis. Professor Sorsa has always been there when needed. He has continuously believed in the project even when I have been ready to throw in the towel after some setbacks. Timo has an amazing knowledge of VFLHQFHHVSHFLDOO\LQWKHDUHDRIWKHWLVVXHSURWHLQDVHVDQGLQÀDPPDWLRQ

I am very grateful to Prof. Caj Haglund for all the support and for making me feel well accepted in his research group. I am also very grateful to Prof. Tuula Salo for the collaboration in Oulu and for the good advices. I would like to thank people in our research laboratory and especially Johanna Korvala, PhD, Docent Taina Tervahartiala, Marjatta Kivekäs, Kirsti Kari, Msc, Docent Pirkko Pussinen, Mikko Nieminen, PhD, Elisa Kallio, PhD, Aino Salminen, D.D.S, Kati Hyvärinen, PhD, Elina Aspiala. In Addition I would like to thank Päivi Peltokangas for excellent technical assistance and for the great coffee breaks.

I could not have done this work without my friends and family. Thanks for all the support and love.

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