Projects

 

I. Epidemiology and detection of oral cancer
Senior researcher: Saara Kantola, DDS, PhD, Specialist in Oral Pathology

The incidence of tongue cancer has been found to be increasing in Western countries, including Finland. The survival rate has not improved during the last decade because the majority of patients still present at an advanced stage. Patient delay has remained the same over the years and has been found to be difficult to influence. There is also a delay in diagnosis by physicians and dentists due to misdiagnosis of tongue cancer at the initial professional evaluation (Kantola et al. 2001). Our aim is to extend our investigation to all forms of oral cancer in Finland. In particular we aim to understand the process of diagnosis of oral cancer in primary care in order to improve the ways to reduce the delay of the detection and early treatment of the oral cancer patients.

II. Endogenous angiogenesis inhibitors and oral cancer
Senior researcher: Pia Nyberg, PhD
Academy of Finland Research Scientist 2007-2009
Phone (08) 537 5515, email pia.nyberg(at)oulu.fi
Doctoral Students:
Sini Nurmenniemi, MSc
Angiogenesis, the formation of new capillaries, is among the key factors in cancer growth. The expansion of solid tumors is critically dependent on angiogenesis. MMPs were previously thought to facilitate cancer progression by promoting angiogenesis, invasion and metastasis, but new concepts have emerged: MMPs play crucially important roles in liberating anti-angiogenic and anti-tumor fragments from the matrix as well as modulating growth factor and receptor functions.
Series of anti-angiogenic factors have been described, of which many are fragments of naturally occurring extracellular matrix proteins. Endostatin was the first matrix-derived angiogenesis and tumor growth inhibitor identified. Arresten is another anti-angiogenic and anti-tumor cryptic fragments derived from a collagen molecule. Although the main focus has been on the anti-angiogenic activity of these molecules, it should be noted that they inhibit tumor growth not only via endothelial cells but also by directly affecting the behavior of carcinoma cells and the tumor microenvironment. The results from this project will shed light to the mechanisms of endogenous inhibitors of angiogenesis, particularly in the growth of aggressive oral SCCs.

 

III. Organotypic carcinoma models
Senior researcher: Pia Nyberg, PhD
Academy of Finland Research Scientist 2007-2009
Tel (08) 537 5515, email pia.nyberg(at)oulu.fi
Sirpa Salo, PhD
Doctoral Students:
Sini Nurmenniemi, MSc
Overall in the cancer research field, it is most important to design experiments that mimic the complex tumor microenvironment as closely as possible. The three-dimensional organotypic carcinoma models have become increasingly popular as they include the carcinoma cells, fibroblasts and extracellular matrix molecules into the same experimental system. We have developed and characterized a novel organotypic carcinoma model to mimic the actual tumor environment better than the previous models. Carcinoma cell invasion has traditionally been studied in organotypic cultures composed of type I collagen and fibroblasts. However, this system is artificial compared to the real tumor microenvironment. Our novel organotypic model is based on human uterine leiomyoma tissue that creates a more natural environment for carcinoma cells and is an improved tool to better understand the complex nature of tumor microenvironment, to study cell-cell and cell-matrix interactions and to develop effective new strategies for treatment of oral cancer.
IV. Tumor-associated trypsin-2 in tongue cancer
Senior researcher: Pia Nyberg, PhD
Academy of Finland Research Scientist 2007-2009
Phone (08) 537 5515, email pia.nyberg(at)oulu.fi
Virve Pääkkönen, PhD
Doctoral Students:
Suvi-Tuuli Vilen, DDS (Biomedicum, Helsinki)
The tumor microenvironment includes various proteases that are able to affect each others activity via proteolytic cascades. In addition to MMPs, other protease families, such as serine proteases are involved in oral SCC growth. Trypsins are serine proteases that play an important role in carcinoma progression although originally characterized as digestive enzymes in the pancreas. Tumor-associated trypsins differ from their pancreas counterparts based on enzymatic and chemical properties. We have demonstrated that cancer-related trypsin-2 activates efficiently various MMPs at remarkable low concentrations in vitro, and efficiently fragments also fibrillar collagen type I. Overexpression of tumor trypsin-2 in tongue carcinoma cells significantly increases the amount of active MMP-9 and tumor cell invasion. Furthermore, trypsin-2 and MMP-9 are co-localized in vesicles within the carcinoma cells, and our most recent experiments show that trypsin-2 makes the oral carcinoma cells more metastatic in nude mice. Our purpose is to further analyze the role and mechanisms of trypsin-2 in cancer progression.
V. Role of matrix metalloproteinase-8 in oral diseases and biology
Doctoral students:
Pirjo Åström, MSc
Jarkko Korpi, BDS
Matrix metalloproteinase-8 (MMP-8) is a type I collagenase expressed and stored mainly by polymorphonuclear leukocytes. MMP-8 is released to the tissue upon inflammatory conditions and an increased level of MMP-8 has been detected in chronic inflammations, including periodontitis, as well as in cancer
Our study aims to find the molecular mechanisms by which MMP-8 participates in tumor formation and oral diseases.
Results from our project demonstrate that MMP-8 expression is associated with improved survival of tongue carcinoma patients and results from animal studies are in support of this. MMP-8 could therefore be a potential marker for tongue carcinoma diagnostics in the future.
We have further studied the role of MMP-8 in oral mucosal and tooth socket wound healing. Preliminary findings show that lack of MMP-8 accelerates oral mucosal wound healing, indicating that MMP-8 might have a growth repressing role in the oral mucosa which could be beneficial for cancer patients.
VI. Protective role of MMP-8 and destructive role of MMP-28 in oral cancer
Senior researcher: Meeri Sutinen, PhD
Laboratory Chief (substitute 1.1.2007–16.12.2009)
Phone (08) 537 5499, email: meeri.sutinen(at)oulu.fi
Deregulation of several MMPs is associated with tumor progression in head and neck cancers. The absence of MMP-8 strongly increases the incidence of skin tumors in mice and MMP-8 expression improves the survival of tongue cancer patients, especially in females. MMP-28 (epilysin) is the newest member of the MMP family. It is expressed in a number of normal tissues. Enhanced MMP-28 expression has been observed in different forms of cancer and upregulation of MMP-28 in oral squamous cell carcinomas has been described.
We will study further the protective role of MMP-8 and the destructive role of MMP-28 in tongue carcinomas using separate transfections of MMP-8 and -28 constructs into tongue SCC cell lines (high and low invasive) and analyzing their effects on apoptosis, adhesion, growth, migration and invasion of transfected cells by using both Transwell® and organotypic assays.
It is hoped that this study will give an insight into the role of protective and destructive MMPs in the occurrence and progression of oral cancer. The purpose of these studies is to detect the changes occurring in the cell behaviour after overexpression of MMP-8 or -28. It is supposed that differences in MMP-8 and -28 expression are important in tumor progression and behaviour.
VII. Effects of Emdogain® on oral health
Doctoral student: Matti Laaksonen, DDS (Biomedicum, Helsinki)
Emdogain, a widely used commercial product in dentistry, is isolated from the developing teeth of pigs. It is powerful in promoting periodontal regeneration, i.e. the restoration of alveolar bone and collagenous ligaments. The predominant compound of this product is amelogenin (>90%), but EMD contains also various partially still unknown growth factors. It has been shown that EMD enhances periodontal ligament cell, gingival fibroblast, as well as osteogenic cell proliferation and migration but reduces the normal epithelial cell migration. Our study aims to find the effects of EMD on oral mucosal health, including cancer.
VIII. Claudins in oral tumors
Doctoral student: Ibrahim Bello, DDS
Claudins form a family of at least 24 members of the epithelial tight junction trans-membrane protein complex. Claudins regulate transport of ions, water and proteins between epithelial cells (gate function), and play an important role in maintaining cell polarity (fence function). Claudins take part in cancer growth and invasion processes at least to some extent through MMP-dependent pathways. Our purpose is to analyze the role of MMP-modulation of claudins in oral carcinomas and odontogenic tumors.
IX. Defensin expression in human oral keratinocytes
Doctoral student: Aleksi Rytkönen, DDS
Defensins are small cationic antimicrobial peptides produced by neutrophils and epithelial cells that play an important role in the innate host defense system. They participate in the response to infection by signaling host responses. They act as chemoattractants and activators of immune cells. Innate immunity maintains the microbial ecology of healthy oral mucosa. The alfa- and beta-defensin subfamilies exhibit broad-spectrum activity against gram-positive and gram-negative bacteria, mycobacteria, and fungi. In cancer progression defensins have cytotoxic, anti-angiogenic and immunomodulatory properties. Our purpose is to study the variation of beta-defensin expression in oral epithelial keratinocytes in vivo and in vitro.