Oral squamous cell carcinoma (OSCC) develops through multistep process, that is, from normal mucosa to hyperplastic area and progressed to dysplasia, carcinoma in situ, and finally to invasive carcinoma. The purpose of this study is to investigate the histological types of the transitional area from normal oral mucosa to invasive carcinoma for the baseline data to search intermediate end point markers for early detection of OSCC. For this purpose, we reviewed the 85 patients who were diagnosed as OSCC in the Department of Oral Pathology, Yonsei University College of Dentistry, from 2002 to 2008. We classified these histopathologic findings by light-microscopy, according to the histologic pattern of transitional areas. As results, stepwise transformation from normal oral mucosa, to dysplasia and to OSCC was shown in 47 patients. Intermittent lesions were seen in 16 patients, in which normal oral mucosa, dysplasia, and OSCC were alternately arranged. Twenty two patients showed abruptly transformed to OSCC from normal oral mucosa. These preliminary data will be used for searching biomarkers for early detection of OSCC.

A rare case of primary intraosseous squamous cell carcinoma(PISCC) arising from lining epithelium of a dentigerous cyst is described. The case occurred at the left mandibular 3rd molar region in a 56-year-old Japanese woman. Clinical observation revealed cyst formation with an impacted 3rd molar, a common finding in dentigerous cyst, in the left mandible. Histopathologically, the lining epithelium of the cyst demonstrated transition from epithelial dysplasia to invasive squamous cell carcinoma(SCC). This case was diagnosed as PISCC arising from lining epithelium of a dentigerous cyst.

Plasminogen activator(PA) system such as urokinase plasminogen activator(uPA), urokinase PA Receptor(uPAR), tissue, tissue PA, and PA inhibitor-1&2(PAI-1&2) play a role in tumor invasion, metastasis, and proliferation. It is interested that these factors in patients with primary oral squamous cell carcinoma(Oral SCC) will be evaluated and correlated with clinicopathologic variables. Recently, these expression of primary oral SCC has been restricted to clinical or immunohistochemical study such in vivo study. The purpose of this study were to investigate the mRNA expression and cytologic concentration of uPA, uPAr, tPA, and PAI-1,2 in oral SCC cell lines compared to NHOK and to apply these results to evaluate early detection biomarkers of oral SCC in future. All the cell lines(NHOK, HN 4 and SCC 25) were cultured under KBM bullet kit at 37℃ in a 5% CO2 incubator. We studied a possible association between mRNA expression and cytosolic concentrations of uPA, uPAR, tPA, and PAI-1,2 in oral SCC cell lines compared to NHOK using RT-PCR and an enzyme-linked immunoassay(ELISA) method. uPA mRNA expression was about 5-6 folds, while uPAR was a bout 3 f olds, and PAI-1 was about 1 .5-1.6 f olds. PAI-2 was a bout1.2 -1.3 f olds t han that o f NHOK, w hile t PA w as l ower t han that of NHOK. uPA cytosolic concentrations was about 15-19 folds, while uPAR was about 8 folds, and PAI-1 was about 3-4.5 folds. PAI-2 was about 2 folds than that of NHOK, while tPA was lower than that of NHOK. Both uPA, uPAR, and PAI-1,2 cytologic concentrations were correlated with mRNA expression of oral SCC cell lines. From the aboving results, high cytosolic concentrations of uPA, uPAR, and PAI-1 & 2 were correlated with mRNA expression. It suggested that these might be specific markers for oral SCC cell lines and these results would be contributed to evaluate early detection biomarkers for human oral squamous cell carcinoma.

Runt-related transcription factor (RUNX) 3 is well known as a developmental regulators, as well as candidate tumor suppressor gene in human breast cancer, gastric cancer, esophageal cancer, and so on. The present study was aimed to analyze the expression of RUNX3 protein in oral squamous cell carcinoma (OSCC) from Korean patients. The immunohistochemical stain was performed with 14 normal oral mucosa (NOM) and 25 OSCCs, and statistical analysis was carried out to find out the correlation between the expression of RUNX and clinicopathological parameters of OSCC patients. In OSCC, the expression of RUNX3 protein was found to increase more than in NOM. Moreover, in the univariate correlation analysis, the gender, regional lymph node metastasis, and histopathologic differentiation of OSCC patients were positively correlated with the expression of RUNX3 (p<0.05). These results indicate that RUNX3 can play a role as an oncogene in OSCC, in contrast to some reports on RUNX3 in other human cancers. In addition, RUNX3 may be considered as new malignant biomarker of OSCC.

Pleomorphic adenoma (PA) is the most common benign salivary gland tumor. It is biphasic and is characterized by an admixture of epithelial and spindle-shaped myoepithelial cells in a variable background stroma. Epithelial-myoepithelial carcinoma (EMC) is a malignant biphasic salivary gland tumor typically composed of clear myoepithelial cells that surround epithelial-lined ducts resembling intercalated ducts. The differential diagnosis between the two tumor may be occasionally encountered because of the shared histophatologic feature. And then, it would be more reliable to differentiate the tumors based on biological behavior such as the expression of distinct intermediate filaments such as cytokeratin, invasiveness- related molecules, and the growth factor receptor to aberrantly facilitate the tumor growth, and the growth fraction of tumors. Therefore, from the 10 cases of PA and 6 cases of EMC, we immunohistochemically examined the differential expression of the cytokine 7 and 14, matrix metalloproteinase-9, C-KIT, and Ki-67 between the two tumor. At the results, there were significant differences of CK7 expression in non-luminal cells (P = 0.000) and CK14 expression in luminal and non-luminal cells of the both tumors (P = 0.025 and P = 0.000, respectively). In the comparison of the biologic behavior, a significantly increased expression of MMP-9, C-KIT and Ki-67 was found in the cases of EMC when compared to those of PA (P = 0.043, P = 0.011, and P = 0.000, respectively). In conclusion, the differences of CK expression in luminal and non-luminal cells between PA and EMC seem to reflect the difference of the origin and the level of the maturation of the tumor cell. Increased expression of MMP-9, C-KIT, and Ki-67 in EMC may represent more aggressive biologic behavior of the tumor compared with benign salivary tumor such as PA. Our results may be helpful to understand the histiogenesis of the two tumors and the difference of biologic behavior and to differentiate them when the limited specimen was submitted. Further study of many more cases of EMC is needed to validate the usefulness of these molecules as the diagnostic aid.

Oral squamous cell carcinoma (OSCC) is the most common cancer of oral cancers. Recent data suggest that chemokines could be essential players in carcinogenesis and that tumor cells express chemokine receptors and use chemokines to metastasize to the target organ in many malignancies in humans. The aim of this study was to test the hypothesis that expression of SNPs in chemokine, CXCL1 and CXCL2 correlates with oral squamous cell carcinomas in Korean population. The CXCL1 and CXCL2 genotypes were determined in 21 subjects with oral squamous cell carcinoma and 90 control subjects without oral squamous cell carcinoma. The genotypes were determined by direct sequencing. The genotype distribution and allele frequency within the OSCC patients were not significantly different from those of control subjects. But among OSCC subjects, there was significant difference of CXCL1 gene in the degree of nuclear aberration. These findings suggest that CXCL1 -442C/T polymorphism and CXCL2 -264T/C polymorphism are not related to the development of OSCC but polymorphism of CXCL1 gene might have a relation with progression of OSCC in Korean population.

Malignant tumor cells outgrow new blood vessel formation and tend to be in hypoxic state. Hypoxic cancer cells adapt to hypoxic conditions by transforming its characteristics. On the other hand, one of the most important features of cancer cells is that carcinoma cells loses its inherent epithelial phenotype and acquires mesenchymal characteristics, called as epithelial-mesenchymal transition(EMT). It has been already well known that EMT contributes to tumor invasion and metastasis. The present study investigated whether hypoxia play a major role in induction of phenotypic changes of oral squamous cell carcinoma(OSCC). Furthermore, the mechanism of EMT in oral squamous cell carcinoma cells by hypoxia has been clarified. To mimic hypoxic condition, cobalt chloride and desferoxamine, well-known hypoxic mimetic agents, were used. This study shows that hypoxia suppresses the expression of E-cadherin(epithelial marker) and increases vimentin and N-cadherin( mesenchymal markers) in OSCC. In addition, α5 integrin protein, which is a receptor for fibronectin and an important molecule for tumor invasion, is prominently induced by hypoxia.

Tumor cell biological factors, such as urokinase plasminogen activator(uPA) and its inhibitor plasminogen activator inhibitor- 1(PAI-1) play a role in tumor invasion, metastasis, and proliferation. These factors in patients with primary oral squamous cell carcinoma(Oral SCC) will be evaluated and correlated with clinicopathologic variables. However, relatively rarely has been known in oral squamous cell carcinoma in vivo and in vitro study . The purpose of this study were to investigate the protein expression of uPA and PAI-1 in oral SCC cell lines cell line compared to NHOK and to study migration and adhesion assay. All the cell lines were cultured under KBM bullet kit at 37℃ in a 5% CO2 incubator. We studied a possible association between cytosolic uPA and PA-1 concentrations in oral SCC cell line compared to NHOK using an enzyme-linked immunoassay(ELISA). Cell adhesion and migration assay were done in all the cell l ines. In migration assay oral SCC cell lines were about 70 folds higher than NHOK. In adhesion assay oral SCC cell line were about 7-12 folds higher than NHOK. uPA cy tosolic concentrations was about 15-19 folds and PAI-1 was 3 to 4.5 folds than that of NHOK. Both uPA and PAI-1 concentrations were correlated with migration and adhesion assay. High cytosolic concentrations o f uPA and PAI-1 were correlated with migration and adhesion assay . It suggested that these markers might be specific for oral SCC cell line and these results would be contributed to treatment and prognosis of human oral squamous cell carcinoma.

Oral squamous cell carcinoma (SCC) is one of the leading causes of cancer mortality worldwide. It is generally thought that adjuvant chemotherapy provides modest prolongation of survival in various carcinoma. Docetaxel (Taxotere, TXT) play a significant role in the treatment of various solid tumors of epithelial origin. CsA (immunosuppressive drug) was widely used as adjunct for the treatment of cancer. Thus, it is important to pursue the apoptosis of IHOK and oral SCC induced by TXT combined with CsA related to the pathogenesis of oral SCC. But TXT combined CsA effect on IHOK and oral SCC remains unclear. After cultured IHOK and HN 22 oral squamous cell carcinoma cell line treated by 10 nM TXT and 1 μM, and caspase inhobitor, respectively, apoptosis index, cytochrome c and caspase-3 -8, -9 mRNA expression by RT-PCR, and procaspase-3 protein amount by immunoslot blotting was prepared. The purpose of this study were to examine the TXT-induced apoptosis pathway via caspase activation by CsA enhancement, and to apply these results to an effective therapeutic treatment plan for oral SCC by TXT combined CsA . 10 nM TXT showed about 60%, 55% celluar apoptosis of IHOK and HN 22, cell line, respectively, while CsA alone did not induce apoptosis in IHOK and HN 22 cell line. 1 μM CsA combined with 10 nM TXT increased apoptosis in IHOK and HN 22 cell line through caspase-3 and cytochrome c mRNA expression, while could not effect on caspase-8 and -9. Caspase inhibitor suppressed apoptosis of IHOK and HN 22 cell line induced by a combination of 1 μM CsA and 10 nM TXT. Immnoslot blotting showed procaspase-3 activation by a combination 1 μM CsA and 10 nM TXT, while caspase inhibitor inhibited activation. It suggested that a combination of CsA and TXT might induce increased apoptosis of IHOK and HN 22 oral squamous cell carcinoma cell line through caspase-3 activation. This treatment with a combination of TXT and CsA may be an effective therapeutic strategy for oral squamous cell carcinoma

The human embryonic-lethal abnormal vision-like protein, HuR, stabilizes mRNA containing adenine- and uridine- rich elements in their 3’untranslated region. Because cyclooxygenase-2 (COX-2) mRNA is a cellular transcript that contains an adenine- and uridine-rich element, it can be regulated by the HuR protein. In this study, we examined the relationship between COX-2, HuR, MVD, and the clinicopathological parameters. Nineteen out of 43 cases of HNSCC showed high level of COX-2expression, and 68% of these patients showed high COX-2 immuno-reactivity indicating the strong expression of the cytoplasmic HuR protein. Also, MVD expression in the cases with high COX-2 expression was higher than in the cases with low COX-2 expression. These results suggest a strong correlation between the overexpression of cytoplasmic HuR and COX-2 expression in HNSCC, and that COX-2 is associated with MVD in HNSCC. In conclusion, COX-2 regulated by cytoplasmic HuR may be a good tumor angiogenic factor in HNSCC.

Adenosquamous carcinoma (ASC) is a rare malignant epithelial tumor in the oral cavity. It is regarded as a variant of squamous cell carcinoma (SCC) because ASC originates from the surface epithelium, has similar clinical features, and includes SCC portion which is histologically identical to the traditional form. This case report deals with two cases of ASC occurring in the oral mucosa of old male patients. Both case has tubular structures lined by cuboidal, basaloid, or small round cells under the conventional SCC component, which was reminiscent of the glandular differentiation of adenocarcinoma. On immunohistochemical studies, the glandular component of ASC showed positivity to CK-pan, CK7 and HMWCK, while the dysplastic squamous cells exhibited negativity to CK7. Accordingly, CK7 as well as morphological findings can lead towards differentiating ASC from other variants with gland-like structures, such as basaloid squamous cell carcinoma and adenoid squamous cell carcinoma.

Epigallocatechin-3-gallate (EGCG) and theaflavins (TF) are polyphenols included in green and black teas, respectively. Both green and black teas have been studied for their potential health benefits for cancer. Hypoxia-inducible factor (HIF) has been implicated multiple physiological and pathophysiological pathways, particularly, oncogenesis. But, the molecular pathways that govern the cell response to EGCG are not fully elucidated. The present study investigated the intracellular mechanism in oral squamous cell carcinoma (OSCC) cells treated with EGCG, focusing on HIF-1 expression and its effect on epithelial phenotype. EGCG decreased phosphorylated Raf-1 protein in YD 8 OSCC cell, but B-raf protein was not affected at all by EGCG and TF. In addition, we here found that EGCG regulated HIF-1α expression independent of Raf-1 protein. Taken together with our previous result, the result imply that EGCG is attributed to the HIF-1α expression via Raf/MEK/ERK pathway, and the HIF-1α expression is associated with the change of epithelial phenotype in OSCC cell.

Epithelial-myoepithelial carcinoma (EMC) is uncommon, low-grade malignant epithelial neoplasm, and composed of ductal and large, clear-staining myoepithelial differentiated cells. we found four cases of EMC patients among those who visited the dental hospital of Seoul National University from 1998 to 2008. Immunohistochemical staining with epithelial and myoepithelial marker was done to verify the characteristic biphasic cell population. In our cases, the mean age of the patients was 61.5 years, which is consistent with previous reports. However, all the patients were female, and submandibular glands were the most affected sites. This is different from other reports that parotid gland was the most affected sites. There was recurrence and metastasis to lung in one out of four cases.

Green tea, derived from the plant Camellia sinensis, is one of the most common beverages consumed worldwide. Epigallocatechin-3-gallate (EGCG) is the most abundant and bioactive polyphenolic constituent in green tea. Understanding how intracellular signaling pathways respond to EGCG may provide a clue to the difference of cell responses and basis for usefulness of EGCG as a chemopreventive and/or chemotherapeutic agent. In the present study, we tried to check whether EGCG could be a useful agent in chemotherapeutic treatment of oral squamous carcinoma. Furthermore, we investigated which signaling pathway is involved in biologic activities of EGCG. EGCG induced the cell death of oral squamous carcinoma cells. Furthermore, it increased phosphorylation of Akt in serum-strarved oral squamous carcinoma cells. But, initial increase of Akt activation did not affect cell survival. Activities of Raf-1 and Erk showed inconsistent response to EGCG treatment, but Erk phosphorylation is consistent with Raf-1 activity in YD 10B cells. These changes of Raf-1 and Erk activity in EGCG treated cells were different depending on cell line type. Supposedly, the difference of cell component may affect the Raf-1 and Erk reactivity to EGCG treatment. Akt activation by EGCG is independent on activities of PDK1 and PTEN, and expression of bax and bcl-2 proteins were not changed by EGCG treatment. Therefore, EGCG treatment did not induce the apoptosis of YD 10B cell. On the other hand, vascular adhesion molecule (VCAM) was decreased by EGCG treatment, so it is possible that decrease of VCAM can play certain role in survival and/or cell death in EGCG treated cells

Elevated expression of survivin is strongly associated with tumorigenesis and even in human common cancers. Oral squamous cell carcinoma (OSCC) is the 7th most frequent cancer in human and responsible for more than 90% of all oral cancer. The purpose of this study is to confirm whether survivin is associated with oral carcinogenesis, expecially has a role in the development of OSCC. For the control group; 3 specimens obtained from normal oral mucosa without any inflammatory reaction were used a nd for the experimental group, specimens obtained f rom 18 sub jects of OSCC; 6 subjects from Well differentiated type OSCC; 4 subjects from Moderately differentiated type OSCC; 3 subjects from Poorly differentiated type OSCC; 3 subjects from Verrucous carcinoma: and 2 subjects from C arcinoma in situ were used. All the specimens were embedded in paraffin, sectioned 5 μm or more in thickness, and stained with hematoxylin- eosin. For immunostain, the specimens were incubated with 1;200 diluted primary antibody (anti-survivin monoclonal, Biocare Inc, USA), followed by the secondary antibody(NovoLink Polymer detection system, Novocastra Lab., UK). The bound antibodies were visualized by addition of diaminobenzidine tetrahydrochloride(DAB) for 30 minutes at room temperature. The specimens were counterstained with Mayerʼs Hematoxylin and mounted. Quantitation of immunoreactivity was performed under the light microscope with the following criteria ; Intensive reaction; +++, Moderate reaction; ++, Minimal reaction; +. Using the image analyzer(Korea Optical System), immunoreactivity of tumor cells in various field was measured and statistically analyzed with SPSS 15.0 Program. The results were as follows: Expression of survivin in OSCC was significantly increased in the nucleus and the cytoplasm of OSCC as compare to those of control group (p<0.05). Expression of survivin in the nucleus and the cytoplasm of the cells in OSCC is correlated with the cellular malignancy (p<0.05). Expression of survivin in Poorly differentiated type OSCC partly correlated to some extent to cellular malignancy (p<0.05). These results suggest that expression of survivin in OSCC is closely associated with to the development, and malignancy of the OSCC, b ut it is not enough to be used a s a marker f or the c ellular malignancy. Further studies are needed to relate the expression of survivin to cellular malignancy.

Tumor cells under hypoxic conditions are often found due to the rapid outgrowth of their vascular supply, and,in order to survive hypoxia, these cells induce numerous signaling factors. Erk is an important kinase in cell survival, and its activity is regulated by Raf kinases through numerous growth factor receptors. The authors investigated Erk activation and Raf/Erk signaling using the hypoxia-mimetic agent, cobalt chloride (CoCl2), in oral squamous cell carcinoma (OSCC) cells. CoCl2 increases Erk phosphorylation in both a dose- and time-dependent manner. In addition, blocking the activation of epidermal growth factor receptor (EGFR) using PD168393 abolished Erk activation in response to CoCl2, suggesting that Erk phosphorylation by CoCl2 is dependent on EGFR.

A 14-year-old intact female, mixed dog was presented with hematuria and strangury. Mass in the abdominal cavity was seen on radiographs and ultrasound. On the cytological examination in the urethra, clusters of pleomorphic epithelial cell were found. Tissues of the urethra and the urinary bladder were obtained at the time laparotomy and determined the extent of the mass. Transitional cell carcinoma (TCC) of the urinary bladder was found in histopathologic characteristics. Urinary diversion after removal of a complete full section of the TCC in bladder wall was performed. Piroxicam, as a medical therapy for TCC, was orally administrated. Surgical operation and chemotherapy were selected with the goal of maintaining and improving quality of life.

Epithelial-mesenchymal transition (EMT) can play an important role in carcinogenesis of oral squamous cell carcinoma (OSCC). EMT is characterized by morphological and phenotypical change of epithelial cells into mesenchymal cells, and transcriptional repressor of E-cadherin, Snail is critical for EMT. In order to investigate the role of Snail and E-cadherin in OSCC, we analyzed the immunohistochemical pattern of Snail and E-cadherin in 18 OSCCs. The expression of Snail in the OSCC was increased whereas the expression of E-cadherin in the OSCC was decreased in comparison with those of normal oral mucosa, showing reverse correlation. Especially, the fibroblasts near the islands of OSCC showed the positivity of Snail, suggesting the reactive fibroblasts to the EMT of epithelial tumor cells. In metastatic squamous cell carcinoma in cervical lymph node, the positivity of Snail of tumor cells was higher than that of primary OSCC. We concluded that the increased Snail expression and the decreased E-cadherin expression were involved in the progression, invasion and metastasis of OSCC.

Metastatic tumors in oral cavity are rare, where their prognoses are considered to be extremely poor. Unless recognizing its primary origin, pathologic diagnoses for metastatic cancer have been troublesome for oral pathologists. This retrograde analysis was aimed at providing practical suggestion for the diagnoses of metastatic cancers to oral and maxillofacial region. We reviewed 20 patients diagnosed as metastatic cancers to oral cavity from 1991 to 2007. The patients were classified according to their clinical and histologic findings. We also reviewed 19 patients of mucoepidermoid carcinoma and 16 patients of adenoid cystic carcinoma to compare with those of metastatic cancers. Immunohistochemical staining for CK 5/6, CK 17, TTF-1, CEA was performed for differential diagnosis. Histologically, 20 cases compromised 11 cases of adenocarcinoma, 5 cases of undifferentiated carcinoma, 3 cases of squamous cell carcinoma, and one papillary carcinoma. The lung was the most common site for primary site (5/20), followed by the breast (2/20). In metastatic adenocarcinoma, TTF-1 positive cases were one lung cancer and a rectal cancer, and carcinomas from breast and rectum showed CK5/6 positive reaction. CEA was expressed in gastric and rectal carcinomas. In 19 cases of mucoepidermoid carcinoma, 13 cases (68.4%) are CK5/6 (+). In 16 cases of adenoid cystic carcinoma, 11 cases (68.8%) showed the positive reaction for CK5/6. TTF-1 is an antibody to show high sensitivity and specificity for lung adenocarcinoma, therefore, TTF-1 is helpful to make a diagnosis of metastatic adenocarcinomas from lung. Adenocarcinomas originated from salivary glands show high CK5/6 expression, but metastatic adenocarcinomas, except of those from breast and rectum, show no CK5/6 expression, lending support that CK5/6 may be useful to differentiate metastatic adenocarcinomas from carcinomas of salivary gland origin.

Amino acid transporters are essential for the growth and proliferation in all living cells. Among the amino acid transporters, the system L amino acid transporters are the major nutrient transport system responsible for the Na+-independent transport of neutral amino acids including several essential amino acids. The L-type amino acid transporter 1 (LAT1), an isoform of system L amino acid transporter, is highly expressed in cancer cells to support their continuous growth and proliferation. 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid(BCH) is a model compound for study of amino acid transporter as a system L selective inhibitor. We have examined the effect and mechanism of BCH on cell growth suppression in FaDu human head and neck squamous cell carcinoma. The BCH inhibited the L-leucine transport in a concentration-dependent manner with a IC 50 value of 43.8±4.3μM. The majority of L-leucine uptake is, therefore, mediated by LAT1 in FaDu cells. The growth of FaDu cells was inhibited by BCH in the time- and concentration- dependent manners. The formation of DNA ladder was not observed with BCH treatment in the cells. Furthermore, the proteolytic processing of caspase-3 and caspase-7 in the cells was not detected by BCH treatment. These results suggest that the BCH inhibits the growth of FaDu human head and neck squamous cell carcinoma through the intracellular depletion of neutral amino acids for cell growth without apoptotic processing