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Roles of IL-1α in the Growth of Keratocystic Odontogenic Tumor

Oral Science International.2007;4(1):19-27.

Keratocystic odontogenic tumors have a high level of proliferative activity in epithelial cells and they tend to grow aggressively in the jaw. The tumor dramatically decreases in size by decompression of the intracystic fluid pressure. We herein focused on the roles of interleukin (IL)-1α and demonstrated the biochemical mechanisms of the tumor growth. We found that IL-1α is strongly expressed in the lining epithelial cells of the tumors, and the intracystic fluid levels of IL-1α are significantly higher than the levels of the other inflammatory cytokines of IL-6 and tumor necrosis factor-α (TNF-α). The expression of IL-1α in the epithelial cells decreases after the marsupialization of the tumor. In vitro experiments also reveal that positive pressure enhances the expression of IL-1α in the tumor epithelial cells in culture. IL-1α stimulates the production of matrix metalloproteinase (MMP)-9, and activates the released proMMP-9 by increasing the expression of proMMP-3 and plasminogen activator urokinase (u-PA) in the tumor epithelial cells. In the fibroblasts isolated from the tumors, IL-1α increases the expression of proMMP-1, proMMP-2, and proMMP-3. IL-1α also activates proMMP-2 by inducing the expression of membrane-type 1 matrix metalloproteinase (MT1-MMP) synergistically with type I collagen. Furthermore, IL-1α increases the expression of macrophage colony-stimulating factor (M-CSF) and cyclooxygenase (COX)-2 in the fibroblasts. The COX-2 synthesizes prostaglandin E₂ (PGE₂), and the secreted PGE₂ stimulates the expression of receptor activator of nuclear factor-κB ligand (RANKL), while neither IL-1α nor PGE₂ affects the expression of osteoprotegerin (OPG) in the fibroblasts. The fibroblasts express Ca²⁺-sensing receptor (CasR) on the cell surface, and extracellular Ca²⁺ activates COX-2 expression via the CasR. A strong relationship may thus be present between the intracystic fluid pressure and IL-1α expression in epithelial cells, and the released IL-1α may play a crucial role in the growth of keratocystic odontogenic tumors by stimulating proteolytic enzyme production and osteoclastogenesis.

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Expression of Copper Efflux Transporter (ATP7B) in the Transport of Cisplatin in Cell Lines Derived From Invasive Oral Squamous Cell Carcinoma

Kunio Yoshizawa ; Shinichi Nozaki ; Hiroko Kitahara ; Teruhisa Ohara ; Koroku Kato ; Shuichi Kawashiri ; Kiyomasa Nakagawa

Oral Science International.2007;4(1):28-37.

Intrinsic or acquired resistance to cisplatin (CDDP) is a problem for its use in cancer chemotherapy. This resistance has been reported to correlate with expression of the human copper transporter 1 and two copper export pumps, ATP7A and ATP7B. In the current study, we investigated the correlation between the expression of these transporters and sensitivity to CDDP using four cell lines derived from each of high invasive oral squamous cell carcinoma (OSCC) and low invasive OSCC. We found that the amount of CDDP accumulated in high invasive OSCC cell lines (Yamamoto-Kohama criteria: grade 4C and 4D) with strong intrinsic tolerance was lower than in low invasive OSCC cell lines (grade 3) with weak intrinsic tolerance. Additionally, overexpression of ATP7B mRNA in cell lines derived from high invasive OSCC conferred low sensitivity to CDDP. Furthermore, the accumulation and sensitivity of CDDP was higher in HOC313 cells transfected with the ATP7B siRNA than in cells transfected with the nonsense siRNA. These results suggest that the overexpression of ATP7B results in the export of and, therefore, resistance to CDDP. Furthermore, ATP7B may be a key determinant of the intrinsic resistance to CDDP.

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Expression of Urokinase-type Plasminogen Activator (uPA), uPA Receptor, and Plasminogen Activator Inhibitor-1 in Oral Squamous Cell Carcinoma

Yoshiko Inoue ; Tsuyoshi Sugiura ; Ryousuke Matsuki ; Kotaro Ishii ; Katsuhiro Seki ; Kanemitsu Shirasuna

Oral Science International.2007;4(1):38-44.

We investigated whether the expression levels of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1) correlate with clinicopathological features of oral squamous cell carcinoma (SCC). We immunohistochemically examined the expression levels of uPA, uPAR, and PAI-1 in 160 biopsy specimens of oral SCC. Positive stainings for uPA, uPAR, and PAI-1 were observed mainly in SCC cells, and their intensity and number of positive cells were related to lymph node involvement (p < 0.001, p < 0.001, and p < 0.001, respectively). The expression levels of uPA and uPAR were also related to the pattern of invasion (p < 0.05 and p < 0.001, respectively), while both were associated with tumor size (p < 0.05). Moreover, a poor survival rate was related to the expression of uPAR (p < 0.01) and PAI-1 (p < 0.05). These findings suggest that the uPA system may regulate the invasion and metastasis of oral SCC cells.

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Multilineage Cells from Apical Pulp of Human Tooth with Immature Apex

Shigehiro Abe ; Satoshi Yamaguchi ; Teruo Amagasa

Oral Science International.2007;4(1):45-58.

The human tooth with immature apex is a developing organ available for investigation. In this tooth, especially in the apical pulp, the proliferation and differentiation of various cells are activated to make a complete tooth. We investigated the notion that unique cells are included in the apical pulp of human tooth with immature apex. Human impacted third molars with immature apex freshly extracted for orthodontic reasons or treatment were obtained. Histological analyses revealed that BrdU-incorporating cells and cells positive for the mesenchymal stem cell markers SH2 and SH3 were located in the same region. The cells from the apical pulp of a human tooth with immature apex, designated here as apical pulp-derived cells (APDCs), can be cultured easily in vitro under ordinary serum-supplemented culture condition. The expression of surface markers of expanded APDCs is similar to that of bone marrow mesenchymal stem cells, except for CD49d (α4-integrin). APDCs differentiated into mineralized cells, adipocytes, chondroblasts and neural cells in vitro. APDCs have a high capacity for proliferation and multilineage potential in vitro. Our results indicate that human tooth with immature apex is a precious tissue source for the research of human adult stem cells and for the advancement of dental and regenerative medicine.

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Treatment for Localized Langerhans' Cell Histiocytosis of the Maxilla by Corticosteroid Injection

Yoichi Nakagawa ; Satoshi Idesaki ; Kameji Matsumoto ; Katsunori Ishibashi

Oral Science International.2007;4(1):59-62.

This report describes a case of localized Langerhans' cell histiocytosis which occurred in the maxilla of a 23-year-old male. The lesion was treated by an injection of corticosteroids. Corticosteroid treatment for Langerhans' cell histiocytosis of the maxilla is considered to be beneficial because no sequelae remain following the treatment.

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Cancer in Bone

Toshiyuki Yoneda

Oral Science International.2007;4(2):63-72.

Bone is one of the most preferential metastatic target sites for cancers such as breast, prostate and lung cancers. Although the precise molecular mechanism underlying this preference needs to be elucidated, bone appears to possess unique biological microenvironments that allow circulating cancer cells to home, proliferate and survive. As a consequence of cancer expansion, cellular and molecular homeostasis of bone microenvironments is disturbed and bone is destroyed, leading to the development of bone metastases. Thus, understanding of the crosstalk between cancer cells and bone is critical to design mechanism-based effective and specific therapeutic interventions for bone metastases.

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Chemokine Receptor Expression in Oral Squamous Cell Carcinoma

Katsumi Muraoka ; Kazuhiko Okumura ; Hiroyuki Kitajo ; Hidetaka Kato ; Makoto Arisue

Oral Science International.2007;4(2):73-85.

Metastasis is the chief cause of mortality in cancer patients. Recently, chemokines and chemokine receptors were shown to play an important role in the metastasis of various cancers. We examined the role of chemokine receptor-mediated signaling in the invasion potential of human oral squamous cell carcinoma (OSCC) cell lines that were derived from 5 primary tumors and 6 cervical lymph node metastases. Comprehensive analysis of the mRNAs for human chemokine receptors showed that the OSCC cell lines had uniform expression patterns of chemokine receptors. Overall, there were no consistent differences in the expression of chemokine receptors between primary site- and lymph node metastasis-derived cell lines. However, a highly invasive OSCC cell line (SAS-H1) expressed up-regulation of CCR5, CCR6, CCR7, CXCR1, CXCR6 and CX3CR1 compared to a poorly invasive OSCC cell line (SAS-L1). Then we examined whether factors in the tumor microenvironment regulated chemokine receptor expression in SAS-H1 cells. Specifically, transforming growth factor (TGF) -β1 enhanced the expression of CCR5, CCR6, CCR7 and CX3CR1. Pretreatment of SAS-H1 cells with transforming growth factor (TGF) -β1 increased the expression of CCR7 and CX3CR1, and then enhanced CCL21- and CX3CL1-induced directional migration (1.5-fold enhancement as compared with untreated control). In addition, CX3CL1 increased the adhesion of SAS-H1 cells on uncoated tissue culture plates. Neither chemokine stimulated cell proliferation. Treatment of SAS-H1 cells with CX3CL1 activated the phosphotidylinositol-3-kinase (PI3K) and MEK signal transduction pathways. Our results suggest that chemokine receptor-mediated signaling is involved in the local invasion and metastasis of human OSCC.

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Radiological Morphometric Analysis for the Trabecular Bone Structure of Mandibular Condyle after Ovariectomy in Mature Cynomolgus Monkeys

Michiharu Shimamoto ; Yusuke Kozai ; Yukiko Matsumoto ; Ryota Kawamata ; Takashi Sakurai ; Isamu Kashima

Oral Science International.2007;4(2):86-96.

To investigate the effects of experimental osteoporosis on the trabecular structure of the mandibular condyle in cynomolgus monkeys by radiological bone morphometry, ovariectomy (OVX) was performed on 10-year-old female cynomolgus monkeys, which were fed a controlled diet for 2 years. Ten sham control groups were fed under the same conditions. Using a microfocus tube and computed radiography, the removed mandibular condyle samples were imaged by standardized magnification radiography. The structural parameters were measured using radiological bone morphometric analysis. The bone mineral density (BMD) was measured by dual energy X-ray absorptiometry. The thickness of the cortical bone was measured using magnified radiographic images. The thickness of the cortical bone and the BMD in the OVX group were significantly lower than in the sham group. In the results of skeletal structure of the mandibular condyle, the trabecular structure of the mandibular condyle was markedly deteriorated in the OVX group. The trabecular structure of the mandibular condyle for the OVX group was significantly decreased, thus it was suggested that osteoporosis is a potential risk factor of osteoarthritis of the temporomandibular joint.

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A Computational Tongue Model and its Clinical Application

Satoru Fujita ; Jianwu Dang ; Noriko Suzuki ; Kiyoshi Honda

Oral Science International.2007;4(2):97-109.

The tongue possesses a complex muscular structure, and its motor functions are also intricate. Therefore, it would be beneficial to use a computational physiological model of the tongue to examine its vital functions in normal and pathological conditions. Thus far, the studies of tongue models have focused on symmetric movements for normal speech. For clinical purposes, it is necessary to develop a physiological model to deal with daily vital activities such as mastication and swallowing. To do so, we constructed a full 3D physiological model of the tongue based on MRI data from a normal subject, and verified the basic functions of the model based on anatomic and physiological knowledge. In this study, the model was applied to clinical issues: prediction and verification of the changes in movements of the tongue with a tumor before and after partial glossectomy, respectively. Tongue protrusion and lateral bending motion were examined for the prediction and verification. The simulation results were consistent with the observations for a patient with a tumor in the tongue. Comparisons of the simulation and observation in the clinical case showed that the model could predict potential effects of the glossectomy on the tongue movements. It is suggested that the model is a useful tool for pre-operative planning of glossectomy.

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Secondary Squamous Cell Carcinoma of the Oral Cavity in Young Adults after Hematopoietic Stem Cell Transplantation for Leukemia

Kenji Kawano ; Hideyuki Goto ; Yoshihiro Takahashi ; Yoshihisa Kaku ; Kazunari Oobu ; Shigetaka Yanagisawa

Oral Science International.2007;4(2):110-116.

Two cases of secondary oral squamous cell carcinoma (SCC), which developed in recipients of hematopoietic stem cell transplantation (HSCT) for leukemia, are reported. The first patient underwent allogeneic HSCT for chronic myelogenous leukemia at 32 years of age. He suffered from chronic graft-versus-host-disease (GVHD) of the oral mucosa after HSCT, and has subsequently received immunosuppressive therapy. He experienced metachronous multiple SCCs in the maxillary gingiva and the dorsum of the tongue at 36 years and 40 years of age, respectively. The second patient received autologous HSCT for acute myelogenous leukemia at 22 years of age, and she did not experience GVHD after transplantation. SCC developed in the lateral border of the tongue at 27 years of age. PCR analysis detected both HPV16 and HPV18 in the tongue tumor of the first patient, and only HPV18 in that of the second patient, suggesting that the infection of high-risk HPVs was possibly involved in the development of post-HSCT oral cancers in these patients. Since risk factors for post-HSCT oral SCC are not yet well recognized, long-term close follow-up is necessary for the early detection of secondary oral cancers in all transplant recipients.

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