Wiley Acta Medica Okayama 2050-0904 13 7 2025 Tongue Schwannoma at the Median Inferior Surface in the Elderly: A Case Report e70506 EN Kiho Fukushima Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kisho Ono Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kyoichi Obata Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Izumi Yamamoto Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yuki Kunisada Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hirokazu Yutori Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Soichiro Ibaragi Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University We report the extremely rare case of an atypical schwannoma that occurred at the median inferior surface of the tongue in an elderly patient. We performed an excisional biopsy to achieve a definitive diagnosis. Based on the histopathological findings, we diagnosed a schwannoma (mixed type, Antoni A/B). No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2090-6447 2024 2024 A Rare Case of Multiple Myeloma Identified Following the Diagnosis of Amyloidosis of the Tongue 8836103 EN Hideka Kanemoto Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kyoichi Obata Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Koichi Kadoya Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kisho Ono Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hotaka Kawai Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuki Kunisada Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mayumi Yao Department of Oral and Maxillofacial Surgery, Tsuyama Chuo Hospital Soichiro Ibaragi Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Amyloidosis is a disease in which amyloid protein is deposited in organs and tissues, resulting in functional impairment. Amyloidosis occurs in 12%-30% of patients with multiple myeloma, but in rare cases, amyloidosis may precede the diagnosis of multiple myeloma. Our patient was a 76-year-old Japanese male on dialysis. Multiple nodules accompanied by ulcers were observed on his tongue. He had no subjective symptoms or clinical findings associated with multiple myeloma. The histopathological findings suggested amyloidosis. We suspected both systemic and localized amyloidosis and performed a comprehensive systemic examination. Since the patient had been on dialysis for only a short period of time (similar to 3 months), dialysis-related amyloidosis was ruled out. After blood and urine tests, a diagnosis of multiple myeloma was made. Chemotherapy treatment was started, but the patient's multiple myeloma could not be suppressed and the tongue amyloidosis worsened, leading to his death 2 years and 2 months after the initial diagnosis. No potential conflict of interest relevant to this article was reported.

Anticancer Research USA Inc. Acta Medica Okayama 1109-6535 21 5 2024 Terrein Exhibits Anti-tumor Activity by Suppressing Angiogenin Expression in Malignant Melanoma Cells 464 473 EN TAIRA HIROSE Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences YUKI KUNISADA Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences KOICHI KADOYA Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences HIROKI MANDAI Department of Pharmacy, Faculty of Pharmacy, Gifu University of Medical Science YUMI SAKAMOTO Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences KYOICHI OBATA Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences KISHO ONO Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences HIROAKI TAKAKURA Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences KAZUHIRO OMORI Department of Pathophysiology-Periodontal Science, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University SHOGO TAKASHIBA Department of Pathophysiology-Periodontal Science, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University SEIJI SUGA Division of Applied Chemistry, Graduate School of Natural Sciences and Technology, Okayama University SOICHIRO IBARAGI Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Background/Aim: Malignant melanoma is a tumor with a poor prognosis that can metastasize distally at an early stage. Terrein, a metabolite produced by Aspergillus terreus, suppresses the expression of angiogenin, an angiogenic factor. However, the pharmacological effects of natural terrein have not been elucidated, because only a small amount of terrein can be extracted from large fungal cultures. In this study, we investigated the antineoplastic effects of terrein on human malignant melanoma cells and its underlying mechanisms. Materials and methods: Human malignant melanoma cell lines were cultured in the presence of terrein and analyzed. Angiogenin production was evaluated using ELISA. Ribosome biosynthesis was evaluated using silver staining of the nucleolar organizer region. Intracellular signaling pathways were analyzed using western blotting. Malignant melanoma cells were transplanted subcutaneously into the backs of nude mice. The tumors were removed at 5 weeks and analyzed histopathologically. Results: Terrein inhibited angiogenin expression, proliferation, migration, invasion, and ribosome biosynthesis in malignant melanoma cells. Terrein was shown to inhibit tumor growth and angiogenesis in animal models. Conclusion: This study demonstrated that terrein has anti-tumor effects against malignant melanoma. Furthermore, chemically synthesized non-natural terrein can be mass-produced and serve as a novel potential anti-tumor drug candidate. No potential conflict of interest relevant to this article was reported.

American Society for Clinical Investigation Acta Medica Okayama 2379-3708 9 10 2024 Double-faced CX3CL1 enhances lymphangiogenesis-dependent metastasis in an aggressive subclone of oral squamous cell carcinoma e174618 EN Htoo Shwe Eain Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hotaka Kawai Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Masaaki Nakayama Department of Oral Microbiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University May Wathone Oo Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Toshiaki Ohara Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama Universit Yoko Fukuhara Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kiyofumi Takabatake Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Quisheng Shan Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yamin Soe Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kisho Ono Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Keisuke Nakano Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Nobuyoshi Mizukawa Department of Oral and Maxillofacial Reconstructive Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Seiji Iida Department of Oral and Maxillofacial Reconstructive Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hitoshi Nagatsuka Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Because cancer cells have a genetically unstable nature, they give rise to genetically different variant subclones inside a single tumor. Understanding cancer heterogeneity and subclone characteristics is crucial for developing more efficacious therapies. Oral squamous cell carcinoma (OSCC) is characterized by high heterogeneity and plasticity. On the other hand, CX3C motif ligand 1 (CX3CL1) is a double-faced chemokine with anti- and pro -tumor functions. Our study reported that CX3CL1 functioned differently in tumors with different cancer phenotypes, both in vivo and in vitro. Mouse OSCC 1 (MOC1) and MOC2 cells responded similarly to CX3CL1 in vitro. However, in vivo, CX3CL1 increased keratinization in indolent MOC1 cancer, while CX3CL1 promoted cervical lymphatic metastasis in aggressive MOC2 cancer. These outcomes were due to double-faced CX3CL1 effects on different immune microenvironments indolent and aggressive cancer created. Furthermore, we established that CX3CL1 promoted cancer metastasis via the lymphatic pathway by stimulating lymphangiogenesis and transendothelial migration of lymph -circulating tumor cells. CX3CL1 enrichment in lymphatic metastasis tissues was observed in aggressive murine and human cell lines. OSCC patient samples with CX3CL1 enrichment exhibited a strong correlation with lower overall survival rates and higher recurrence and distant metastasis rates. In conclusion, CX3CL1 is a pivotal factor that stimulates the metastasis of aggressive cancer subclones within the heterogeneous tumors to metastasize, and our study demonstrates the prognostic value of CX3CL1 enrichment in long-term monitoring in OSCC. No potential conflict of interest relevant to this article was reported.

Anticancer Research USA Inc. Acta Medica Okayama 0250-7005 43 11 2023 Multimodal Prediction of Cervical Lymph Node Metastasis and Recurrence in Oral Squamous Cell Carcinoma 4993 5001 EN HIDEKA KANEMOTO Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences KYOICHI OBATA Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences KOKI UMEMORI Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences KAZUAKI HASEGAWA Department of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital SAWAKO ONO Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences KISHO ONO Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences HIROKAZU YUTORI Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences SOICHIRO IBARAGI Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Background/Aim: Oral squamous cell carcinoma (OSCC) is the most common malignancy in the head/neck region, and cervical lymph node (CLN) metastasis is a strong poor-prognosis factor. In addition, many patients with OSCC experience recurrence despite multidisciplinary treatment. We sought to identify factors associated with CLN metastasis and recurrence in patients with OSCC. Patients and Methods: We evaluated a total of 45 patients and 233 target CLNs. The longest diameter of the target CLN, the shortest diameter of the target CLN (LS), the area of the target CLN, and the relative computed tomography (CT) values of the target CLNs calculated based on the CT values of the internal jugular vein (LCT) were obtained from preoperative CT images, and the maximum standardized uptake values of the primary tumor (pSUV) and target CLN (nSUV) were obtained from preoperative 18F-fluorodeoxyglucose-positron emission tomography/CT images. We performed immunohistochemical staining for cytokeratin 13 (CK13) and 17 (CK17) on neck dissection tissues. Results: A discrimination equation was used that can predict CLN metastasis with a 92.2% discrimination rate using LS, LCT, pSUV, and nSUV. The CLNs were divided into discrimination and non-discrimination groups based on discriminant equations and CK13 and CK17 were used as the objective variables. A significantly higher recurrence rate was observed in the non-discrimination group (CK13: 5-year recurrence rate 28.6% vs. 64.3%, p<0.01; CK17: 5-year recurrence rate 28.0% vs. 76.0%, p<0.01). Conclusion: CLN metastases in OSCC can be assessed by combining preoperative imaging. The combined use of CK13 and CK17 expression with imaging findings offers an integrated approach to predict OSCC recurrence. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 1368-8375 142 2023 EpEX, the soluble extracellular domain of EpCAM, resists cetuximab treatment of EGFR-high head and neck squamous cell carcinoma 106433 EN Koki Umemori Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kisho Ono Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takanori Eguchi Department of Dental Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hotaka Kawai Department of Oral Pathology and Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tomoya Nakamura Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tatsuo Ogawa Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kunihiro Yoshida Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hideka Kanemoto Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kohei Sato Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kyoichi Obata Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shoji Ryumon Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hirokazu Yutori Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Naoki Katase Department of Oral Pathology, Graduate School of Biomedical Sciences, Nagasaki University Tatsuo Okui Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine Hitoshi Nagatsuka Department of Oral Pathology and Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Soichiro Ibaragi Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Objectives: Cetuximab (Cmab) is a molecularly targeted monoclonal antibody drug for head and neck squamous cell carcinoma (HNSC), although cetuximab resistance is a serious challenge. Epithelial cell adhesion molecule (EpCAM) is an established marker for many epithelial tumors, while the soluble EpCAM extracellular domain (EpEX) functions as a ligand for epidermal growth factor receptor (EGFR). We investigated the expression of EpCAM in HNSC, its involvement in Cmab action, and the mechanism by which soluble EpEX activated EGFR and played key roles in Cmab resistance. Materials and methods: We first examined EPCAM expression in HNSCs and its clinical significance by searching gene expression array databases. We then examined the effects of soluble EpEX and Cmab on intracellular signaling and Cmab efficacy in HNSC cell lines (HSC-3 and SAS). Results: EPCAM expression was found to be enhanced in HNSC tumor tissues compared to normal tissues, and the enhancement was correlated with stage progression and prognosis. Soluble EpEX activated the EGFR-ERK signaling pathway and nuclear translocation of EpCAM intracellular domains (EpICDs) in HNSC cells. EpEX resisted the antitumor effect of Cmab in an EGFR expression-dependent manner. Conclusion: Soluble EpEX activates EGFR to increase Cmab resistance in HNSC cells. The EpEX-activated Cmab resistance in HNSC is potentially mediated by the EGFR-ERK signaling pathway and the EpCAM cleavage-induced nuclear translocation of EpICD. High expression and cleavage of EpCAM are potential biomarkers for predicting the clinical efficacy and resistance to Cmab. No potential conflict of interest relevant to this article was reported.

AME Publishing Company Acta Medica Okayama 2227-684X 11 10 2022 Lip pleomorphic adenomas: case series and literature review 1730 1740 EN Koki Umemori Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kisho Ono Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideka Kanemoto Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kyoichi Obata Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hotaka Kawai Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoya Nakamura Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keisuke Nakano Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Soichiro Ibaragi Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hitoshi Nagatsuka Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akira Sasaki Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Background: Pleomorphic adenoma (PA) is the most frequent benign salivary gland tumor, but a lip PA is rare. Although this tumor may be definitively diagnosed by imaging or a tissue biopsy if it is reasonably large, PAs on the lip are relatively small, and they present findings that are similar to those of other lip lesions, which can make a preoperative diagnosis difficult. Methods: We analyzed all PAs in the oral region and lesions on the lips treated in our department over the past 20 years, and we discuss them together with the relevant literature. Results: We found that 11.8% (n=6) of the PAs occurred on a lip (upper lip: 9.8%, lower lip: 2.0%), and ~1% of all mass lesions of the lips were PAs. The average size of the lip PAs was 1.5±0.7 cm (range, 0.7–2.2 cm). For preoperative diagnostic assistance, ultrasonography (US) (n=4), magnetic resonance (MR) (n=3), or no imaging (n=2) was used. An excisional biopsy was performed in all cases, and to date, no recurrence or malignant transformation has been observed. Conclusions: Lip PA is relatively rare. Because almost all of these lesions are small, a preoperative diagnosis is more difficult compared to palatal lesions. This tumor is also prone to long-term neglect and has the potential for recurrence and malignant transformation. It is thus necessary to perform an excision that includes the capsule and surrounding tissues, and careful postoperative follow-up should be continued. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2075-4418 12 9 2022 Craniomaxillofacial Fibrous Dysplasia Improved Cosmetic and Occlusal Problem by Comprehensive Treatment: A Case Report and Review of Current Treatments 2146 EN Kisho Ono Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Norie Yoshioka Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yuki Kunisada Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tomoya Nakamura Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yuko Nakamura Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kyoichi Obata Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Soichiro Ibaragi Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shogo Minagi Department of Occlusal and Oral Functional Rehabilitation, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Akira Sasaki Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Fibrous dysplasia (FD) is a fibrous lesion of immature bone, with an incidence of 10-20% in the head and neck region. Most cases are monostotic, but when a lesion occurs on the maxillofacial region and spreads to the surrounding bone, it is classified as polyostotic, despite its localized occurrence. In some cases, surgical intervention is required to improve the cosmetic or functional disturbance of a FD in the maxillofacial region, but it is necessary to confirm symmetry of the maxillofacial region in real time, and a surgical support system is required to compensate. Furthermore, prosthetic intervention is considered when postoperative acquired defects occur or further cosmetic or occlusal function improvement is needed. A comprehensive approach by an oral surgeon and a maxillofacial prosthodontist is necessary for the successful treatment and rehabilitation of such patients. In this article, we describe the case of a craniomaxillofacial FD patient with facial asymmetry and denture incompatibility with improved quality of life measures by integrating surgical treatment using a navigation system and postoperative prosthetic rehabilitation. We also discuss recent diagnostic methods and treatment strategies for craniomaxillofacial FD in the literature. No potential conflict of interest relevant to this article was reported.

Ivyspring International Publisher Acta Medica Okayama 1449-1907 19 8 2022 Reproduction of the Antitumor Effect of Cisplatin and Cetuximab Using a Three-dimensional Spheroid Model in Oral Cancer 1320 1333 EN Kisho Ono Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kohei Sato Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tomoya Nakamura Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yume Yoshida Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shogo Murata Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kunihiro Yoshida Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hideka Kanemoto Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Koki Umemori Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hotaka Kawai Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kyoichi Obata Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shoji Ryumon Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kazuaki Hasegawa Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yuki Kunisada Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tatsuo Okui Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine Soichiro Ibaragi Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hitoshi Nagatsuka Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Akira Sasaki Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Background/Aim: Cancer research has been conducted using cultured cells as part of drug discovery testing, but conventional two-dimensional culture methods are unable to reflect the complex tumor microenvironment. On the other hand, three-dimensional cultures have recently been attracting attention as in vitro models that more closely resemble the in vivo physiological environment. The purpose of this study was to establish a 3D culture method for oral cancer and to verify its practicality. Materials and Methods: Three-dimensional cultures were performed using several oral cancer cell lines. Western blotting was used for protein expression analysis of the collected cell masses (spheroids), and H-E staining was used for structural observation. The cultures were exposed to cisplatin and cetuximab and the morphological changes of spheroids over time and the expression changes of target proteins were compared. Results: Each cell line formed spheroidal cell aggregates and showed enhancement of cell adhesion molecules over time. H-E staining showed tumor tissue-like structures specific to each cell line. Cisplatin showed concentration-dependent antitumor effects due to loss of cell adhesion and spheroid disruption in each cell line, while cetuximab exhibited antitumor effects that correlated with EGFR expression in each cell line. Conclusion: Spheroids made from oral cancer cell lines appeared to have tumor-like characteristics that may reflect their clinical significance. In the future, it may become possible to produce tumor spheroids from tissue samples of oral cancer patients, and then apply them to drug screening and to develop individualized diagnostic and treatment methods. No potential conflict of interest relevant to this article was reported.

American Society for Clinical Investigation Acta Medica Okayama 2379-3708 7 1 2022 Resident stroma-secreted chemokine CCL2 governs myeloid-derived suppressor cells in the tumor microenvironment e148960 EN May Wathone Oo Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hotaka Kawai Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kiyofumi Takabatake Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Takanori Eguchi Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kisho Ono Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Qiusheng Shan Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Toshiaki Ohara Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Saori Yoshida Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Haruka Omori Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shintaro Sukegawa Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Keisuke Nakano Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kuniaki Okamoto Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Akira Sasaki Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hitoshi Nagatsuka Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Accumulating evidence has shown that cancer stroma and BM-derived cells (BMDCs) in the tumor microenvironment (TME) play vital roles in tumor progression. However, the mechanism by which oral cancer stroma recruits any particular subset of BMDCs remains largely unknown. Here, we sought to identify the subset of BMDCs that is recruited by cancer stroma. We established a sequential transplantation model in BALB/c nude mice, including (a) BM transplantation of GFP-expressing cells and (b) coxenografting of patient-derived stroma (PDS; 2 cases, designated PDS1 and PDS2) with oral cancer cells (HSC-2). As controls, xenografting was performed with HSC-2 alone or in combination with normal human dermal fibroblasts (HDF). PDS1, PDS2, and HDF all promoted BMDC migration in vitro and recruitment in vivo. Multicolor immunofluorescence revealed that the PDS coxenografts recruited Arginase-1(+)CD11b(+)GR1(+)GFP(+) cells, which are myeloid-derived suppressor cells (MDSCs), to the TME, whereas the HDF coxenograft did not. Screening using microarrays revealed that PDS1 and PDS2 expressed CCL2 mRNA (encoding C-C motif chemokine ligand 2) at higher levels than did HDF. Indeed, PDS xenografts contained significantly higher proportions of CCL2(+) stromal cells and CCR2(+)Arginase-1(+)CD11b(+)GR1(+) MDSCs (as receiver cells) than the HDF coxenograft. Consistently, a CCL2 synthesis inhibitor and a CCR2 antagonist significantly inhibited the PDS-driven migration of BM cells in vitro. Furthermore, i.p. injection of the CCR2 antagonist to the PDS xenograft models significantly reduced the CCR2(+)Arginase-1(+)CD11b(+)GR1(+) MDSC infiltration to the TME. In conclusion, oral cancer stroma-secreted CCL2 is a key signal for recruiting CCR2(+) MDSCs from BM to the TME. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2075-4418 11 8 2021 Comparative Study on Epstein-Barr Virus-Positive Mucocutaneous Ulcer and Methotrexate-Associated Lymphoproliferative Disorders Developed in the Oral Mucosa: A Case Series of 10 Patients and Literature Review 1375 EN Kyoichi Obata Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tatsuo Okui Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine Sawako Ono Department of Pathology, Kagawa Prefectural Central Hospital Koki Umemori Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shoji Ryumon Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kisho Ono Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mayumi Yao Department of Dentistry and Dental Surgery, Tsuyama Chuo Hospital Norie Yoshioka Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Soichiro Ibaragi Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akira Sasaki Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is an iatrogenic immunodeficiency-associated lymphoproliferative disorder that occurs mainly with MTX use. This disorder has been associated with Epstein-Barr virus (EBV) infection. In 2017, the WHO newly defined the disease concept of EBV-positive mucocutaneous ulcer (EBV-MCU) as a good-prognosis EBV-related disease. Here, we report 10 cases of MTX-LPD or EBV-MCU in the oral mucosa. This retrospective, observational study was conducted with MTX-LPD or EBV-MCU in the oral mucosa patients who visited us during the nine year period from 2012 to 2021. We gathered the basic information, underlying disease, histopathological evaluation, treatment and prognosis for the subjects. All were being treated with MTX for rheumatoid arthritis. EBV infection was positive in all cases by immunohistochemistry. A complete or partial response was obtained in all cases with the withdrawal of MTX. Our results suggests that the most common risk factor for developing EBV-MCU is the use of immunosuppressive drugs. The most common site of onset is the oral mucosa, which may be attributed to the mode of EBV infection and the high incidence of chronic irritation of the oral mucosa. A small number of patients had been diagnosed with MTX-LPD, but we consider that these cases were EBV-MCU based on our study. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2050-0904 9 6 2021 A case of langerhans cell histiocytosis of the mandible that spontaneously regressed after biopsy in a child e04321 EN Kisho Ono Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Tatsuo Okui Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Yuki Kunisada Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Kyoichi Obata Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Masanori Masui Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Shoji Ryumon Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Soichiro Ibaragi Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Tomoya Nakamura Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Akira Sasaki Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine In younger patients of LCH, we should consider that the effectiveness of follow-up without aggressive treatment for SS-type LCH in the oral and maxillofacial bone. However, there are very rare case in which an SS-type LCH recurred after showing a healing tendency. Regular follow-up must be performed even after healing. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 22121374 26 2021 The HMGB1/RAGE axis induces bone pain associated with colonization of 4T1 mouse breast cancer in bone 100330 EN Tatsuo Okui Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Masahiro Hiasa Department of Biomaterials and Bioengineerings, University of Tokushima Graduate School of Dentistry Shoji Ryumon Kisho Ono Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Yuki Kunisada Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Soichiro Ibaragi Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Akira Sasaki Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science G. David Roodman Department of Medicine, Hematology Oncology, Indiana University School of Medicine Fletcher A. White Department of Anesthesia, Paul and Carole Stark Neurosciences Research Institute Toshiyuki Yoneda Department of Cellular and Molecular Biochemistry, Osaka University Graduate School of Dentistry Bone pain is a common complication of breast cancer (BC) bone metastasis and is a major cause of increased morbidity and mortality. Although the mechanism of BC-associated bone pain (BCABP) remains poorly understood, involvement of BC products in the pathophysiology of BCABP has been proposed. Aggressive cancers secrete damage-associated molecular patterns (DAMPs) that bind to specific DAMP receptors and modulate cancer microenvironment. A prototypic DAMP, high mobility group box 1 (HMGB1), which acts as a ligand for the receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs), is increased in its expression in BC patients with poor outcomes. Here we show that 4T1 mouse BC cells colonizing bone up-regulate the expression of molecular pain markers, phosphorylated ERK1/2 (pERK) and pCREB, in the dorsal root ganglia (DRGs) innervating bone and induced BCABP as evaluated by hind-paw mechanical hypersensitivity. Importantly, silencing HMGB1 in 4T1 BC cells by shRNA reduced pERK and pCREB and BCABP with decreased HMGB1 levels in bone. Further, administration of a neutralizing antibody to HMGB1 or an antagonist for RAGE, FPS-ZM1, ameliorated pERK, pCREB and BCABP, while a TLR4 antagonist, TAK242, showed no effects. Consistent with these in vivo results, co-cultures of F11 sensory neuron-like cells with 4T1 BC cells in microfluidic culture platforms increased neurite outgrowth of F11 cells, which was blocked by HMGB1 antibody. Our results show that HMGB1 secreted by BC cells induces BCABP via binding to RAGE of sensory neurons and suggest that the HMGB1/RAGE axis may be a potential novel therapeutic target for BCABP. No potential conflict of interest relevant to this article was reported.

Taylor & Francis Acta Medica Okayama 2001-3078 9 1 2020 Triple knockdown of CDC37, HSP90‐alpha and HSP90‐beta diminishes extracellular vesicles‐driven malignancy events and macrophage M2 polarization in oral cancer 1769373 EN Kisho Ono Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Chiharu Sogawa Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hotaka Kawai Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Manh Tien Tran Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Eman A. Taha Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yanyin Lu Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University May Wathone Oo Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Yuka Okusha Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hirohiko Okamura Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Soichiro Ibaragi Department of Oral and Maxillofacial Surgery, Okayama University Hospital Masaharu Takigawa Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ken-Ichi Kozaki Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hitoshi Nagatsuka Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Akira Sasaki Department of Oral and Maxillofacial Surgery, Okayama University Hospital Kuniaki Okamoto Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Stuart K. Calderwood Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School Takanori Eguchi Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Evidence has been accumulating to indicate that extracellular vesicles (EVs), including exosomes, released by cancer cells can foster tumour progression. The molecular chaperones – CDC37, HSP90α and HSP90β play key roles in cancer progression including epithelial‐mesenchymal transition (EMT), although their contribution to EVs‐mediated cell–cell communication in tumour microenvironment has not been thoroughly examined. Here we show that triple depletion of the chaperone trio attenuates numerous cancer malignancy events exerted through EV release. Metastatic oral cancer‐derived EVs (MEV) were enriched with HSP90α HSP90β and cancer‐initiating cell marker CD326/EpCAM. Depletion of these chaperones individually induced compensatory increases in the other chaperones, whereas triple siRNA targeting of these molecules markedly diminished the levels of the chaperone trio and attenuated EMT. MEV were potent agents in initiating EMT in normal epithelial cells, a process that was attenuated by the triple chaperone depletion. The migration, invasion, and in vitro tumour initiation of oral cancer cells were significantly promoted by MEV, while triple depletion of CDC37/HSP90α/β reversed these MEV‐driven malignancy events. In metastatic oral cancer patient‐derived tumours, HSP90β was significantly accumulated in infiltrating tumour‐associated macrophages (TAM) as compared to lower grade oral cancer cases. HSP90‐enriched MEV‐induced TAM polarization to an M2 phenotype, a transition known to support cancer progression, whereas the triple chaperone depletion attenuated this effect. Mechanistically, the triple chaperone depletion in metastatic oral cancer cells effectively reduced MEV transmission into macrophages. Hence, siRNA‐mediated knockdown of the chaperone trio (CDC37/HSP90α/HSP90β) could potentially be a novel therapeutic strategy to attenuate several EV‐driven malignancy events in the tumour microenvironment. No potential conflict of interest relevant to this article was reported.

Spandidos Publications Acta Medica Okayama 1021-335X 44 6 2020 High mobility group box 1 induces bone pain associated with bone invasion in a mouse model of advanced head and neck cancer 2547 2558 EN Tomoya Nakamura Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Tatsuo Okui Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Kazuaki Hasegawa Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Shoji Ryumon Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Soichiro Ibaragi Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Kisho Ono Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Yuki Kunisada Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Kyoichi Obata Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Masanori Masui Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Tsuyoshi Shimo Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido Akira Sasaki Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Advanced head and neck cancer (HNC) can invade facial bone and cause bone pain, thus posing a significant challenge to the quality of life of patients presenting with advanced HNC. The present study was designed to investigate HNC bone pain (HNC‑BP) in an intratibial mouse xenograft model that utilized an HNC cell line (SAS cells). These mice develop HNC‑BP that is associated with an expression of phosphorylated ERK1/2 (pERK1/2), which is a molecular indicator of neuron excitation in dorsal root ganglia (DRG) sensory neurons. Our experiments demonstrated that the inhibition of high mobility group box 1 (HMGB1) by short hairpin (shRNA) transduction, HMGB1 neutralizing antibody, and HMGB1 receptor antagonist suppressed the HNC‑BP and the pERK1/2 expression in DRG. It was also observed that HNC‑derived HMGB1 increased the expression of the acid‑sensing nociceptor, transient receptor potential vanilloid 1 (TRPV1), which is a major cause of osteoclastic HNC‑BP in DRG. Collectively, our results demonstrated that HMGB1 originating in HNC evokes HNC‑BP via direct HMGB1 signaling and hypersensitization for the acid environment in sensory neurons. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2050-0904 9 1 2020 Surgical resection of a giant peripheral ossifying fibroma in mouth floor managed with fiberscopic intubation 180 184 EN Tatsuo Okui Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Soichiro Ibaragi Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kisho Ono Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuaki Hasegawa Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akira Sasaki Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tracheal intubation for general anesthesia can sometimes be difficult in patients with a large mass in the mouth floor. Preoperative evaluation of the patient's airway is most important when treating large oral disease. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 0006-291X 531 3 2020 High-mobility group box 1 induces bone destruction associated with advanced oral squamous cancer via RAGE and TLR4 422 430 EN Yumi Sakamoto Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Tatsuo Okui Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Toshiyuki Yoneda Department of Cellular and Molecular Biochemistry, Osaka University Graduate School of Dentistry Shoji Ryumon Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Tomoya Nakamura Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Hotaka Kawai Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yuki Kunisada Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Soichiro Ibaragi Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Masanori Masui Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Kisho Ono Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Kyoichi Obata Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Tsuyoshi Shimo Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido Akira Sasaki Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Bone destruction of maxillary and mandibular bone by invasive oral squamous cell cancer (OSCC) raises various problems in the management of patients, resulting in poor outcomes and survival. However, the mechanism behind bone destruction by OSCC remains unclear. High-mobility group box 1 (HMGB1), a highly conserved ubiquitous nuclear non-histone DNA-binding protein, has been demonstrated to be secreted by aggressive cancers and regulate osteoclastogenesis, a central player during bone destruction. We therefore reasoned that HMGB1 secreted by OSCCs contributes to bone destruction. Our results showed that HMGB1 is produced by human cell lines of OSCC and promotes osteoclastogenesis via up-regulation of the expression of receptor activator of nuclear factor kappa-Β ligand in osteoblasts and osteocytes, and consequently osteoclastic bone destruction in mice. Further, we found that these actions of HMGB1 are mediated via the receptor for advanced glycation end products and toll-like receptors. These findings suggest that HMGB1 of OSCC and its down-stream signal pathways are potential targets for the treatment of bone destruction associated with advanced OSCC. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2079-7737 9 3 2020 A Novel Model of Cancer Drug Resistance: Oncosomal Release of Cytotoxic and Antibody-Based Drugs 47 EN Takanori Eguchi Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Eman Ahmed Taha Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Stuart K. Calderwood Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School Kisho Ono Department of Oral and Maxillofacial Surgery, Okayama University Hospital Extracellular vesicles (EVs), such as exosomes or oncosomes, often carry oncogenic molecules derived from tumor cells. In addition, accumulating evidence indicates that tumor cells can eject anti-cancer drugs such as chemotherapeutics and targeted drugs within EVs, a novel mechanism of drug resistance. The EV-releasing drug resistance phenotype is often coupled with cellular dedifferentiation and transformation in cells undergoing epithelial-mesenchymal transition (EMT), and the adoption of a cancer stem cell phenotype. The release of EVs is also involved in immunosuppression. Herein, we address different aspects by which EVs modulate the tumor microenvironment to become resistant to anticancer and antibody-based drugs, as well as the concept of the resistance-associated secretory phenotype (RASP). No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2050-0904 8 12 2020 A case of oral cancer with delayed occipital lymph node metastasis: Case report 2469 2475 EN Kisho Ono Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Norie Yoshioka Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Masanori Masui Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Kyoichi Obata Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Yuki Kunisada Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Tatsuo Okui Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Soichiro Ibaragi Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Hotaka Kawai Department of Oral Pathology and Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Hitoshi Nagatsuka Department of Oral Pathology and Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Akira Sasaki Department of Oral and Maxillofacial Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Consideration of unexpected metastasis in patients who have undergone neck dissection with advanced tumors must be anticipated with careful follow-up. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2072-6694 12 4 2020 Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer 881 EN Yuka Okusha Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takanori Eguchi Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Manh T. Tran Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Chiharu Sogawa Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kaya Yoshida Department of Oral Healthcare Education, Institute of Biomedical Sciences, Tokushima University Graduate School Mami Itagaki Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Eman A. Taha Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kisho Ono Department of Oral and Maxillofacial Surgery, Okayama University Hospital Eriko Aoyama Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hirohiko Okamura Department of Oral Morphology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Ken-Ichi Kozaki Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Stuart K. Calderwood Division of Molecular and Cellular Biology, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School Masaharu Takigawa Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kuniaki Okamoto Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Matrix metalloproteinase 3 (MMP3) plays multiple roles in extracellular proteolysis as well as intracellular transcription, prompting a new definition of moonlighting metalloproteinase (MMP), according to a definition of protein moonlighting (or gene sharing), a phenomenon by which a protein can perform more than one function. Indeed, connective tissue growth factor (CTGF, aka cellular communication network factor 2 (CCN2)) is transcriptionally induced as well as cleaved by MMP3. Moreover, several members of the MMP family have been found within tumor-derived extracellular vesicles (EVs). We here investigated the roles of MMP3-rich EVs in tumor progression, molecular transmission, and gene regulation. EVs derived from a rapidly metastatic cancer cell line (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich, LuM1-derived EVs were disseminated to multiple organs through body fluid and were pro-tumorigenic in an allograft mouse model, which prompted us to define LuM1-EVs as oncosomes in the present study. Oncosome-derived MMP3 was transferred into recipient cell nuclei and thereby trans-activated the CCN2/CTGF promoter, and induced CCN2/CTGF production in vitro. TRENDIC and other cis-elements in the CCN2/CTGF promoter were essential for the oncosomal responsivity. The CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects such as the inhibition of migration and invasion of tumor cells, and a reduction in CCN2/CTGF promoter activity and fragmentations in vitro. A high expression level of MMP3 or CCN2/CTGF mRNA was prognostic and unfavorable in particular types of cancers including head and neck, lung, pancreatic, cervical, stomach, and urothelial cancers. These data newly demonstrate that oncogenic EVs-derived MMP is a transmissive trans-activator for the cellular communication network gene and promotes tumorigenesis at distant sites. No potential conflict of interest relevant to this article was reported.