口腔扁平上皮癌の悪性化における転写因子NF-Bの役割

金沢大学附属病院口腔扁平上皮癌においても,び漫性に局所浸潤した腫瘍制御の困難さが指摘され,臨床病理学的にもがん浸潤様式が転移形成率や生存率に強く影響することが明らかにされている.また,口腔扁平上皮癌の浸潤・転移の分子機構も検討され,様々な悪性形質との関連性が報告され,それらの多くは転写因子NF-κBに制御されている.しかし,がんの悪性化に伴い刺激を受けることなく,ある種の腫瘍においては恒常的にNF-κBの活性化を認めることも知られている.そこで,口腔扁平上皮癌の浸潤様式と転写因子NF-κBの恒常的な異常活性化に関連性があると考えられた.平成14年度は,口腔扁平上皮癌における間質細胞である線維芽細胞との相互作用で,転写因子NF-κBの恒常的な活性化が起こり,がんの進展に強く働くものと考えられたとの実績を報告した.本年度は,NF-κBは口腔扁平上皮癌の治療標的として評価できるか否かを検討した.NF-κBを標的とした治療はがんに対するアポトーシス誘導ばかりでなく,腎移植・慢性関節リウマチ・糖尿病網膜症に対する抗炎症作用にもおよんでいる.また,国内においても血管拡張術後およびステント後再狭窄に対するNF-κBデコイの臨床応用が開始されようとしている.われわれも,NF-κB活性化を特異的に抑制することで抗がん剤の耐性を阻止できると考えている.その不活性化に対する候補として,NF-κBデコイやハーブ由来成分のparthenolideが考えられる.しかし,今回の検討にてNF-κBデコイの効果は認められなかったことから,ベクターの使用やdelivery systemの開発に課題が残り,同時に,様々なNF-κB活性化阻害薬剤が報告されている中,より安全で効果の高い補助療法が望まれた.これらの問題を解決することが今度の研究課題と考えられる。研究課題/領域番号:14771126, 研究期間(年度):2002-2003出典：「口腔扁平上皮癌の悪性化における転写因子NF-Bの役割」研究成果報告書　課題番号14771126（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-14771126/)を加工して作

OK-432・ブレオマイシン併用療法に関する基礎的検討ならびに口腔粘膜癌への臨床応用

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第1069号, 学位授与年月日：平成5年3月25日,学位授与年：199

Immunohistochemical analysis of an ectopic endometriosis in the uterine round ligament

A rare case of the inguinal endometriosis was reported with immunohistochemical analysis. A 28-year-old woman had a thumb-sized tumor in the right groin for two years with a gradual increase in size and pain. An operation revealed an elastic hard tumor with an unclear margin and adhesion to the uterine round ligament. The histology showed irregular proliferation of the endometrial glands and stroma. The glandular epithelium stained weakly positive against CD125 antibody and the stromal matrix stained strongly positive against CD10 antibody. The nucleus in both the epithelial and stromal cells stained strongly positive against progesterone and estrogen receptor antibodies, and the cytoplasm in both types of cells stained moderately positive against COX-2 (cyclooxygenase-2) antibody. In conclusion, the combination of estrogen or progesterone receptor antibody for the nucleus and CD10 or COX-2 antibody for the cytoplasm could enhance the accuracy of diagnosis for ectopic endometriosis

Inhibition of breast cancer regrowth and pulmonary metastasis in nude mice by anti-gastric ulcer agent, irsogladine.

金沢大学医学部附属病院Irsogladine is a commonly used anti-gastric ulcer agent in Japan, and recent in vivo studies have shown it to have anti-angiogenic properties. The exact role of irsogladine as an inhibitor of angiogenesis remains uncertain. In this study, we show that irsogladine inhibited breast cancer regrowth and pulmonary metastasis but had no anti-angiogenic function against HUVEC cells. Irsogladine failed to inhibit proliferation, tubular formation, and the uPA/MMP-1 mRNA expression of HUVEC cells. We also examined the effect of irsogladine in an orthotopic transplant model of human breast cancer metastasis in athymic mice. Human MDA-MB-435 cells were injected into the mammary fat pads. After 9 weeks, the tumors were resected under general anesthesia. Irsogladine or vehicle was given p.o. daily thereafter. Daily administration of irsogladine at 120 mg/kg per day over a 5-week period had no effect on the body weight of the mice. Tumor regrowth, average volume of pulmonary metastases, and the number of metastases were inhibited by 40, 48 and 64%, respectively. These results suggest that irsogladine may be useful in the breast cancer adjuvant setting

Two elderly patients with advanced maxillary gingival carcinoma with complete response to concurrent radiotherapy and S-1 chemotherapy

金沢大学附属病院歯科口腔外科The use of the novel oral fluoropyrimidine anticancer drug S-1 as a single agent or in combined chemotherapy has been reported to be useful for the treatment of advanced oral cancer. We report two elderly patients with advanced oral cancer who achieved complete response (CR) after concurrent radiotherapy and S-1 chemotherapy. Patient 1 was an 81-year-old woman who had a 50. mm × 40. mm tumor erosion in the right upper gingival region. At 2.5 years after the end of concurrent radiotherapy and S-1 chemotherapy, tumor relapse was observed, although CR continued temporarily. The patient died 3 years after the end of concurrent radiotherapy and S-1 chemotherapy due to tumor relapse and high blood pressure resulting in deterioration of patient condition. Patient 2 was an 89-year-old woman who had a 40. mm × 30. mm tumor ulcer in the right gingiva. Neither relapse nor metastasis was seen, and patient condition remained good for the 3 years after concurrent radiotherapy and S-1 chemotherapy. In both patients, MRI showed that the tumor had deeply invaded the palatal bone, almost reaching the nasal cavity, with metastasis to the right upper superior internal jugular nodes. In both patients, biopsy showed a well-differentiated squamous cell carcinoma. Concurrent radiotherapy and S-1 chemotherapy induced CR without severe adverse effects. © 2010 Asian Association of Oral and Maxillofacial Surgeons

Loss of maspin is a negative prognostic factor for invasion and metastasis in oral squamous cell carcinoma

金沢大学附属病院歯科口腔外科Objective: Maspin, a 42-kDa protein, belongs to the serpin family of protease inhibitors and is known to have tumor-suppressor function. In this study, we investigated the interrelationship between clinicopathologic findings and maspin expression in oral squamous cell carcinoma (OSCC). Methods: Using immunohistochemical techniques to examine the expression levels of maspin in OSCC, maspin expression in OSCC was detected in 46 (64.8%) of 71 cases. We also compared the clonicopathologic features of OSCC cases with maspin expression levels. Moreover, we examined expression of maspin in eight cell lines derived from OSCC using reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. Results: There was a significant correlation between decreased maspin expression and T-category (P < 0.01), lymph metastasis (P < 0.0001), and mode of invasion (P < 0.0001). Patients with positive maspin expression had a significantly better prognosis (P < 0.001). Lower expression of maspin was also seen in cell lines derived from grade 4D, which shows stronger invasive potential than other grades of OSCC. Conclusion: Maspin may be a useful marker to identify the potential for progression in OSCC. © 2008 Blackwell Munksgaard

Inhibition of invasion and metastasis in oral cancer by targeting urokinase-type plasminogen activator receptor

金沢大学医学部附属病院There have been reports of strong correlations between poor prognosis in various cancers and concomitant expression of urokinase-type plasminogen activator (uPA) and its surface receptor (uPAR). We and others have previously shown that the uPA system plays a significant role in a subset of head and neck squamous cell carcinoma. In the present study, we found that uPAR is required for invasion and metastasis of highly malignant oral cancer cells (OSC-19). Treating OSC-19 cells with antisense oligonucleotides (AS) targeting uPAR resulted in a dramatic decrease of uPAR mRNA expression. Furthermore, pretreatment with AS or siRNA targeting uPAR inhibited progression of OSC-19 cells in experimental models. These results suggest that overexpression of uPAR increases the invasiveness and metastasis of OSC-19 cells, and that uPAR is a promising therapeutic target for regulation of progression of oral cancer

DNA methylation status of REIC/Dkk-3 gene in human malignancies

The REIC (reduced expression in immortalized cells)/Dkk-3 is down-regulated in various cancers and considered to be a tumor suppressor gene. REIC/Dkk-3 mRNA has two isoforms (type-a,b). REIC type-a mRNA has shown to be a major transcript in various cancer cells, and its promoter activity was much stronger than that of type-b. In this study, we examined the methylation status of REIC/Dkk-3 type-a in a broad range of human malignancies. We examined REIC/Dkk-3 type-a methylation in breast cancers, non-small-cell lung cancers, gastric cancers, colorectal cancers, and malignant pleural mesotheliomas using a quantitative combined bisulfite restriction analysis assay and bisulfate sequencing. REIC/Dkk-3 type-a and type-b expression was examined using reverse transcriptional PCR. The relationships between the methylation and clinicopathological factors were analyzed. The rate of REIC/Dkk-3 type-a methylation ranged from 26.2 to 50.0% in the various primary tumors that were examined. REIC/Dkk-3 type-a methylation in breast cancer cells was significantly heavier than that in the other cell lines that we tested. REIC/Dkk-3 type-a methylation was inversely correlated with REIC/Dkk-3 type-a expression. There was a correlation between REIC/Dkk-3 type-a and type-b mRNA expression. REIC/Dkk-3 type-a expression was restored in MDA-MB-231 cells using 5-aza-2'-deoxycytidine treatment. We found that estrogen receptor-positive breast cancers were significantly more common among the methylated group than among the non-methylated group. REIC/Dkk-3 type-a methylation was frequently detected in a broad range of cancers and appeared to play a key role in silencing REIC/Dkk-3 type-a expression in these malignancies

Amebiasis in HIV-1-Infected Japanese Men: Clinical Features and Response to Therapy

Invasive amebic diseases caused by Entamoeba histolytica are increasing among men who have sex with men and co-infection of ameba and HIV-1 is an emerging problem in developed East Asian countries. To characterize the clinical and epidemiological features of invasive amebiasis in HIV-1 patients, the medical records of 170 co-infected cases were analyzed retrospectively, and E. histolytica genotype was assayed in 14 cases. In this series of HIV-1-infected patients, clinical presentation of invasive amebiasis was similar to that described in the normal host. High fever, leukocytosis and high CRP were associated with extraluminal amebic diseases. Two cases died from amebic colitis (resulting in intestinal perforation in one and gastrointestinal bleeding in one), and three cases died from causes unrelated to amebiasis. Treatment with metronidazole or tinidazole was successful in the other 165 cases. Luminal treatment was provided to 83 patients following metronidazole or tinidazole treatment. However, amebiasis recurred in 6 of these, a frequency similar to that seen in patients who did not receive luminal treatment. Recurrence was more frequent in HCV-antibody positive individuals and those who acquired syphilis during the follow-up period. Various genotypes of E. histolytica were identified in 14 patients but there was no correlation between genotype and clinical features. The outcome of metronidazole and tinidazole treatment of uncomplicated amebiasis was excellent even in HIV-1-infected individuals. Luminal treatment following metronidazole or tinidazole treatment does not reduce recurrence of amebiasis in high risk populations probably due to amebic re-infection