The involvement of platelet-derived growth factor receptors and insulin-like growth factor-I receptors signaling during mineralized nodule formation by human periodontal ligament cells.

BACKGROUND AND OBJECTIVE: Periodontal ligament cells are regarded to have the capacity to differentiate into cementoblasts or osteoblasts, and are capable of forming a mineralized nodule in vitro. However, the precise mechanisms are unclear. Here we evaluated the possible involvement of growth factor receptors, such as the platelet-derived growth factor receptor (PDGFR), insulin-like growth factor-I receptor (IGF-IR), and epidermal growth factor receptor (EGFR) on periodontal ligament cells and their ligands during periodontal ligament cells differentiation in vitro. METHODS: Human periodontal ligament cells were differentiated via culturing in the presence of dexamethasone, ascorbic acid, and beta-glycerophosphate for mineralized nodule formation, characterized by von Kossa staining. Expressions of receptors and their ligands were analyzed by flow cytometry/reverse transcription-polymerase chain reaction. RESULTS: During the differentiation, PDGFR-alpha was held at a lower level compared with the control. PDGFR-beta, however, was maintained at a slightly higher level that was reversed to the control level when mineralized nodules formed. In contrast, IGF-IR and EGFR were not substantially different from the control. The mineralized nodule formation was strongly inhibited by a PDGFR kinase blocker (AG1295 and AG1296), partially inhibited by an IGF-IR kinase blocker (I-Ome-AG538 and AG1024), and not inhibited by an EGFR kinase blocker (AG99). PDGF-A, PDGF-C, PDGF-D, IGF-I, and IGF-II, but not PDGF-B, were expressed on the control as well as dexamethasone/ascorbic acid-treated periodontal ligament cells during mineralized nodule formation; however, the pattern of their expressions was quite different. CONCLUSION: These findings suggest that a pathway of PDGFs/PDGFR and IGFs/IGF-IR on periodontal ligament cells are involved during mineralized nodule formation, and that PDGFs and IGFs expressed by periodontal ligament cells may contribute to the formation.

Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) in human hepatocellular carcinoma.

One of the major obstacles in the treatment of hepatocellular carcinoma (HCC) is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Copper-transporting P-type adenosine triphosphate (ATP7B) has been reported to be associated with cisplatin resistance in vitro. However, the expression of ATP7B has not previously been addressed in human liver and HCC. Our purpose was to investigate ATP7B expression in human liver and hepatocellular carcinoma and its clinical significance. We retrospectively examined the expression of ATP7B in primary hepatocellular carcinoma. Immunohistochemical analysis of ATP7B was performed using a monoclonal antibody against ATP7B in 19 surgically removed hepatocellular carcinomas. A variable degree of cytoplasmic staining of tumor cells was observed in 21.1% (4/19) of the analyzed carcinomas. ATP7B expression was not observed in normal hepatic cells. Strong expression of ATP7B was observed in all the analyzed bile ducts. These findings suggest that overexpression of ATP7B in hepatocellular carcinoma might be associated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. Further, ATP7B is expressed in bile duct epithelial cells, where it may mediate copper secretion into bile fluid.

Benign cementoblastoma involving multiple maxillary teeth: report of a case with a review of the literature.

A rare case of benign cementoblastoma involving multiple deciduous and permanent teeth is presented with a review of the literature. A 12-year-old boy was admitted for a swelling in the right maxillary premolar-molar region. A radiologic examination revealed a well-defined, round, radiopaque mass extending from the right maxillary first premolar to the second permanent molar. The tumor was removed with all associated teeth. A histologic examination of the surgical specimen revealed a well-circumscribed tumor composed of cementum-like tissue surrounded by a fibrous capsule. The tumor was attached to the roots of the second deciduous molar, first premolar, and the first and second permanent molars and embedded in the crown and root of the right maxillary second premolar, suggesting that the lesion had arisen from the second deciduous molar. There has been no recurrence of the lesion more than 18 months after the surgical procedure.

Mutation analysis of copper-transporting P-type adenosine triphosphatase (ATP7B) in human solid carcinomas.

A major obstacle in the treatment of human solid carcinomas is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Copper-transporting P-type adenosine triphosphatase (ATP7B) has been reported to be associated with cisplatin resistance in vitro. ATP7B is overexpressed in human solid carcinomas such as breast, gastric and oral squamous cell carcinomas. ATP7B expression has an influential effect on some subsets of patients with cisplatin-treated carcinomas. ATP7B mutation is well-known as a cause of Wilson's disease. In addition, the six copper-binding domain and ATP-binding domain of ATP7B are important for the transportation of metals. Therefore, we performed the mutation analysis at the six copper-binding domain and ATP-binding domain of ATP7B. No mutation at the six copper-binding domain and ATP-binding domain was observed in breast, gastric and oral squameous cell carcinomas. These results indicate that the analysis of the ATP7B gene and/or protein will be helpful for the choice of chemotherapy in patients with human solid carcinomas.

Expression of copper-transporting P-type adenosine triphosphatase in human esophageal carcinoma.

A major obstacle in the treatment of esophageal carcinoma is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Copper-transporting P-type adenosine triphosphatase (ATP7B) has been reported to be associated with cisplatin resistance in vitro. However, the clinical significance of this transporter has not previously been addressed. Our goal was to investigate if ATP7B is expressed in esophageal carcinoma and whether its expression correlates with reduced responsiveness to cisplatin treatment. We retrospectively examined the expression of ATP7B in primary esophageal carcinoma and its association with chemotherapeutic effect. Tissues were surgically removed from 17 esophageal carcinoma patients. Twelve of them received cisplatin-based chemotherapy before surgery. We performed immunohistochemical analysis of ATP7B using a monoclonal antibody against ATP7B in 17 esophageal carcinomas. A variable degree of cytoplasmic staining of tumor cells was observed in 76.5% (13/17 cases) of the analyzed carcinomas. ATP7B expression was not observed in adjacent non-neoplastic tissues. ATP7B positivity was not significant in gender, age, histopathological grading or TNM categories. Patients with ATP7B-positive tumors tended to have an inferior response to chemotherapy compared with the patients with ATP7B-negative tumors. These findings suggest that overexpression of ATP7B in esophageal carcinoma could be associated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. Therefore, ATP7B gene expression might be considered as a chemoresistance marker for cisplatin in the patients of esophageal carcinoma and provider of important information on the strategy against esophageal carcinoma.

Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) as a chemoresistance marker in human oral squamous cell carcinoma treated with cisplatin.

An important clinical problem in the treatment of oral squamous cell carcinoma is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Copper-transporting P-type adenosine triphosphate (ATP7B) has been reported to be associated with cisplatin resistance in vitro (Komatsu et al., Cancer Res 60, 1312-1316,2000). However, the clinical significance of this transporter has not previously been addressed. Our aim of this study was to investigate if ATP7B is expressed in oral squamous cell carcinoma and whether its expression correlates with prognosis and reduced responsiveness to cisplatin treatment. Biopsy tissues were obtained from the tumors of 70 patients with oral SCC, and 51 patients received cisplatin-based preoperative chemotherapy. We performed immunohistochemical analysis of ATP7B using monoclonal antibody against ATP7B in 51 oral SCC and adjacent neoplastic tissues. The significance of ATP7B in the prognosis of patients with oral SCC was also examined in the survival analysis of mortality follow-up data covering the period 1991 through 2000. We retrospectively examined the expression of ATP7B in primary oral SCC carcinoma and its association with chemotherapeutic effect. A variable degree of cytoplasmic staining of tumor cells was observed in 54.9% (28/51 cases) of the analyzed carcinomas. Patients with ATP7B-positive tumors had a significantly inferior response to chemotherapy compared with the patients with ATP7B-negative tumors (P = 0.03). The patients who received cisplatin-based chemotherapy with ATP7B-positive carcinomas had a significantly poorer overall survival than those with ATP7B-negative tumors (P = 0.015). These findings suggest that high levels of ATP7B expression in oral SCC are associated with unfavorable clinical outcome in patients with oral SCCs treated with cisplatin-based chemotherapy. ATP7B expression may be a preoperative indicator for a choice of cisplatin in some patients.

Uridine phosphorylase is a potential prognostic factor in patients with oral squamous cell carcinoma.

BACKGROUND: Uridine phosphorylase (UPase) catalyzes the reversible phosphorolysis of uridine to uracil. The expression levels and the enzymatic activity of UPase are reported to be higher in human solid tumors than in adjacent normal tissues. However, to the authors' knowledge the clinical significance of UPase expression as determined by immunohistochemical analysis has not been demonstrated in human malignancies. METHODS: The authors prepared the antibody against UPase, examined the staining of UPase in 72 cases of oral squamous cell carcinoma (SCC) with immunohistochemical analysis using the antibody, and analyzed its relation to clinical and pathologic factors. RESULTS: UPase stained mainly within the invasive edges of tumors and macrophages. UPase-positive staining was observed in 56 of the 72 tumors (77.8%). High staining of UPase (defined as > 50% of cells in a tumor biopsy that are positive for UPase) in primary tumors frequently was associated with the presence of metastasis to lymph nodes (P = 0.007 by the Fischer exact test) and with lower overall survival (P = 0.03 by the log-rank test). CONCLUSIONS: The high rate of UPase staining in biopsies from patients with oral SCC may be a prognostic marker for these individuals.