Kristiina Heikinheimo

• DDS, MS, PhD
• University of Turku

Oral tumors are relatively common in dogs, and canine oral squamous cell carcinoma (COSCC) is the most prevalent oral malignancy of epithelial origin. COSCC is locally aggressive with up to 20% of patients showing regional or distant metastasis at the time of diagnosis. The treatment of choice most typically involves wide surgical excision. Althoug...

Oral tumors are relatively common in dogs, and canine oral squamous cell carcinoma (COSCC) is the most prevalent oral malignancy of epithelial origin. COSCC is locally aggressive with up to 20% of patients showing regional or distant metastasis at the time of diagnosis. The treatment of choice most typically involves wide surgical excision. Althoug...

Ameloblastoma is a benign, locally invasive epithelial odontogenic neoplasm of the jaw. Treatment of choice is jaw resection, often resulting in significant morbidity. The aim of this study was to recapitulate ameloblastoma in a completely humanised 3D disease model containing ameloblastoma cells, osteoblasts and activated osteoclasts to investigat...

Tumour development and progression is dependent upon tumour cell interaction with the tissue stroma. Bioengineering the tumour-stroma microenvironment (TME) into 3D biomimetic models is crucial to gain insight into tumour cell development and progression pathways and identify therapeutic targets. Ameloblastoma is a benign but locally aggressive epi...

Ameloblastoma is an odontogenic neoplasm characterized by slow intraosseous growth with progressive jaw resorption. Recent reports have revealed that ameloblastoma harbours an oncogenic BRAF V600E mutation with mitogen‐activated protein kinase (MAPK) pathway activation and described cases of ameloblastoma harbouring a BRAF V600E mutation in which p...

Ameloblastomas are odontogenic tumors that are rare in people but have a relatively high prevalence in dogs. Because canine acanthomatous ameloblastomas (CAA) have clinicopathologic and molecular features in common with human ameloblastomas (AM), spontaneous CAA can serve as a useful translational model of disease. However, the molecular basis of C...

The cover image is based on the SHORT COMMUNICATION Ultra‐frequent HRAS p.Q61R somatic mutation in canine acanthomatous ameloblastoma reveals pathogenic similarities with human ameloblastoma by Santiago Peralta et al., https://doi.org/10.1111/vco.12487. The cover image is based on the SHORT COMMUNICATION Ultra‐frequent HRAS p.Q61R somatic mutation...

Ameloblastoma is a locally aggressive odontogenic tumor that occurs in humans and dogs. Most ameloblastomas in humans (AM) harbor mutually‐exclusive driving mutations in BRAF, HRAS, KRAS, NRAS or FGFR2 that activate MAPK signaling, and in SMO that activates Hedgehog signaling. The remarkable clinical and histological similarities between canine aca...

BRAF V600E is the most common mutation in conventional ameloblastoma (AM) of the mandible. In contrast, maxillary AMs appear to harbor more frequently RAS, FGFR2, or SMO mutations. Unicystic ameloblastoma (UAM) is considered a less aggressive variant of ameloblastoma, amenable to more conservative treatment, and classified as a distinct entity. The...

Periosteal fasciitis, considered a subtype of nodular fasciitis, is a rare benign soft tissue mass often misdiagnosed as a malignant lesion due to its fast and infiltrative growth pattern and histological features. Nodular fasciitis is usually found in the upper extremities in adults and in the head and neck region in children. Incorrect diagnosis...

Background Inhibition of activin/myostatin pathway has emerged as a novel approach to increase muscle mass and bone strength. Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that leads to progressive muscle degeneration and also high incidence of fractures. The aim of our study was to test whether inhibition of activin receptor IIB li...

The human mandible is said to arise from desmal ossification, which, however, is not true for the entire body of the mandible: Meckel’s cartilage itself is prone to ossification, at least its anterior part in the canine and incisor region. Also, within the coronoid and in the condylar processes there are cartilaginous cores, which eventually underg...

The aim of the study was to characterize the molecular relationship between ameloblastoma and keratocystic odontogenic tumor (KCOT) by means of a genome-wide expression analysis. Total RNA from 27 fresh tumor samples of 15 solid/multicystic intraosseous ameloblastomas and 12 sporadic KCOTs was hybridized on Affymetrix whole genome arrays. Hierarchi...

Ameloblastoma is a benign but locally infiltrative odontogenic neoplasm. Although ameloblastomas rarely metastasise, recurrences together with radical surgery often result in facial deformity and significant morbidity. Development of non-invasive therapies has been precluded by a lack of understanding of the molecular background of ameloblastoma pa...

The often observed directional asymmetry (DA) in human limb bones may have a genetic/developmental basis and/or could emerge from different mechanical loadings across sides due to handedness. Because behavioural lateralization in itself has a genetic basis, it has been suggested that DA in limbs could develop prenatally as a pre-adaptation to adult...

Clinical information for KCOT patients and normal sample donors.

Primer and probe sequences used in real-time RT–PCR and targeted cDNA sequencing.

Real-time RT–PCR analysis of the expression of ERBB4 receptor isoforms in ameloblastoma, keratocystic odontogenic tumour (KCOT) and normal oral mucosa.

Ratios of digit lengths are studied intensively as markers of prenatal sex hormone levels. Study sexual dimorphism in ratios of metacarpals, which received less attention. We studied six metacarpal ratios in deceased human fetuses of ages 10 to 42weeks. We found no indication of a sexual dimorphism at this early stage of development.

Ameloblastomas are locally invasive odontogenic tumors that exhibit a high rate of recurrence and often associate with the third molars. They are suggested to originate from dental epithelium because the tumor cells resemble epithelial cells of developing teeth. Expression of the transcription factor SOX2 has been previously localized in epithelial...

Past investigations of prenatal craniofacial growth have largely relied on histological sections. Few studies have taken measurements on three-dimensional representations (3D reconstruction, 3D CT, postmortem) or varying depth levels (ultrasound), and we know of no craniofacial growth studies done on cleared-and-stained specimens of whole fetal hea...

Patients with Duchenne muscular dystrophy (DMD) carry a mutation in the dystrophin gene that leads to progressive muscle degeneration. In addition, DMD patients develop low bone mass especially in long bones and have high incidence of fractures. The underlying mechanisms for decreased bone mass remain unclear but muscle weakness and increased IL6 l...

Tooth renewal is initiated from epithelium associated with existing teeth. The development of new teeth requires dental epithelial cells that have competence for tooth formation, but specific marker genes for these cells have not been identified. Here, we analyzed expression patterns of the transcription factor Sox2 in two different modes of succes...

Mucoepidermoid carcinoma is the most common salivary gland malignancy, and includes a spectrum of lesions ranging from non-aggressive low-grade tumors to aggressive high-grade tumors. To further characterize this heterogeneous group of tumors we have performed a comprehensive analysis of copy number alterations and CRTC1-MAML2 fusion status in a se...

Tooth enamel has the highest degree of biomineralization of all vertebrate hard tissues. During the secretory stage of enamel formation, ameloblasts deposit an extracellular matrix that is in direct contact with the ameloblast plasma membrane. Although it is known that integrins mediate cell–matrix adhesion and regulate cell signaling in most cell...

In humans, an increasing body of evidence has linked the frequency of cervical ribs to stillbirths, other malformations and early childhood cancers. However, the frequency of cervical ribs in a putatively healthy fetal population is not sufficiently known to assess the actual medical risks of these prenatal findings. We therefore analyzed the prese...

Objectives: Tooth enamel has the highest degree of biomineralization of all hard tissues in the body. During the secretory stage of enamel formation, epithelial ameloblasts deposit an extracellular matrix whose proteins are cleaved by enamelysin (MMP-20) and kallikrein-4 (Klk-4), resulting in almost total enamel matrix protein degradation. During t...

Desmoplakin (DP) anchors the intermediate filament cytoskeleton to the desmosomal cadherins and thereby confers structural stability to tissues. In this study, we present a patient with extensive mucocutaneous blisters, epidermolytic palmoplantar keratoderma, nail dystrophy, enamel dysplasia, and sparse woolly hair. The patient died at the age of 1...

Regeneration of mineralized tissues affected by chronic diseases comprises a major scientific and clinical challenge. Periodontitis, one such prevalent disease, involves destruction of the tooth-supporting tissues, alveolar bone, periodontal-ligament and cementum, often leading to tooth loss. In 1997, it became clear that, in addition to their func...

Some oral squamous cell carcinomas (OSCCs) overexpress epidermal growth factor receptor (EGFR) but little is known about the receptor system overall during oral carcinogenesis. We studied all four ERBB receptors (EGFR, ERBB2-4) in developing (n=2), normal (n=7), dysplastic (n=23) and malignant (n=26) oral epithelia by means of immunohistochemistry....

A hypothesis that OSCCs originating from different types of oral epithelia may have different patient and tumor characteristics was evaluated in this retrospective analysis of 188 patients with primary OSCC treated at Turku University Central Hospital, Turku, Finland in 1988-1997. The tumors were categorized according to the type of oral epithelium...

Little is known about the genetic background of keratocystic odontogenic tumors (KCOT, odontogenic keratocysts). Our aim was to characterize genomic aberrations in sporadic KCOT using cDNA-expression arrays and array-comparative genomic hybridization. For cDNA-expression arrays, 10 KCOT specimens and 20 fetal tooth germs were studied. Quantitative...

Extracellular matrix proteins have been shown to play important roles in the cell migration and differentiation in both normal and pathological conditions. In the present study, we used immunohistochemistry and in situ hybridization to determine the distribution of laminin-5 in ameloblastomas and developing human teeth. In ameloblastomas, the immun...

During the last decade, several molecules regulating tooth development have been identified (http://bite-it.helsinki.fi/). Especially members of the transforming growth factor beta (TGF-β) supergene family, structurally relates cytokines, are essential for teeth to develop. These include TGF-βs, activin A, bone morphogenetic proteins (BMPs), and th...

Whereas developmental biology studies of mice are uncovering details about molecular signaling and morphogenesis, present day knowledge about development remains often too crude to address question about evolutionary transitions. Small changes in spatial configuration of cusps is a frequently modified aspect of mammalian evolution. As intercellular...

Gene expression profiles were studied in 13 cases of salivary gland carcinoma including mucoepidermoid carcinoma (MEC), acinic cell carcinoma (ACC), and salivary duct carcinoma (SDC) using a cDNA array. A total of 162 genes were deregulated. Only 5 genes were overexpressed in all carcinomas including fibronectin 1 (FN1), tissue metalloproteinase in...

Introduction: Six cases are reported, each presented at the 11th Biennial Congress of the International Association of Oral Pathologists as an instructive case for differential diagnosis on the basis of clinical, imaging or histological features. Clinical picture: Case diagnoses included a large, possibly intraosseous, myofibroma presenting with...

Snuff is a locally irritative agent causing hyperkeratinization and hyperplasia of the oral epithelium. The aim of the study was to investigate the effects of snuff on epithelial cell growth and differentiation in vitro. Three-dimensional HaCaT cell cultures were grown for 6, 12, 14, and 18 days in the presence of 1% snuff extract. Ki-67, p53 and c...

The CD44v6 adhesion molecule has been linked to progression of various carcinomas, but its role in relation to oral-cancer development is not clear. The study was designed to determine whether CD44v6 levels were clinically significant in oral dysplasias. Twenty-nine oral dysplasias were immunostained with CD44v6 antibody on follow-up. Developing no...

Syndecan-1 expression is enhanced in cutaneous and mucosal wounds. We have previously demonstrated that wounding-induced syndecan-1 expression in the skin occurs transcriptionally, through a fibroblast-growth-factor-inducible element (FiRE). Here, we show that FiRE is also activated in mucosal wounds. However, both the expression patterns and the a...

We assessed the immunohistochemical profile of an unusual case of multiple similarly looking tumors in the jawbone of a young patient. Histologically, the tumors exhibited features of adenomatoid odontogenic tumor (AOT) and adenomatoid dentinoma but showed no resemblance to any other defined odontogenic tumor entities. They expressed high amounts o...

The molecular and genetic characteristics of ameloblastoma are still poorly understood. We analyzed gene expression in fresh-frozen ameloblastomas and human fetal tooth germs, using a cDNA microarray. Thirty-four genes exhibited significant changes in expression levels in the ameloblastoma. Eleven genes were overexpressed more than three-fold, and...

Cell proliferation and chromosomal imbalances, important parameters in relation to tumor progression, were studied in ameloblastoma (n=20), a benign odontogenic tumor of locally recurrent nature. Immunocytochemical staining with MIB-1 antibody and comparative genomic hybridization (CGH) were performed on formalin-fixed paraffin-embedded ameloblasto...

The gene for activin betaA is expressed in the early odontogenic mesenchyme of all murine teeth but mutant mice show a patterning defect where incisors and mandibular molars fail to develop but maxillary molars develop normally. In order to understand why maxillary molar tooth development can proceed in the absence of activin, we have explored the...

Tuftelin has been suggested to play an important role during the development and mineralization of enamel. We isolated the full-length human tuftelin cDNA using reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (5′ RACE and 3′ RACE) methods. Sequence analysis of the tuftelin cDNA revealed an open reading...

Bone morphogenetic protein (BMP-6, also known as vegetal-pale-gene-related and decaplentaplegic-vegetal-related) is a member of the transforming growth factor-beta superfamily of multifunctional signaling molecules. BMP-6 appears to play various biological roles in developing tissues, including regulation of epithelial differentiation. To study the...

Although targeted gene disruption of GDF-9, an oocyte derived growth factor, leads to an arrest of folliculogenesis and causes infertility in female mice, little is known on the expression of GDF-9 protein in the ovary. We show that GDF-9 protein is expressed in rat oocytes during folliculogenesis from the early primary follicle stage onwards but t...

Extracellular matrix proteins have been shown to play important roles in the cell migration and differentiation in both normal and pathological conditions. In the present study, we used immunohistochemistry and in situ hybridization to determine the distribution of laminin-5 in ameloblastomas and developing human teeth. In ameloblastomas, the immun...

Activins and bone morphogenetic proteins (BMPs) belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related cytokines. Results of recent in vivo and in vitro studies suggest that activin A, several BMPs, and their cell surface receptors may participate in tooth development. In addition, follistatin an extracellular...

To investigate the feasibility of topical psoralen PUVA (sensitization in photosensitizing psoralen drug + UVA radiation) treatment of oral lichenoid lesions (OLL). A total of 16 patients with OLL were treated using a 0.01% trioxsalen ointment and UVA doses in the 0.09 to 1.80 J/cm2 range. The average number of sessions was 8.7 and a mean cumulativ...

It has recently been shown that mice deficient in activin-beta A subunits and follistatin exhibit major defects in dentition. To increase understanding of the roles played by these molecules during tooth development, we determined the temporospatial expression of activin-beta A subunit and follistatin messenger RNA and their corresponding proteins...

We have shown, by using two monoclonal antibodies (143DB7 and 100EB2), that the expression of the extracellular matrix protein tenascin (Tn) is increased in the connective tissue of biopsies taken from snuff users' and tobacco smokers' oral mucosa. In normal oral mucosa Tn was, seen to underlie the epithelium as a thin delicate band. The most inten...

Differences in the expression of cytokeratins (CK) in specimens obtained from snuff-affected oral epithelium of the maxillary vestibular sulcus and clinically normal sulcular epithelium were studied by indirect immunofluorescence staining with a panel of monoclonal antibodies (MAbs). CK 14, a marker of stratified squamous epithelium was not seen ex...

Formation and degradation of dental basement membrane (BM) are important for tooth development. Data on the expression of genes for type IV collagen (the major structural component of the BM) and type IV collagenases [MMP-2 (72 kDa) and MMP-9 (92 kDa)], enzymes that degrade type IV collagen during human tooth development, are lacking. We studied ex...

Members of the decapentaplegic-Vg-related (DVR) gene family are diffusible signaling molecules regulating inductive tissue interactions during vertebrate development. Expression of DVR/bone morphogenetic protein (BMP) 2, 4, and 6 was studied in human fetal teeth. Sequential morphogenetic stage-specific studies of DVR/BMP 2 and 4 mRNA expression by...

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) regulate cell proliferation and functional maturation through the EGF receptor (EGF-R). Their roles in human tooth development and odontogenic tumorigenesis have not been explored. We studied the expression of EGF, TGF-alpha and EGF-R in human fetal teeth (cap stage to e...

We studied the expression of inhibin/activin subunit mRNAs in granulosa-luteal cells of preovulatory ovarian follicles obtained from women undergoing in vitro fertilization, and in corpus luteum tissue samples of early pregnancy. Northern analysis of granulosa-luteal cell and corpus luteum RNA with single-stranded cDNA or cRNA probes revealed an 1....

Dysregulation of TGF beta 2, a modulator of cell growth and differentiation, can result in uncontrolled growth and tumor formation. Our comparative studies on the expression of TGF beta 2 mRNA and protein indicate that TGF beta 2 may primarily be a regulator of epithelial differentiation during tooth development (between 13 and 20 gestational wk) a...

Inhibin subunit messenger ribonucleic acids (mRNAs) are expressed during the gonadal development of rodent, ovine, and bovine fetuses. We investigated the expression of inhibin subunit mRNAs in human fetal gonads between 13 and 25 weeks of gestational age. In testes, the alpha-subunit mRNA was highly expressed at the beginning of the second trimest...

Transforming growth factor-alpha (TGF-alpha) mRNA is expressed in several pancreatic cancer cell lines, but its expression during normal fetal pancreas development has not been studied. We investigated the expression of TGF-alpha, its receptor (EGF-R) and insulin mRNA and their corresponding peptides in human fetal pancreata (15-20 gestation weeks)...

In situ and Northern hybridization was carried out to study cytokeratin (Ck) 1, 4, 8, 18, and 19 and vimentin (Vim) gene expression in 13- to 24-week-old human fetal tooth germs, including overlying oral epithelium and odontogenic tumors (N = 6) of epithelial (ameloblastoma) and epithelial-ectomesenchymal (ameloblastic fibroma) origin. The results...

A detailed immunohistochemical characterization of different cytokeratin subclasses was performed on frozen tumour tissue from three classical chordomas. Simple epithelium cytokeratins Nos 8, 18, and 19 were detected in all tumour cells while cytokeratin No. 7 was not found. Cytokeratins characteristic of squamous differentiation, including keratin...

In situ hybridization is a new molecular biological technique which has made it possible to demonstrate messenger RNA (mRNA) transcription of a specific gene in tissue sections and in cell preparations. In addition to the immunocytochemical methods widely used to locate gene products, e.g. a protein, nucleic acid hybridization techniques are having...

The distribution of two cellular fibronectins (cFn), tenascin, laminin, as well as type VII collagen was studied in 14 benign odontogenic tumours of epithelial (ameloblastoma) and epithelial-ectomesenchymal (ameloblastic fibroma) origins, as well as in developing human teeth by immunocytochemical means using monoclonal antibodies (Mabs). An extrado...

Using an immunohistochemical assay 10 benign odontogenic tumors were evaluated for expression of the HRAS- and KRAS-encoded gene products p21RAS. Overexpression of p21RAS was found in ameloblastomas, ameloblastic fibromas and odontogenic myxomas compared with normal human developing teeth. The highest expression was noted in a recurrent plexiform a...

Using an immunohistochemical assay 10 benign odontogenic tumors were evaluated for expression of the HRAS- and KRAS-encoded gene products p21RAS. Overexpression of p21RAS was found in ameloblastomas, ameloblastic fibromas and odontogenic myxomas compared with normal human developing teeth. The highest expression was noted in a recurrent plexiform a...

Non-Hodgkin's lymphomas (NHL) presenting through oral symptoms are rare. Between 1976 and 1987, a total of 17 cases (7 male, 10 female) were diagnosed in our departments. The first symptom was an intraoral tumour mass in 9 cases, loosening of teeth in 2 cases and paraesthesia in another 2. Most tumours (13/17) were located in the lower jaw. In only...

Monoclonal antibodies (Mab) were used to study the expression of cytokeratins and vimentin in various histological types of ameloblastoma and in human fetal tooth germ. The ameloblastoma and the tooth germ epithelia showed characteristics of both simple glandular and stratified squamous epithelial cells. Cytokeratin No. 18 was detected focally in m...

Monoclonal antibodies (Mab) were used to study the expression of cytokeratins and vimentin in various histological types of ameloblastoma and in human fetal tooth germ. The ameloblastoma and the tooth germ epithelia showed characteristics of both simple glandular and stratified squamous epithelial cells. Cytokeratin No. 18 was detected focally in m...

Intermediate filaments are found in most nucleated cells as part of their cytoskeleton. Intermediate filaments are formed by different proteins in cells of major tissues types. Therefore, antibodies against intermediate filaments can be used in tissue typing, in the analysis of cell lineages during development and in the elucidation of the origin o...

A botryoid odontogenic cyst (BOC) which recurred 4 times over a period of 9 years is presented. Immunocytochemical comparison of cytokeratin composition of the cyst epithelium with that of the overlying oral epithelium showed distinct differences. The cyst epithelium expressed keratins typical of both simple and nonkeratinizing squamous epithelia....

Immunocytochemistry has opened a new era in research and diagnosis. The development of immunocytochemical methods has made it possible to identify in situ normal and pathological tissue constituents, which it has not been possible to detect using ordinary histological methods. However, immunocytochemical techniques involve several pitfalls, which w...

Members ofthedecapentaplegic-Vg-related (DVR) genefamily arediffusible signaling molecules regulating inductive tissue interactions during vertebrate development. Expression ofDVR/bone morphogenetic protein (BMP) 2,4, and6 wasstudied inhumanfetal teeth. Sequential morphogenetic stage-specific studies ofDVR/BMP2and4 mRNAexpression byinsitu hybridiza...