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Presents the letter of reply to the comments made by Fumio Ide regarding oral endovascular papillary angioendothelioma or Dabska tumor of the tongue. Rejection of Ide's suggestion of the intravascular papillary endothelial hyperplasia (IPEH) as the pathological diagnosis; Confirmation of the diagnosis as an endovascular papillary angioendothelioma (EPA); Suggestion of the feasibility of the lesion in the case study as a mature form of IPEH instead of an EPA; Difference of opinions regarding the existence of of capsule in EPA; Importance of the glomerulus appearance on the histological feature of the EPA.

To understand the role of cyclooxygenase (COX)-2 in metastatic potential of oral cancer, COX-2 overexpressing KB/COX-2 cells were inoculated orthotopically into the masseter muscle or injected into the left cardiac ventricle of nude mice. KB/COX-2 showed about 4-fold increase of COX-2 protein expression as compared to KB/Neo which was a mock transfected control. In orthotopic inoculation, metastasis to the regional lymph nodes occurred in 2 out of 15 mice, and metastasis to the lung in 3 out of 15 mice. On the other hand, in intra-cardiac injection, hematogenous metastasis to the lung and bone occurred in 8 out of 10 mice in KB/COX-2, but no metastasis occurred except for only one metastasis to the femur bone out of 10 mice in KB/Neo. Treatment of KB/COX-2 with COX-2 small interfering RNA (siRNA) inhibited the colony formation but not cell growth in vitro, and suppressed tumorigenicity and hematogenous metastasis in nude mice. When expression of adhesion molecules such as E-cadherin, alpha-catenin, beta-catenin and CD44 was examined, there was no difference in alpha- and beta-catenin between the cells. However, expression of E-cadherin was detected in KB/Neo, but not in KB/COX-2. In contrast, expression of CD44 was markedly increased in KB/COX-2 as compared to KB/Neo. Treatment with COX-2 siRNA resulted in suppression of CD44 expression and detectable expression of E-cadherin in KB/COX-2. These findings suggested that overexpression of COX-2 increased hematogenous metastasis, at least in KB cells, via down-regulating E-cadherin and up-regulating CD44 expression.

Inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 are major inflammatory mediators. Nitric oxide (NO) produced by iNOS has been shown to have an important role in carcinogenesis. Recent studies have suggested that COX-2 expression also contributes to carcinogenesis, as well as tumor growth, invasion, and metastasis. COX-2 inhibitors such as celecoxib are widely recognized to have antitumor activity, but can cause adverse effects. We investigated possible relations between COX-2 and NO with the use of a human epidermoid carcinoma cell line, designated KB, in which overexpression of COX-2 protein was induced by gene transfer. We also assessed the possibility of using NOS inhibitor as an antitumor drug. We isolated a COX-2 transfected clone (KB/COX-2) and used a neomycin-transfected clone (KB/neo) as control. NG-nitro-L-arginine-methyl ester (L-NAME) was used as a NOS inhibitor, dihydrochloride (1400W) as an iNOS inhibitor, and celecoxib as a selective COX-2 inhibitor. All agents inhibited the cell growth of both clones to similar extents in a dose-dependent manner. Prostaglandin E2 (PGE2) production and COX-2 expression in KB/COX-2 were inhibited not only by celecoxib, but also by L-NAME and 1400W. The decreases in PGE2 production and COX-2 expression were most prominent with celecoxib and L-NAME. In vivo, L-NAME and celecoxib significantly inhibited the proliferation of KB/COX-2-xenografted tumors. Tumor weight was reduced by L-NAME (60.6% decrease), 1400W (38.0% decrease), and celecoxib (74.5% decrease) as compared with the control after 21 days of treatment. Immunohistochemically, xenografted tumors expressed COX-2, iNOS, and eNOS. Such expression was suppressed by treatment with L-NAME and celecoxib. These results suggest that L-NAME and celecoxib significantly inhibit the proliferation of murine squamous cell carcinoma in vivo. L-NAME as well as celecoxib might thus be useful for the design and development of new antitumor drugs.

In order to investigate the involvement of cyclooxygenase (COX)-2 in oral carcinogenesis and chemoprevention for it, we examined the COX-2 expression during dimethylbenzanthracene (DMBA)-induced hamster cheek pouch carcinogenesis and the inhibitory effect of sulindac, a non-steroidal anti-inflammatory drug (NSAID), on the carcinogenesis and its derived squamous carcinoma cell line HCPC-1. From the beginning of DMBA application, basal diet or diets containing sulindac 200 or 400 ppm were given to hamsters, and observation of tumor development and measurement of body weight were performed. Immunohistochemical analysis revealed that COX-2 expression was increased toward carcinogenesis from epithelial dysplasia to squamous cell carcinoma (SCC). All hamsters developed SCC, but the onset of carcinoma formation was significantly delayed up to 14.8 and 11.8 weeks in the 200 ppm, and 400 ppm sulindac group, respectively, as compared to 8.7 weeks in the control group. In addition, tumor growth was retarded in the group of sulindac treatment, and mean survival time was 23.7 weeks in the control group and 36.3 and 33.8 weeks in the 200 and 400 ppm sulindac group, respectively. Body weight loss was not observed during the experimental period. Histologically, administration of sulindac inhibited angiogenesis in the tumor stroma. Treatment with sulindac sulfide, an active metabolite of sulindac, caused inhibition of cell growth, PGE2 production and VEGF production in HCPC-1 cells in vitro. Expression of COX-2 protein in HCPC-1 cells was also decreased 2-fold by treatment with sulindac sulfide. It was thus indicated that inhibitory effects were partly due to inhibition of tumor angiogenesis by sulindac. These findings suggested the involvement of COX-2 in DMBA-induced hamster cheek pouch carcinogenesis and the chemopreventive potential of sulindac.

Adenoid cystic carcinoma (ACC) may acquire a chemokine-mediated mechanism during the process of metastasis. To investigate the involvement of chemokines in metastasis from ACC, expression of CXCR4 in surgical specimens of ACC and two tumor lines transplantable to nude mice was examined immunohistochemically. In addition, the expression levels of CXCR4 protein and mRNA were examined by Western blotting and reverse-transcription polymerase chain reaction. Our results showed that patients whose tumors expressed high levels of CXCR4 had metastases to the regional lymph nodes and the lung, resulting in poor outcomes. ACCs showing a solid or cribriform pattern with distant metastasis were strongly positive for CXCR4, while those showing a tubular or cribriform pattern without metastasis were weakly positive for CXCR4. In the in vivo model, ACCY tumor showed increasing expression levels of CXCR4 with tumor growth, and the histological pattern changed from cribriform to solid. The histological pattern of ACCI, associated with spontaneous metastasis to the neck, changed from cribriform to undifferentiated carcinoma and was highly metastatic to the lung. This tumor showed high levels of CXCR4 protein and mRNA. These results suggest that CXCR4 expression, histological patterns, and metastatic potential are closely related in ACC.