76 results on '"Yu‐ichiro Koma"'
Search Results
2. Preclinical evaluation of the efficacy of an antibody to human SIRPα for cancer immunotherapy in humanized mouse models
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Yasuyuki Saito, Rie Iida-Norita, Tania Afroj, Alaa Refaat, Daisuke Hazama, Satomi Komori, Shinya Ohata, Tomoko Takai, Okechi S. Oduori, Takenori Kotani, Yohei Funakoshi, Yu-Ichiro Koma, Yoji Murata, Kimikazu Yakushijin, Hiroshi Matsuoka, Hironobu Minami, Hiroshi Yokozaki, Markus G. Manz, and Takashi Matozaki
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humanized mouse ,tumor-associated macrophages ,SIRP alpha ,cancer immunotherapy ,patient-derived xenograft (PDX) model ,macrophage checkpoint ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and are considered potential targets for cancer immunotherapy. To examine the antitumor effects of agents targeting human TAMs in vivo, we here established preclinical tumor xenograft models based on immunodeficient mice that express multiple human cytokines and have been reconstituted with a human immune system by transplantation of human CD34+ hematopoietic stem and progenitor cells (HIS-MITRG mice). HIS-MITRG mice supported the growth of both human cell line (Raji)– and patient-derived B cell lymphoma as well as the infiltration of human macrophages into their tumors. We examined the potential antitumor action of an antibody to human SIRPα (SE12C3) that inhibits the interaction of CD47 on tumor cells with SIRPα on human macrophages and thereby promotes Fcγ receptor–mediated phagocytosis of the former cells by the latter. Treatment with the combination of rituximab (antibody to human CD20) and SE12C3 inhibited Raji tumor growth in HIS-MITRG mice to a markedly greater extent than did rituximab monotherapy. This enhanced antitumor effect was dependent on human macrophages and attributable to enhanced rituximab-dependent phagocytosis of lymphoma cells by human macrophages. Treatment with rituximab and SE12C3 also induced reprogramming of human TAMs toward a proinflammatory phenotype. Furthermore, the combination treatment essentially prevented the growth of patient-derived diffuse large B cell lymphoma in HIS-MITRG mice. Our findings thus support the study of HIS-MITRG mice as a model for the preclinical evaluation in vivo of potential therapeutics, such as antibodies to human SIRPα, that target human TAMs.
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- 2023
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3. IFI16 Induced by Direct Interaction between Esophageal Squamous Cell Carcinomas and Macrophages Promotes Tumor Progression via Secretion of IL-1α
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Yuki Azumi, Yu-ichiro Koma, Shuichi Tsukamoto, Yu Kitamura, Nobuaki Ishihara, Keitaro Yamanaka, Takashi Nakanishi, Shoji Miyako, Satoshi Urakami, Kohei Tanigawa, Takayuki Kodama, Mari Nishio, Manabu Shigeoka, Yoshihiro Kakeji, and Hiroshi Yokozaki
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esophageal squamous cell carcinoma ,tumor-associated macrophage ,direct co-culture ,IFI16 ,IL-1α ,Cytology ,QH573-671 - Abstract
Tumor-associated macrophages (TAMs), one of the major components of the tumor microenvironment, contribute to the progression of esophageal squamous cell carcinoma (ESCC). We previously established a direct co-culture system of human ESCC cells and macrophages and reported the promotion of malignant phenotypes, such as survival, growth, and migration, in ESCC cells. These findings suggested that direct interactions between cancer cells and macrophages contribute to the malignancy of ESCC, but its underlying mechanisms remain unclear. In this study, we compared the expression levels of the interferon-induced genes between mono- and co-cultured ESCC cells using a cDNA microarray and found that interferon-inducible protein 16 (IFI16) was most significantly upregulated in co-cultured ESCC cells. IFI16 knockdown suppressed malignant phenotypes and also decreased the secretion of interleukin-1α (IL-1α) from ESCC cells. Additionally, recombinant IL-1α enhanced malignant phenotypes of ESCC cells through the Erk and NF-κB signaling. Immunohistochemistry revealed that high IFI16 expression in human ESCC tissues tended to be associated with disease-free survival and was significantly associated with tumor depth, lymph node metastasis, and macrophage infiltration. The results of this study reveal that IFI16 is involved in ESCC progression via IL-1α and imply the potential of IFI16 as a novel prognostic factor for ESCC.
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- 2023
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4. Hepatic Inflammatory Pseudotumor—Focusing on Its Heterogeneity
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Soo Ryang Kim, Soo Ki Kim, Yu-ichiro Koma, Motoko Sasaki, Akira Asai, and Hiroki Nishikawa
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hepatic inflammatory pseudotumor ,pathological findings ,pathogenesis ,differential diagnosis ,heterogeneity ,Medicine (General) ,R5-920 - Abstract
Hepatic inflammatory pseudotumors (IPTs) are defined as benign, non-malignant, non-metastasizing tumors characterized by the presence of myofibroblastic spindle cells, hetorogenous populations of inflammatory cells, particularly plasma cells, lymphocytes and macrophages, as well as locations of fibrosis and necrosis without cellular anaplasia or atypical mitoses. Despite subsequent reports in the references, hepatic IPT remains difficult to diagnose; while posing major issues specifically for its differential diagnosis compared with that of other various benign diseases and malignant hepatic tumors. Histopathological findings are always a requisite for confirming the diagnosis, particularly given that the pathogenesis of IPT remains ambiguous to date. Hepatic IPT is a heterogeneous entity in terms of its clinical features, pathological findings, and pathogenesis. Once the diagnosis is confirmed, however, needless surgery such as wedge resection and lobectomy should be avoided. Here, we discuss the heterogeneity of hepatic IPT, its clinical features, pathological findings, and pathogenesis, and describe its differential diagnosis.
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- 2023
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5. Significance of Wnt/β-Catenin Signal Activation for Resistance to Neoadjuvant Chemoradiotherapy in Rectal Cancer
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Shoji Miyako, Takeru Matsuda, Yu-ichiro Koma, Takahiro Koide, Ryuichiro Sawada, Hiroshi Hasegawa, Kimihiro Yamashita, Hitoshi Harada, Naoki Urakawa, Hironobu Goto, Shingo Kanaji, Taro Oshikiri, and Yoshihiro Kakeji
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rectal cancer ,β-catenin ,NACRT ,Biology (General) ,QH301-705.5 - Abstract
Although a therapeutic response to neoadjuvant chemoradiotherapy (NACRT) is important to improve oncological outcomes after surgery in patients with locally advanced rectal cancer, there is no reliable predictor for this. The Wnt/β-catenin signal is known to be crucial for the tumorigenesis of colorectal cancer. This study aimed to investigate the association of Wnt/β-catenin signal activation with a pathological response to NACRT. The immunohistochemical expression of nuclear and membranous β-catenin was analyzed in biopsy samples obtained from 60 patients with locally advanced rectal cancer who received curative surgery following NACRT. The association of Wnt/β-catenin signal activation with their clinical outcomes was investigated. Notably, the body mass index of these patients was significantly higher in the low nuclear β-catenin expression group. Moreover, patients in the high nuclear β-catenin expression group tended to have more advanced disease and a higher rate of positive vascular invasion than those in the low expression group. Furthermore, the rate of good histological responses was significantly higher in the low nuclear β-catenin expression group (72% vs. 37.1%, p < 0.01). Overall, relapse-free survival tended to be better in patients with low nuclear/high membranous β-catenin expression (n = 9) than in other individuals (n = 51) (p = 0.093 and p = 0.214, respectively). Activation of the Wnt/β-catenin signal pathway represented by nuclear β-catenin accumulation was significantly associated with a poor response to NACRT in patients with rectal cancer. Analysis of nuclear β-catenin accumulation before starting treatment might help predict the therapeutic response to NACRT.
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- 2023
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6. CD163+ macrophages infiltration correlates with the immunosuppressive cytokine interleukin 10 expression in tongue leukoplakia
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Manabu Shigeoka, Yu‐ichiro Koma, Mari Nishio, Takahide Komori, and Hiroshi Yokozaki
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interleukin‐10 ,macrophage ,tongue leukoplakia ,Dentistry ,RK1-715 - Abstract
Abstract Objective Accumulating evidence suggests that macrophages are involved in the immunoediting of oral squamous cell carcinoma but the role of macrophages in oral carcinogenesis is unclear. We aimed to clarify the role of macrophages in oral leukoplakia, which is the most common oral potentially malignant disorder from immunotolerance viewpoint. Materials and methods The study included 24 patients who underwent surgical resection for tongue leukoplakia. The relationships between macrophage markers and clinicopathological factors were assessed. Conditioned medium was harvested from the CD163+ human monocytic leukaemia cell line, THP‐1. The phenotypic alteration of human oral keratinocytes by the conditioned medium treatment was assessed using quantitative reverse transcription‐polymerase chain reaction and enzyme‐linked immunosorbent assay. Moreover, the clinical samples were evaluated using immunohistochemistry. Results Tongue leukoplakia tissues with high CD163+ macrophage infiltration were associated with significantly higher degrees of epithelial dysplasia, abnormal Ki‐67 expression and cytokeratin13 loss when compared with the tissues with low CD163+ macrophage infiltration. In vitro, CD163+ THP‐1 conditioned medium induced immunosuppressive molecules, especially interleukin‐10 (IL‐10) in human oral keratinocytes. The IL‐10 expression levels showed significant positive correlations with not only the numbers of FOXP3+ regulatory T cells but also that of CD163+ macrophages. Conclusions In tongue leukoplakia, CD163+ macrophages infiltration correlates with immunosuppressive cytokine IL‐10 expression.
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- 2019
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7. Tongue Cancer Cell-Derived CCL20 Induced by Interaction With Macrophages Promotes CD163 Expression on Macrophages
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Manabu Shigeoka, Yu-ichiro Koma, Takayuki Kodama, Mari Nishio, Masaya Akashi, and Hiroshi Yokozaki
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tongue cancer ,CCL20 ,cancer microenvironment ,macrophage ,CD163 ,cell–cell interaction ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundCD163-positive macrophages contribute to the aggressiveness of oral squamous cell carcinoma. We showed in a previous report that CD163-positive macrophages infiltrated not only to the cancer nest but also to its surrounding epithelium, depending on the presence of stromal invasion in tongue carcinogenesis. However, the role of intraepithelial macrophages in tongue carcinogenesis remains unclear. In this study, we assessed the biological behavior of intraepithelial macrophages on their interaction with cancer cells.Materials and MethodsWe established the indirect coculture system (intraepithelial neoplasia model) and direct coculture system (invasive cancer model) of human monocytic leukemia cell line THP-1-derived CD163-positive macrophages with SCC25, a tongue squamous cell carcinoma (TSCC) cell line. Conditioned media (CM) harvested from these systems were analyzed using cytokine array and enzyme-linked immunosorbent assay and extracted a specific upregulated cytokine in CM from the direct coculture system (direct CM). The correlation of both this cytokine and its receptor with various clinicopathological factors were evaluated based on immunohistochemistry using clinical samples from 59 patients with TSCC. Moreover, the effect of this cytokine in direct CM on the phenotypic alterations of THP-1 was confirmed by real-time polymerase chain reaction, western blotting, immunofluorescence, and transwell migration assay.ResultsIt was shown that CCL20 was induced in the direct CM specifically. Interestingly, CCL20 was produced primarily in SCC25. The expression level of CCR6, which is a sole receptor of CCL20, was higher than the expression level of SCC25. Our immunohistochemical investigation showed that CCL20 and CCR6 expression was associated with lymphatic vessel invasion and the number of CD163-positive macrophages. Recombinant human CCL20 induced the CD163 expression and promoted migration of THP-1. We also confirmed that a neutralizing anti-CCL20 antibody blocked the induction of CD163 expression by direct CM in THP-1. Moreover, ERK1/2 phosphorylation was associated with the CCL20-driven induction of CD163 expression in THP-1.ConclusionsTongue cancer cell-derived CCL20 that was induced by interaction with macrophages promotes CD163 expression on macrophages.
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- 2021
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8. Intraepithelial Macrophage Expressing CD163 Is a Histopathological Clue to Evaluate the Malignant Potency of Oral Lichenoid Condition: A Case Report and Immunohistochemical Investigation
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Manabu Shigeoka, Yu-ichiro Koma, Maki Kanzawa, Masaya Akashi, and Hiroshi Yokozaki
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macrophage ,CD163 ,malignant potency ,oral lichenoid condition ,biopsy ,Medicine (General) ,R5-920 - Abstract
Oral lichenoid conditions (OLC), including oral lichen planus (OLP), oral lichenoid lesions and oral lichenoid dysplasia, differ in pathogenesis and biological malignancy. However, distinguishing them based on clinical or histological features is difficult. It is well known that CD163+ macrophages are associated with oral cancer aggressiveness. We recently demonstrated that CD163+ macrophages of noncancerous lesions infiltrate the stroma, not the intraepithelial area. In this report, we describe a case of OLC that was not detected as malignant by the first local biopsy. Furthermore, we evaluated the malignant potency of OLC by retrospectively comparing the histological findings between local biopsy and resected specimens focusing on CD163+ macrophages. A 72-year-old man with a white lesion in the unilateral buccal mucosa was diagnosed with OLP through the biopsy although invasive cancer was detected two years later. Intraepithelial CD163+ macrophages were found not only on the resected specimen but also biopsy. This is the first report to demonstrate that intraepithelial CD163+ macrophages may be noteworthy indicators to identify the malignant potency of OLC.
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- 2020
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9. CD163+ Foamy Macrophages Are Associated with the Morphogenesis of Oral Verruciform Xanthoma through Angiogenesis by VEGF Expression: An Immunohistochemical Study
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Manabu Shigeoka, Yu-ichiro Koma, Takayuki Kodama, Mari Nishio, Masaya Akashi, and Hiroshi Yokozaki
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oral verruciform xanthoma ,foamy macrophage ,cd163 ,angiogenesis ,vegf ,Dentistry ,RK1-715 - Abstract
Oral verruciform xanthoma (OVX) is an uncommon benign lesion that is characterized histologically by the accumulation of several foamy macrophages in the lamina propria papillae. The pathogenesis of OVX has not been completely elucidated, although the significance of macrophage polarization (M1, tumor suppression; and M2, tumor promotion) and the contribution of M2 macrophages to angiogenesis are well established. This study investigated the role of foamy macrophages in OVX, with a focus on angiogenesis. Four patients who underwent surgical excision or total excisional biopsy for OVXs were enrolled in this study. We evaluated the expression of the macrophage markers CD68 (broad) and CD163 (M2) and the CD34-positive microvessel density (MVD) of OVXs. The foamy macrophages of all patients exhibited positivity to CD68 and CD163. We evaluated the MVD and the expression of the vascular endothelial growth factor (VEGF) based on histological architecture. The MVD of all OVX cases was significantly higher than that of the corresponding normal epithelia. Interestingly, the MVD of verrucous-type OVX cases was higher than that of the other type. VEGF was expressed on foamy macrophages in all cases. Overall, the foamy macrophages expressing CD163 were associated with the morphogenesis of OVX through the process of angiogenesis by VEGF expression.
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- 2020
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10. Utility of Gd-EOB-DTPA-Enhanced MRI in Diagnosing Small Hepatocellular Carcinoma
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Soo Ryang Kim, Susumu Imoto, Taisuke Nakajima, Kenji Ando, Keiji Mita, Katsumi Fukuda, Ryo Nishikawa, Yu-ichiro Koma, Toshiyuki Matsuoka, Masatoshi Kudo, and Yoshitake Hayashi
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Gd-EOB-DTPA-enhanced MRI ,Hepatocyte function ,Ultrasound ,CT during arteriography ,Well-differentiated hepatocellular carcinoma ,Small hepatocellular carcinoma ,CT during arterial portography ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
We describe an 8-mm hepatocellular carcinoma (HCC) with hepatitis C virus-related cirrhosis in a 74-year-old woman. Ultrasound (US) revealed an 8-mm hyperechoic nodule in segment 6 of the liver. Contrast-enhanced computed tomography (CT) and US revealed no hypervascularity in the early phase and no washout in the late phase and the Kupffer phase, respectively. CT during arteriography revealed no hypervascularity and CT during arterial portography disclosed no perfusion defect. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) revealed no hypervascularity in the early phase, but disclosed a defect in the hepatobiliary phase. Histologically, the nodule was diagnosed as well-differentiated HCC characterized by more than two-fold the cellularity of the non-tumorous area, with a high nuclear:cytoplasmic ratio, increased cytoplasmic eosinophilia, fatty change, and slight cell atypia with an irregular thin trabecular pattern. Our case demonstrates the utility of Gd-EOB-DTPA-enhanced MRI in the diagnosis of small HCC.
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- 2009
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11. Hepatic Inflammatory pseudotumor differentiated from malignant hepatic tumor: A case report
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Soo Ryang Kim, Soo Ki Kim, Hisato Kobayashi, Takako Fujii, Toyokazu Okuda, Atsushi Nakai, Yumi Fujii, Takanobu Hayakumo, Ryuji Suzuki, Aya Otani, Noriko Sasase, Ke-Ih Kim, Tsutomu Kumabe, Yu-ichiro Koma, and Osamu Nakashima
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Hepatology - Published
- 2023
12. Drug-induced sarcoidosis-like reaction three months after BNT162b2 mRNA COVID-19 vaccination: A case report and review of literature
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Soo Ryang Kim, Soo Ki Kim, Takako Fujii, Hisato Kobayashi, Toyokazu Okuda, Takanobu Hayakumo, Atsushi Nakai, Yumi Fujii, Ryuji Suzuki, Noriko Sasase, Aya Otani, Yu-ichiro Koma, Motoko Sasaki, Tsutomu Kumabe, and Osamu Nakashima
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General Medicine - Published
- 2023
13. Roles of IL-7R Induced by Interactions between Cancer Cells and Macrophages in the Progression of Esophageal Squamous Cell Carcinoma
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Yu Kitamura, Yu-ichiro Koma, Kohei Tanigawa, Shuichi Tsukamoto, Yuki Azumi, Shoji Miyako, Satoshi Urakami, Takayuki Kodama, Mari Nishio, Manabu Shigeoka, Yoshihiro Kakeji, and Hiroshi Yokozaki
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Cancer Research ,Oncology ,tumor-associated macrophages ,esophageal cancer ,direct co-culture ,IL-7R ,prognostic factor ,immunohistochemistry - Abstract
High infiltration of tumor-associated macrophages (TAMs), which contribute to the progression of several cancer types, is correlated with poor prognosis of esophageal squamous cell carcinoma (ESCC). In addition to the previously reported increase in migration and invasion, ESCC cells co-cultured directly with macrophages exhibited enhanced survival and growth. Furthermore, interleukin-related molecules are associated with ESCC; however, the precise mechanism underlying this association is unclear. Therefore, we explored the role of interleukin-related molecules in ESCC progression. A cDNA microarray analysis of monocultured and co-cultured ESCC cells revealed that the interleukin 7 receptor (IL-7R) was upregulated in ESCC cells co-cultured with macrophages. Overexpression of IL-7R promoted the survival and growth of ESCC cells by activating the Akt and Erk1/2 signaling pathways. The IL-7/IL-7R axis also contributed to the promotion of ESCC cell migration via the Akt and Erk1/2 signaling pathways. Furthermore, immunohistochemistry showed that ESCC patients with high IL-7R expression in cancer nests exhibited a trend toward poor prognosis in terms of disease-free survival, and showed significant correlation with increased numbers of infiltrating macrophages and cancer-associated fibroblasts. Therefore, IL-7R, which is upregulated when directly co-cultured with macrophages, may contribute to ESCC progression by promoting the development of various malignant phenotypes in cancer cells.
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- 2023
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14. Radiological and histopathological analyses of two bile duct adenoma cases focused on washout in the portal phase of contrast-enhanced ultrasound
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Takakazu Matsushita, Hironori Tanaka, Soo Ki Kim, Osamu Nakashima, Hisato Kobayashi, Toyokazu Okuda, Tsutomu Kumabe, Soichi Kubo, Takanobu Hayakumo, Atsushi Nakai, Hiroshi Yasui, Aya Ohtani, Yu-ichiro Koma, Yumi Fujii, Akira Yamada, Ke-Ih Kim, Soo Ryang Kim, Motoko Sasaki, and Takako Fujii
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Hepatology ,business.industry ,Radiological weapon ,Portal phase ,Washout ,Medicine ,Nuclear medicine ,business ,Bile Duct Adenoma ,Contrast-enhanced ultrasound - Published
- 2021
15. Matrix Metalloproteinase 9 Induced in Esophageal Squamous Cell Carcinoma Cells via Close Contact with Tumor-Associated Macrophages Contributes to Cancer Progression and Poor Prognosis
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Shuichi Tsukamoto, Yu-ichiro Koma, Yu Kitamura, Kohei Tanigawa, Yuki Azumi, Shoji Miyako, Satoshi Urakami, Masayoshi Hosono, Takayuki Kodama, Mari Nishio, Manabu Shigeoka, and Hiroshi Yokozaki
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Cancer Research ,tumor-associated macrophage ,Oncology ,activator of transcription 3 ,immunohistochemistry ,interleukin-8 ,matrix metalloproteinase 9 ,direct contact ,prognostic factor ,esophageal squamous cell carcinoma ,direct co-culture ,signal transducer - Abstract
Tumor-associated macrophages (TAMs) contribute to disease progression in various cancers, including esophageal squamous cell carcinoma (ESCC). We have previously used an indirect co-culture system between ESCC cell lines and macrophages to analyze their interactions. Recently, we established a direct co-culture system to closely simulate actual ESCC cell-TAM contact. We found that matrix metalloproteinase 9 (MMP9) was induced in ESCC cells by direct co-culture with TAMs, not by indirect co-culture. MMP9 was associated with ESCC cell migration and invasion, and its expression was controlled by the Stat3 signaling pathway in vitro. Immunohistochemical analyses revealed that MMP9 expression in cancer cells at the invasive front (“cancer cell MMP9”) was related to high infiltration of CD204 positive M2-like TAMs (p < 0.001) and was associated with worse overall and disease-free survival of patients (p = 0.036 and p = 0.038, respectively). Furthermore, cancer cell MMP9 was an independent prognostic factor for disease-free survival. Notably, MMP9 expression in cancer stroma was not associated with any clinicopathological factors or patient prognoses. Our results suggest that close interaction with TAMs infiltrating in cancer stroma or cancer nests induces MMP9 expression in ESCC cells, equipping them with more malignant features.
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- 2023
16. Distant metastasis of hepatocellular carcinoma to Meckel’s cave and cranial nerves: A case report and review of literature
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Ryouhei Komaki, Yu-ichiro Koma, Masahiro Takami, Yumi Fujii, Yuka Saijo, Takako Fujii, Soo Ki Kim, Hisato Kobayashi, Soo Ryang Kim, Toyokazu Okuda, Kanako Yuasa, Aya Ohtani, and Takanobu Hayakumo
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congenital, hereditary, and neonatal diseases and abnormalities ,Hepatocellular carcinoma ,Trigeminal nerve ,digestive system ,Abducens nerve ,Meckel’s cave ,Magnetic resonance imaging ,Cave ,Case report ,Medicine ,geography ,geography.geographical_feature_category ,Hepatology ,medicine.diagnostic_test ,business.industry ,Cranial nerves ,Distant metastasis ,social sciences ,Anatomy ,musculoskeletal system ,medicine.disease ,humanities ,business ,Meckel's cave - Abstract
BACKGROUND Metastasis occurs as a late event in the natural history of hepatocellular carcinoma (HCC), and most patients die of liver failure attributed to the tumor supplanting the liver. Conversely, the brain is a less common metastatic site. CASE SUMMARY We describe a rare case of hepatitis C virus-related multiple HCC metastasizing to the cavernous sinus, Meckel’s cave, and the petrous bone involving multiple cranial nerves in an 82-year-old woman. At admission imaging studies including Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (MRI) revealed multiple HCC nodules in both right and left lobes. Ultrasound guided biopsy of the left lobe revealed moderately differentiated HCC. Molecular targeted therapy with Lenvatinib (8 mg/d for 94 d, per os) and Ramucirumab (340 mg/d and 320 mg/d, two times by intravenous injection) were administered for 4 mo, resulting in progression of the disease. Three months after the start of molecular target therapy, the patient presented with symptoms of hyperalgesia of the right face and limited abduction of the right eye, indicating disturbances in the right trigeminal and abducens nerves. Brain MRI disclosed a mass involving the cavernous sinus, Meckel’s cave and the petrous bone. Contrast-enhanced MRI with gadolinium-chelated contrast medium revealed a well-defined mass with abnormal enhancement around the right cavernous sinus and the right Meckel’s cave. CONCLUSION The diagnosis of metastatic HCC to the cavernous sinus, Meckel’s cave, and the petrous bone was made based on neurological findings and imaging studies including MRI, but not on histological examinations. Further studies may provide insights into various methods for diagnosing HCC metastasizing to the craniospinal area.
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- 2021
17. Significance of intratumoural <scp>CD163</scp> + macrophages in oral malignant melanoma: A preliminary study
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Takayuki Kodama, Manabu Shigeoka, Mari Nishio, Yu‐ichiro Koma, Masaya Akashi, and Hiroshi Yokozaki
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Otorhinolaryngology ,General Dentistry - Published
- 2022
18. Chemokine (C-C Motif) Ligand 1 Derived from Tumor-Associated Macrophages Contributes to Esophageal Squamous Cell Carcinoma Progression via CCR8-Mediated Akt/Proline-Rich Akt Substrate of 40 kDa/Mammalian Target of Rapamycin Pathway
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Mari Nishio, Masataka Fujikawa, Yu-ichiro Koma, Masayoshi Hosono, Manabu Shigeoka, Naoki Urakawa, Hiroshi Yokozaki, Masaki Shimizu, Yoshihiro Kakeji, Kohei Tanigawa, Takayuki Kodama, and Hiroki Sakamoto
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0301 basic medicine ,Chemokine ,Stromal cell ,Esophageal Neoplasms ,Cell ,CCL1 ,CCR8 ,Ligands ,Receptors, CCR8 ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Tumor-Associated Macrophages ,medicine ,Humans ,neoplasms ,Protein kinase B ,Sirolimus ,biology ,Chemistry ,Macrophages ,TOR Serine-Threonine Kinases ,digestive system diseases ,030104 developmental biology ,medicine.anatomical_structure ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer cell ,Carcinoma, Squamous Cell ,Cancer research ,biology.protein ,Esophageal Squamous Cell Carcinoma ,Proto-Oncogene Proteins c-akt - Abstract
Tumor-associated macrophages (TAMs) promote tumor progression. The number of infiltrating TAMs is associated with poor prognosis in esophageal squamous cell carcinoma (ESCC) patients; however, the mechanism underlying this phenomenon is unclear. cDNA microarray analysis indicates that the expression of chemokine (C-C motif) ligand 1 (CCL1) is up-regulated in peripheral blood monocyte-derived macrophages stimulated using conditioned media from ESCC cells (TAM-like macrophages). Here, we evaluated the role of CCL1 in ESCC progression. CCL1 was overexpressed in TAM-like macrophages, and CCR8, a CCL1 receptor, was expressed on ESCC cell surface. TAM-like macrophages significantly enhanced the motility of ESCC cells, and neutralizing antibodies against CCL1 or CCR8 suppressed this increased motility. Recombinant human CCL1 promoted ESCC cell motility via the Akt/proline-rich Akt substrate of 40 kDa/mammalian target of rapamycin pathway. Phosphatidylinositol 3-kinase or Akt inhibitors, CCR8 silencing, and neutralizing antibody against CCR8 could significantly suppress these effects. The overexpression of CCL1 in stromal cells or CCR8 in ESCC cells was significantly associated with poor overall survival (P = 0.002 or P = 0.009, respectively) and disease-free survival (P = 0.009 or P = 0.047, respectively) in patients with ESCC. These results indicate that the interaction between stromal CCL1 and CCR8 on cancer cells promotes ESCC progression via the Akt/proline-rich Akt substrate of 40 kDa/mammalian target of rapamycin pathway, thereby providing novel therapeutic targets.
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- 2021
19. PAI-1 derived from cancer-associated fibroblasts in esophageal squamous cell carcinoma promotes the invasion of cancer cells and the migration of macrophages
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Nobuhide Higashino, Mari Nishio, Masaki Shimizu, Yoshihiro Kakeji, Masataka Fujikawa, Takayuki Kodama, Hiroki Sakamoto, Hiroshi Yokozaki, Kohei Tanigawa, Manabu Shigeoka, and Yu-ichiro Koma
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0301 basic medicine ,Cancer microenvironment ,Male ,Esophageal Neoplasms ,Biology ,Article ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Fibroblast activation protein, alpha ,Cancer-Associated Fibroblasts ,Cell Movement ,Cell Line, Tumor ,Plasminogen Activator Inhibitor 1 ,Humans ,Neoplasm Invasiveness ,Molecular Biology ,Protein kinase B ,neoplasms ,Oncogenesis ,Cells, Cultured ,Aged ,Microarray analysis techniques ,Oesophageal cancer ,Macrophages ,Mesenchymal stem cell ,Cell Biology ,Middle Aged ,LRP1 ,digestive system diseases ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Immunohistochemistry ,Female ,Esophageal Squamous Cell Carcinoma - Abstract
Cancer-associated fibroblasts (CAFs) contribute to the progression of various cancers. Previously, we reported the significance of CAFs in esophageal squamous cell carcinoma (ESCC); however, the functions of CAFs in the ESCC microenvironment remain unknown. To investigate CAFs’ function, we established an indirect coculture assay between human bone marrow-derived mesenchymal stem cells (MSCs) and ESCC cells. Cocultured MSCs expressed more fibroblast activation protein, one of the markers of CAFs, compared with monocultured MSCs. Therefore, we defined cocultured MSCs as CAF-like cells. To identify molecules associated with the ESCC progression in CAFs, we conducted a cDNA microarray analysis on monocultured MSCs and CAF-like cells to compare their gene expression profiles. We found that SERPINE1, which encodes plasminogen activator inhibitor-1 (PAI-1), was more abundant in CAF-like cells than in monocultured MSCs, and the PAI-1 derived from CAF-like cells induced the abilities of migration and invasion in both ESCC cells and macrophages by the Akt and Erk1/2 signaling pathways via the low-density lipoprotein receptor-related protein 1 (LRP1), which is a PAI-1 receptor. Based on immunohistochemistry assays of ESCC tissues, higher expression levels of PAI-1 and LRP1 were correlated with poor prognosis in ESCC patients. These results suggest that the PAI-1/LRP1 axis contributes to the progression of ESCC, making it a potential target for ESCC therapy., The authors show that plasminogen activator inhibitor-1 (PAI-1) derived from cancer-associated fibroblasts promotes the invasion of esophageal squamous cell carcinoma (ESCC) cells and the migration of macrophages via lipoprotein receptor-related protein 1 (LRP1). High expression of PAI-1 and/or LRP1 is associated with poor prognosis in patients with ESCC, and the PAI-1/LRP1 axis could be a target of anticancer therapy.
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- 2021
20. Alteration of Macrophage Infiltrating Compartment: A Novel View on Oral Carcinogenesis
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Masaya Akashi, Mari Nishio, Manabu Shigeoka, Hiroshi Yokozaki, and Yu-ichiro Koma
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Stromal cell ,Carcinogenesis ,Inflammation ,medicine.disease_cause ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Tumor Microenvironment ,medicine ,Humans ,Macrophage ,Compartment (pharmacokinetics) ,Molecular Biology ,Cancer prevention ,Squamous Cell Carcinoma of Head and Neck ,business.industry ,Macrophages ,Cancer ,Cell Biology ,General Medicine ,medicine.disease ,Review article ,stomatognathic diseases ,030220 oncology & carcinogenesis ,Cancer research ,Mouth Neoplasms ,medicine.symptom ,business ,030215 immunology - Abstract
Background: The mortality of oral squamous cell carcinoma (OSCC) has remained high for decades; therefore, methods for early detection of OSCC are warranted. However, in the oral cavity, various mucosal diseases may be encountered, including reactive lesions and oral potentially malignant disorders, and it is difficult to differentiate OSCC from these lesions based on both clinical and histopathological findings. It is well known that chronic inflammation contributes to oral cancer development. Macrophages are among the most common inflammatory cells in cancer stromal tissue and have various roles in cancer aggressiveness. Although the roles of macrophages in cancer development have attracted attention, only a few studies have linked macrophages to carcinogenesis, particularly, oral precancerous lesions. Summary: This review article consists of 3 parts: first, we summarize current knowledge on macrophages in human various epithelial precancerous lesions, excluding the oral cavity, to show the importance and gaps in knowledge regarding macrophages in carcinogenesis; second, we review published data related to the role of macrophages in oral carcinogenesis; finally, we present a novel view on oral carcinogenesis, focusing on crosstalk between epithelial cells and macrophages. Key Messages: The biological features of macrophages in oral carcinogenesis differ drastically depending on the anatomical compartment that they infiltrate. Focusing on the alteration of macrophage infiltrating compartment may serve as a useful novel approach for studying the role of the macrophages in oral carcinogenesis and for gaining further insight into cancer prevention and early detection.
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- 2021
21. Significance of intratumoural CD163
- Author
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Takayuki, Kodama, Manabu, Shigeoka, Mari, Nishio, Yu-Ichiro, Koma, Masaya, Akashi, and Hiroshi, Yokozaki
- Published
- 2022
22. CCL3–CCR5 axis contributes to progression of esophageal squamous cell carcinoma by promoting cell migration and invasion via Akt and ERK pathways
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Naoki Urakawa, Hiroshi Yokozaki, Yu-ichiro Koma, Takayuki Kodama, Aya Kido, Mari Nishio, Manabu Shigeoka, and Noriaki Arai
- Subjects
Male ,Cancer microenvironment ,0301 basic medicine ,MAPK/ERK pathway ,Esophageal Neoplasms ,Receptors, CCR5 ,MAP Kinase Signaling System ,Kaplan-Meier Estimate ,Biology ,Monocytes ,Article ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,stomatognathic system ,Cell Movement ,Cell Line, Tumor ,Humans ,Neoplasm Invasiveness ,neoplasms ,Molecular Biology ,Protein kinase B ,Oncogenesis ,PI3K/AKT/mTOR pathway ,Aged ,Chemokine CCL3 ,Gene Expression Profiling ,Macrophages ,Oesophageal cancer ,Cell migration ,Cell Biology ,Middle Aged ,digestive system diseases ,Gene Expression Regulation, Neoplastic ,Vascular endothelial growth factor A ,030104 developmental biology ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer cell ,Carcinoma, Squamous Cell ,Disease Progression ,Cancer research ,Female ,CC chemokine receptors ,Proto-Oncogene Proteins c-akt - Abstract
Tumor-associated macrophages (TAMs) contribute to the progression and mortality of various malignancies. We reported that high numbers of infiltrating TAMs were significantly associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma (ESCC). In our previous investigation of TAMs’ actions in ESCC, we compared gene expression profiles between peripheral blood monocyte (PBMo)-derived macrophages and TAM-like macrophages stimulated with conditioned media of ESCC cell lines. Among the upregulated genes in the TAM-like macrophages, we focused on CC chemokine ligand 3 (CCL3), which was reported to contribute to tumor progression in several malignancies. Herein, we observed that not only TAMs but also ESCC cell lines expressed CCL3. A CCL3 receptor, CC chemokine receptor 5 (CCR5) was expressed in the ESCC cell lines. Treating the ESCC cell lines with recombinant human (rh)CCL3 induced the phosphorylations of Akt and ERK, which were suppressed by CCR5 knockdown. Migration and invasion of ESCC cells were promoted by treatment with rhCCL3 and co-culture with TAMs. TAMs/rhCCL3-promoted cell migration and invasion were suppressed by inhibition of the CCL3–CCR5 axis, PI3K/Akt, and MEK/ERK pathways. Treatment with rhCCL3 upregulated MMP2 and VEGFA expressions in ESCC cell lines. Our immunohistochemical analysis of 68 resected ESCC cases showed that high expression of CCL3 and/or CCR5 in ESCC tissues was associated with poor prognosis. High CCR5 expression was associated with deeper invasion, presence of vascular invasion, higher pathological stage, higher numbers of infiltrating CD204+ TAMs, and higher microvascular density. High expression of both CCL3 and CCR5 was an independent prognostic factor for disease-free survival. These results suggest that CCL3 derived from both TAMs and cancer cells contributes to the progression and poor prognosis of ESCC by promoting cell migration and invasion via the binding of CCR5 and the phosphorylations of Akt and ERK. The CCL3–CCR5 axis could become the target of new therapies against ESCC., The authors. show that CCL3 derived from both tumor-associated macrophages and esophageal squamous cell carcinoma (ESCC) cells promotes cell migration and invasion of ESCC cells via binding CCR5. High expression of CCL3 and/or CCR5 associates with poor prognosis in ESCC patients. CCL3–CCR5 axis could be a specific target of anti-cancer therapy.
- Published
- 2020
23. Intraepithelial CD163 + macrophages in tongue leukoplakia biopsy: A promising tool for cancer screening
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Manabu Shigeoka, Mari Nishio, Masaya Akashi, Hiroshi Yokozaki, Yu-ichiro Koma, and Takayuki Kodama
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Pathology ,medicine.medical_specialty ,Diagnostic concordance ,tongue leukoplakia ,Lesion ,CD163+ macrophage ,03 medical and health sciences ,0302 clinical medicine ,Histological diagnosis ,Cancer screening ,Biopsy ,Medicine ,General Dentistry ,medicine.diagnostic_test ,business.industry ,030206 dentistry ,medicine.disease ,TONGUE LEUKOPLAKIA ,stomatognathic diseases ,Squamous intraepithelial lesion ,Otorhinolaryngology ,030220 oncology & carcinogenesis ,medicine.symptom ,business ,CD163 ,biopsy specimen - Abstract
Objective Oral leukoplakia has mixed and differing histopathological features, and it is thus difficult to reach an accurate histological diagnosis of oral leukoplakia based on a local biopsy alone. We recently demonstrated the significance of CD163+ macrophages in oral carcinogenesis. Herein we sought to determine whether CD163+ macrophages in biopsy specimens of oral leukoplakia help identify the overall histological nature of the lesion. Patients and methods Twenty-six patients with tongue leukoplakia who underwent a histological examination by both a preoperative local biopsy and consecutive total excision were enrolled. We evaluated clinicopathological factors and the expression of CD163+ macrophages based on a retrospective comparison of the histological diagnostic concordance between the biopsies and excisions. Results Seventeen patients (diagnostic-agreement group) were diagnosed with squamous intraepithelial lesion based on both the biopsy and the excision. Nine patients (diagnostic-discrepancy group) were diagnosed with invasive cancer by excision, although invasive cancer was not observed in their biopsy specimens. Compared to the diagnostic-agreement group, the diagnostic-discrepancy group had more tongue leukoplakia with non-homogenous or high numbers of intraepithelial CD163+ macrophages. Conclusion The evaluation of intraepithelial CD163+ macrophages in local biopsy specimens from tongue leukoplakia patients is a promising tool for cancer screening.
- Published
- 2020
24. CD163(+) macrophages infiltration correlates with the immunosuppressive cytokine interleukin 10 expression in tongue leukoplakia
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Yu-ichiro Koma, Hiroshi Yokozaki, Manabu Shigeoka, Takahide Komori, and Mari Nishio
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Adult ,Keratinocytes ,Male ,Epithelial dysplasia ,Carcinogenesis ,THP-1 Cells ,medicine.medical_treatment ,interleukin-10 ,Antigens, Differentiation, Myelomonocytic ,Receptors, Cell Surface ,macrophage ,tongue leukoplakia ,T-Lymphocytes, Regulatory ,interleukin‐10 ,Tongue ,Antigens, CD ,medicine ,Tumor Microenvironment ,Humans ,General Dentistry ,Aged ,Aged, 80 and over ,business.industry ,Glossectomy ,Squamous Cell Carcinoma of Head and Neck ,Macrophages ,FOXP3 ,Original Articles ,Middle Aged ,medicine.disease ,Tongue Neoplasms ,lcsh:RK1-715 ,Interleukin 10 ,stomatognathic diseases ,Cytokine ,Ki-67 Antigen ,Immunoediting ,lcsh:Dentistry ,Culture Media, Conditioned ,Cancer research ,Immunohistochemistry ,Original Article ,Female ,Leukoplakia, Oral ,business ,Infiltration (medical) ,CD163 - Abstract
Objective Accumulating evidence suggests that macrophages are involved in the immunoediting of oral squamous cell carcinoma but the role of macrophages in oral carcinogenesis is unclear. We aimed to clarify the role of macrophages in oral leukoplakia, which is the most common oral potentially malignant disorder from immunotolerance viewpoint. Materials and methods The study included 24 patients who underwent surgical resection for tongue leukoplakia. The relationships between macrophage markers and clinicopathological factors were assessed. Conditioned medium was harvested from the CD163(+) human monocytic leukaemia cell line, THP-1. The phenotypic alteration of human oral keratinocytes by the conditioned medium treatment was assessed using quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Moreover, the clinical samples were evaluated using immunohistochemistry. Results Tongue leukoplakia tissues with high CD163(+) macrophage infiltration were associated with significantly higher degrees of epithelial dysplasia, abnormal Ki-67 expression and cytokeratin13 loss when compared with the tissues with low CD163(+) macrophage infiltration. In vitro, CD163(+) THP-1 conditioned medium induced immunosuppressive molecules, especially interleukin-10 (IL-10) in human oral keratinocytes. The IL-10 expression levels showed significant positive correlations with not only the numbers of FOXP3(+) regulatory T cells but also that of CD163(+) macrophages. Conclusions In tongue leukoplakia, CD163(+) macrophages infiltration correlates with immunosuppressive cytokine IL-10 expression.
- Published
- 2019
25. Metallothionein 2A Expression in Cancer-Associated Fibroblasts and Cancer Cells Promotes Esophageal Squamous Cell Carcinoma Progression
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Yu Kitamura, Takayuki Kodama, Satoshi Urakami, Hiroki Sakamoto, Shuichi Tsukamoto, Yu-ichiro Koma, Hiroshi Yokozaki, Yoshihiro Kakeji, Nobuhide Higashino, Kohei Tanigawa, Masaki Shimizu, Mari Nishio, and Manabu Shigeoka
- Subjects
Cancer Research ,Gene knockdown ,Growth factor ,medicine.medical_treatment ,Mesenchymal stem cell ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,MT2A ,Biology ,medicine.disease ,Article ,digestive system diseases ,esophageal squamous cell carcinoma ,Oncology ,Fibroblast activation protein, alpha ,Cell culture ,Cancer cell ,medicine ,Cancer research ,IGFBP2 ,Protein kinase B ,neoplasms ,cancer-associated fibroblasts ,RC254-282 - Abstract
Esophageal cancer has the sixth highest mortality rate worldwide. Cancer-associated fibroblasts (CAFs) are involved in the progression of various cancers. Previously, we demonstrated an association between high expression of the CAF marker, fibroblast activation protein, and poor prognosis of esophageal squamous cell carcinoma (ESCC). We also established CAF-like cells by indirect co-culture of bone marrow-derived mesenchymal stem cells with ESCC cell lines and found metallothionein 2A (MT2A) to be highly expressed in them. Here, to explore the function of MT2A in CAFs, we silenced MT2A in the CAF-like cells and ESCC cell lines using small interfering RNA. MT2A knockdown in the CAF-like cells suppressed expression and secretion of insulin-like growth factor binding protein 2 (IGFBP2), recombinant IGFBP2 promoted migration and invasiveness of ESCC cells via NFκB, Akt, and Erk signaling pathways. Furthermore, MT2A knockdown in the ESCC cell lines inhibited their growth, migration, and invasiveness. Immunohistochemistry demonstrated that high MT2A expression in the cancer stroma and cancer nest of ESCC tissues correlated with poor prognosis of ESCC patients. Hence, we report that MT2A in CAFs and cancer cells contributes to ESCC progression. MT2A and IGFBP2 are potential novel therapeutic targets in ESCC.
- Published
- 2021
26. S100A8/A9 Induced by Interaction with Macrophages in Esophageal Squamous Cell Carcinoma Promotes the Migration and Invasion of Cancer Cells via Akt and p38 MAPK Pathways
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Kohei Tanigawa, Shuichi Tsukamoto, Yu-ichiro Koma, Yu Kitamura, Satoshi Urakami, Masaki Shimizu, Masataka Fujikawa, Takayuki Kodama, Mari Nishio, Manabu Shigeoka, Yoshihiro Kakeji, and Hiroshi Yokozaki
- Subjects
Mitogen-Activated Protein Kinase 14 ,Esophageal Neoplasms ,Macrophages ,Tumor Microenvironment ,Calgranulin B ,Humans ,Calgranulin A ,Esophageal Squamous Cell Carcinoma ,Proto-Oncogene Proteins c-akt ,p38 Mitogen-Activated Protein Kinases ,Pathology and Forensic Medicine - Abstract
Tumor-associated macrophages are associated with more malignant phenotypes of esophageal squamous cell carcinoma (ESCC) cells. Previously, an indirect co-culture assay of ESCC cells and macrophages was used to identify several factors associated with ESCC progression. Herein, a direct co-culture assay of ESCC cells and macrophages was established, which more closely simulated the actual cancer microenvironment. Direct co-cultured ESCC cells had significantly increased migration and invasion abilities, and phosphorylation levels of Akt and p38 mitogen-activated protein kinase (MAPK) compared with monocultured ESCC cells. According to a cDNA microarray analysis between monocultured and co-cultured ESCC cells, both the expression and release of S100 calcium binding protein A8 and A9 (S100A8 and S100A9), which commonly exist and function as a heterodimer (herein, S100A8/A9), were significantly enhanced in co-cultured ESCC cells. The addition of recombinant human S100A8/A9 protein induced migration and invasion of ESCC cells via Akt and p38 MAPK signaling. Both S100A8 and S100A9 silencing suppressed migration, invasion, and phosphorylation of Akt and p38 MAPK in co-cultured ESCC cells. Moreover, ESCC patients with high S100A8/A9 expression exhibited significantly shorter disease-free survival (P = 0.005) and cause-specific survival (P = 0.038). These results suggest that S100A8/A9 expression and release in ESCC cells are enhanced by direct co-culture with macrophages and that S100A8/A9 promotes ESCC progression via Akt and p38 MAPK signaling pathways.
- Published
- 2021
27. Tongue Cancer Cell-Derived CCL20 Induced by Interaction With Macrophages Promotes CD163 Expression on Macrophages
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Mari Nishio, Yu-ichiro Koma, Manabu Shigeoka, Hiroshi Yokozaki, Masaya Akashi, and Takayuki Kodama
- Subjects
Cancer Research ,cell–cell interaction ,medicine.medical_treatment ,macrophage ,medicine.disease_cause ,Cell–cell interaction ,cell-cell interaction ,medicine ,Macrophage ,RC254-282 ,Original Research ,cancer microenvironment ,Chemistry ,tongue cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cancer ,hemic and immune systems ,medicine.disease ,CCL20 ,Cytokine ,Oncology ,Cell culture ,Cancer cell ,Cancer research ,CD163 ,Carcinogenesis - Abstract
BackgroundCD163-positive macrophages contribute to the aggressiveness of oral squamous cell carcinoma. We showed in a previous report that CD163-positive macrophages infiltrated not only to the cancer nest but also to its surrounding epithelium, depending on the presence of stromal invasion in tongue carcinogenesis. However, the role of intraepithelial macrophages in tongue carcinogenesis remains unclear. In this study, we assessed the biological behavior of intraepithelial macrophages on their interaction with cancer cells.Materials and MethodsWe established the indirect coculture system (intraepithelial neoplasia model) and direct coculture system (invasive cancer model) of human monocytic leukemia cell line THP-1-derived CD163-positive macrophages with SCC25, a tongue squamous cell carcinoma (TSCC) cell line. Conditioned media (CM) harvested from these systems were analyzed using cytokine array and enzyme-linked immunosorbent assay and extracted a specific upregulated cytokine in CM from the direct coculture system (direct CM). The correlation of both this cytokine and its receptor with various clinicopathological factors were evaluated based on immunohistochemistry using clinical samples from 59 patients with TSCC. Moreover, the effect of this cytokine in direct CM on the phenotypic alterations of THP-1 was confirmed by real-time polymerase chain reaction, western blotting, immunofluorescence, and transwell migration assay.ResultsIt was shown that CCL20 was induced in the direct CM specifically. Interestingly, CCL20 was produced primarily in SCC25. The expression level of CCR6, which is a sole receptor of CCL20, was higher than the expression level of SCC25. Our immunohistochemical investigation showed that CCL20 and CCR6 expression was associated with lymphatic vessel invasion and the number of CD163-positive macrophages. Recombinant human CCL20 induced the CD163 expression and promoted migration of THP-1. We also confirmed that a neutralizing anti-CCL20 antibody blocked the induction of CD163 expression by direct CM in THP-1. Moreover, ERK1/2 phosphorylation was associated with the CCL20-driven induction of CD163 expression in THP-1.ConclusionsTongue cancer cell-derived CCL20 that was induced by interaction with macrophages promotes CD163 expression on macrophages.
- Published
- 2021
28. Tumor-associated macrophage related interleukin-6 in cerebrospinal fluid as a prognostic marker for glioblastoma
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Hiroshi Yokozaki, Satoshi Nakamizo, Yu-ichiro Koma, Hiroaki Nagashima, Takanori Hirose, Takashi Sasayama, Yuichi Fujita, Hirotomo Tanaka, Masamitsu Nishihara, Tatsuo Hori, Kazuhiro Tanaka, Eiji Kohmura, and Masahiro Maeyama
- Subjects
Adult ,Male ,Adolescent ,Angiogenesis ,Tumor-associated macrophage ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,Cell Movement ,Physiology (medical) ,Glioma ,Biomarkers, Tumor ,medicine ,Humans ,Interleukin 6 ,Aged ,Aged, 80 and over ,High concentration ,biology ,Brain Neoplasms ,Interleukin-6 ,business.industry ,Macrophages ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,nervous system diseases ,Neurology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Female ,Surgery ,Neurology (clinical) ,Antibody ,Glioblastoma ,business ,030217 neurology & neurosurgery - Abstract
Interleukin-6 (IL-6) is one of the pleiotropic cytokines and has received attention as a critical factor implicated in the invasion and the angiogenesis of various cancers. In glioma, IL-6 is known to be associated with the prognosis; however, the roles of IL-6 in cerebrospinal fluid (CSF) has not been studied sufficiently. We examined the concentration of CSF IL-6 using 75 CSF samples of glioma (54 glioblastomas (GBMs) and 21 other grades of gliomas) and analyzed the association CSF IL-6 with infiltration levels of tumor-associated macrophages (TAMs) and prognosis. The concentration of CSF IL-6 in GBM patients was significantly higher than that in other grades of gliomas. CSF IL-6 levels were associated with the infiltration rate of TAMs in GBMs, and IL-6 levels were increased in the GBM cells co-cultured with TAM-like macrophages. The CSF of GBM patients, which contained high concentration of IL-6, promoted the migration ability of GBM cells, and neutralization antibodies of IL-6 inhibited its migration ability. Finally, in both univariate and multivariate analysis, higher CSF IL-6 levels were associated with poorer prognosis in GBM patients. These results indicated that the concentration of CSF IL-6 is associated with TAMs' infiltration level and may be a useful prognostic biomarker for the GBM patients.
- Published
- 2019
29. Fibroblast activation protein-positive fibroblasts promote tumor progression through secretion of CCL2 and interleukin-6 in esophageal squamous cell carcinoma
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Nobuhisa Takase, Manabu Shigeoka, Yoshihiro Kakeji, Himiko Kodaira, Masayoshi Hosono, Hiroshi Yokozaki, Yu-ichiro Koma, Nobuhide Higashino, Mari Nishio, and Maiko Okamoto
- Subjects
0301 basic medicine ,Esophageal Neoplasms ,MAP Kinase Signaling System ,medicine.medical_treatment ,Pathology and Forensic Medicine ,03 medical and health sciences ,Esophagus ,0302 clinical medicine ,Cancer-Associated Fibroblasts ,Japan ,Fibroblast activation protein, alpha ,Cell Line, Tumor ,Endopeptidases ,Tumor Microenvironment ,medicine ,Humans ,PTEN ,Interleukin 8 ,neoplasms ,Molecular Biology ,Chemokine CCL2 ,Tumor microenvironment ,biology ,Interleukin-6 ,Chemistry ,Interleukin-8 ,Serine Endopeptidases ,Mesenchymal stem cell ,Membrane Proteins ,Mesenchymal Stem Cells ,Cell Biology ,Actins ,digestive system diseases ,030104 developmental biology ,Cytokine ,Gelatinases ,Tumor progression ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,biology.protein ,Cancer research ,Cytokine secretion - Abstract
Esophageal squamous cell carcinoma (ESCC) is a highly aggressive tumor with frequent recurrence even after curative resection. The tumor microenvironment, which consists of non-cancer cells, such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), was recently reported to promote several cancers, including ESCC. However, the role of CAF as a coordinator for tumor progression in ESCC remains to be elucidated. In our immunohistochemical investigation of ESCC tissues, we observed that the intensity of expression of two CAF markers-alpha smooth muscle actin (αSMA) and fibroblast activation protein (FAP)-in the tumor stroma was significantly correlated with the depth of tumor invasion, lymph node metastasis, advanced pathological stage, and poor prognosis. We co-cultured human bone marrow-derived mesenchymal stem cells (MSCs) with ESCC cells and confirmed the induction of FAP expression in the co-cultured MSCs. These FAP-positive MSCs (which we defined as CAF-like cells) promoted the cell growth and migration of ESCC cells and peripheral blood mononuclear cell-derived macrophage-like cells. CAF-like cells induced the M2 polarization of macrophage-like cells. A cytokine array and ELISA revealed that CAF-like cells secreted significantly more CCL2, Interleukin-6, and CXCL8 than MSCs. These cytokines promoted the migration of tumor cells and macrophage-like cells. The silencing of FAP in CAF-like cells attenuated cytokine secretion. We compared cell signaling of MSCs, CAF-like cells, and FAP-silenced CAF-like cells; PTEN/Akt and MEK/Erk signaling were upregulated and their downstream targets, NF-κB and β-catenin, were also activated with FAP expression. Silencing of FAP attenuated these effects. Cytokine secretion from CAF-like cells were attenuated by inhibitors against these signaling pathways. These findings indicate that the collaboration of CAFs with tumor cells and macrophages plays a pivotal role in tumor progression, and that FAP expression is responsible for the tumor promotive and immunosuppressive phenotypes of CAFs.
- Published
- 2019
30. Intraepithelial Macrophage Expressing CD163 Is a Histopathological Clue to Evaluate the Malignant Potency of Oral Lichenoid Condition: A Case Report and Immunohistochemical Investigation
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Yu-ichiro Koma, Maki Kanzawa, Hiroshi Yokozaki, Manabu Shigeoka, and Masaya Akashi
- Subjects
Pathology ,medicine.medical_specialty ,Clinical Biochemistry ,oral lichenoid condition ,Case Report ,macrophage ,Malignancy ,Lesion ,03 medical and health sciences ,0302 clinical medicine ,Biopsy ,medicine ,biopsy ,lcsh:R5-920 ,medicine.diagnostic_test ,business.industry ,Cancer ,030206 dentistry ,malignant potency ,medicine.disease ,stomatognathic diseases ,Dysplasia ,030220 oncology & carcinogenesis ,Immunohistochemistry ,Oral lichen planus ,CD163 ,medicine.symptom ,business ,lcsh:Medicine (General) - Abstract
Oral lichenoid conditions (OLC), including oral lichen planus (OLP), oral lichenoid lesions and oral lichenoid dysplasia, differ in pathogenesis and biological malignancy. However, distinguishing them based on clinical or histological features is difficult. It is well known that CD163+ macrophages are associated with oral cancer aggressiveness. We recently demonstrated that CD163+ macrophages of noncancerous lesions infiltrate the stroma, not the intraepithelial area. In this report, we describe a case of OLC that was not detected as malignant by the first local biopsy. Furthermore, we evaluated the malignant potency of OLC by retrospectively comparing the histological findings between local biopsy and resected specimens focusing on CD163+ macrophages. A 72-year-old man with a white lesion in the unilateral buccal mucosa was diagnosed with OLP through the biopsy although invasive cancer was detected two years later. Intraepithelial CD163+ macrophages were found not only on the resected specimen but also biopsy. This is the first report to demonstrate that intraepithelial CD163+ macrophages may be noteworthy indicators to identify the malignant potency of OLC.
- Published
- 2020
31. Cancer as a tissue: The significance of cancer-stromal interactions in the development, morphogenesis and progression of human upper digestive tract cancer
- Author
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Mari Nishio, Manabu Shigeoka, Yu-ichiro Koma, and Hiroshi Yokozaki
- Subjects
0301 basic medicine ,Tumor microenvironment ,Pathology ,medicine.medical_specialty ,Stromal cell ,business.industry ,Cancer ,General Medicine ,Tumor-associated macrophage ,Esophageal cancer ,medicine.disease ,Pathology and Forensic Medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Cancer stem cell ,030220 oncology & carcinogenesis ,Cancer cell ,Medicine ,business ,Stomach cancer - Abstract
We review the significance of cancer-stromal interactions (CSIs) in the development, morphogenesis and progression of human gastric and esophageal cancer based on the data obtained from co-culture experiments. Orthotopic fibroblasts in the gastric cancer stroma not only promoted their growth by cancer cells but were also responsible for the mobility, morphogenesis and epithelial-to-mesenchymal transition (EMT) of the cancer cells through CSI. Bone marrow-derived mesenchymal stem cells could be part of the origin of cancer-associated fibroblasts (CAFs) of the gastric cancer providing an advantageous microenvironment for the restoration of cancer stem cells with the induction of the EMT. Tumor-associated macrophages (TAMs) may differentiate from bone marrow-derived monocytes/macrophages within the tumor microenvironment of esophageal cancer and participate in the growth and the progression of esophageal squamous cell carcinomas (ESCCs). Macrophages infiltrated into the intraepithelial neoplastic lesions of the esophagus may function as a biological promoter by promoting the growth and motility of squamous epithelia. Tumor cells build up "cancer as a tissue" by taking advantage of the existing network of growth factors, cytokines and chemokines through the interactions of TAMs, CAFs and cancer cells themselves.
- Published
- 2018
32. Rapid and extensive intrahepatic metastatic recurrence of hepatocellular carcinoma with very small portal vein tumor thrombus after surgery and sustained virological response of HCV with direct‐acting antivirals
- Author
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Takako Fujii, Susumu Imoto, Hisoka Kinoshita, Soo Ki Kim, Masahiro Kido, Toshiyuki Matsuoka, Soo Ryang Kim, Masatoshi Kudo, Yoshitake Hayashi, Naomi Shida, Yu-ichiro Koma, and Yumi Fujii
- Subjects
medicine.medical_specialty ,Pathology ,business.industry ,medicine.medical_treatment ,Portal vein ,General Medicine ,medicine.disease ,Thrombosis ,Gastroenterology ,Pathology and Forensic Medicine ,Virological response ,Text mining ,Tumor thrombus ,Hepatocellular carcinoma ,Internal medicine ,medicine ,Carcinoma ,Hepatectomy ,business - Published
- 2019
33. CXCL8 derived from tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression by promoting migration and invasion of cancer cells
- Author
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Nobuhide Higashino, Mari Nishio, Kazuki Suemune, Nobuhisa Takase, Himiko Kodaira, Hiroshi Yokozaki, Yu-ichiro Koma, Yoshihiro Kakeji, Masayoshi Hosono, Manabu Shigeoka, and Naoki Urakawa
- Subjects
musculoskeletal diseases ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Chemokine ,Cell ,tumor progression ,Tumor-associated macrophage ,03 medical and health sciences ,tumor-associated macrophage ,0302 clinical medicine ,Internal medicine ,medicine ,tumor microenvironment ,CXC chemokine receptors ,Interleukin 8 ,neoplasms ,tumor icroenvironment ,Tumor microenvironment ,biology ,digestive system diseases ,esophageal squamous cell carcinoma ,030104 developmental biology ,medicine.anatomical_structure ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer cell ,CXCL8 ,biology.protein ,Cancer research ,Research Paper - Abstract
Tumor-associated macrophages (TAMs) are involved in tumor progression and poor prognosis in several malignancies. We previously demonstrated the interaction between high numbers of infiltrating TAMs and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To investigate the significance of TAMs in ESCC, we conducted a cDNA microarray analysis of peripheral blood monocytes (PBMo)-derived macrophages and PBMo-derived macrophages stimulated with conditioned media of TE-series ESCC cell lines (TAM-like PBMo-derived macrophages). C-X-C motif chemokine ligand 8 (CXCL8) was up-regulated in the TAM-like PBMo-derived macrophages. Here we confirmed a high expression level of CXCL8 in TAM-like PBMo-derived macrophages and the expression of CXCR1/2, known as CXCL8 receptors, in TE-series ESCC cell lines. Recombinant human CXCL8 induced the ESCC cell lines’ migration and invasion by the phosphorylation of Akt and Erk1/2. In indirect co-cultures, not only signal pathway inhibitors but also neutralizing antibodies against CXCL8, CXCR1 and CXCR2 suppressed these phenotypes induced by TAM-like PBMo-derived macrophages. Immunohistochemical analysis of 70 resected ESCC samples showed that high expression levels of CXCL8 in ESCC tissues were significantly associated with lymph node metastasis and poor prognosis. These results suggest that CXCL8 up-regulated in the microenvironment may contribute to ESCC progression by promoting cancer cells’ migration and invasion.
- Published
- 2017
34. Advanced Verrucous Squamous Cell Carcinoma of the Esophagus: Case Report and Literature Review
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Yasuo Sumi, Taro Oshikiri, Hiroshi Yokozaki, Satoshi Suzuki, Yoshihiro Kakeji, Kimihiro Yamashita, Tetsu Nakamura, Shingo Kanaji, Nobuhisa Takase, Yu-ichiro Koma, Kiyonori Kanemitsu, Masashi Yamamoto, Daisuke Kuroda, and Maki Kanzawa
- Subjects
Pathology ,medicine.medical_specialty ,biology ,medicine.diagnostic_test ,business.industry ,Esophagogastroduodenoscopy ,medicine.disease ,Lesion ,Prone position ,medicine.anatomical_structure ,Ki-67 ,Esophageal stricture ,Biopsy ,Vomiting ,biology.protein ,Medicine ,Surgery ,Esophagus ,medicine.symptom ,business - Abstract
Verrucous squamous cell carcinoma (VSCC) is a rare esophageal tumor histologically defined as a well-differentiated subtype. We present a rare case that was diagnosed as esophageal VSCC preoperatively. A 62-year-old Japanese man was referred to our hospital for further evaluation, presenting with anorexia and postcibal vomiting. An esophagogastroduodenoscopy examination showed esophageal stricture with white-colored papillary nodules in the lower esophagus. We performed repeated superficial endoscopic biopsies of the lesion, but the histologic findings showed nonspecific changes. With an endoscopic boring biopsy, the lesion showed an endophytic growth pattern, well-differentiated SCC with minimal cellular atypia and rare mitosis, and mature squamous epithelium with extensive keratinization. We preoperatively diagnosed the lesion as esophageal VSCC, and we performed a video-assisted thoracoscopic subtotal esophagectomy and cardiectomy with the patient in the prone position. Histologic findings revealed that the invasive well-differentiated SCC extended into the esophageal adventitia and the stomach wall with a pushing border. Regional lymph node metastasis and vascular invasion were negative. The expression of Ki-67 was distributed mainly in the basal cells rather than parabasal cells. Without a conclusive diagnosis, a certain degree of diagnostic prediction is possible by understanding the clinical manifestations, macroscopic form, and histology around the basal cells. It is helpful to obtain the high accuracy provided by an endoscopic biopsy including the basal layer to avoid the diagnostic dilemma that is often presented by esophageal VSCC.
- Published
- 2017
35. Local advanced rectal cancer perforation in the midst of preoperative chemoradiotherapy: A case report and literature review
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Yu-ichiro Koma, Ryohei Sasaki, Masashi Yamamoto, Kimihiro Yamashita, Yoshiko Matsuda, Tetsu Nakamura, Nobuhisa Takase, Shingo Kanaji, Hiroshi Hasegawa, Taro Oshikiri, Yasuo Sumi, Masato Komatsu, Satoshi Suzuki, Yoshihiro Kakeji, and Takeru Matsuda
- Subjects
0301 basic medicine ,medicine.medical_specialty ,genetic structures ,Colorectal cancer ,Perforation (oil well) ,Colonoscopy ,Case Report ,Lymph node metastasis ,Preoperative chemoradiotherapy ,03 medical and health sciences ,0302 clinical medicine ,medicine ,5-fluorouracil ,medicine.diagnostic_test ,business.industry ,Tumor necrosis ,General Medicine ,Local advanced rectal cancer ,medicine.disease ,Surgery ,030104 developmental biology ,Rectal Perforation ,030220 oncology & carcinogenesis ,General malaise ,Rectal perforation ,business ,Chemoradiotherapy - Abstract
Standard chemoradiotherapy (CRT) for local advanced rectal cancer (LARC) rarely induce rectal perforation. Here we report a rare case of rectal perforation in a patient with LARC in the midst of preoperative CRT. A 56-year-old male was conveyed to our hospital exhibiting general malaise. Colonoscopy and imaging tests resulted in a clinical diagnosis of LARC with direct invasion to adjacent organs and regional lymphadenopathy. Preoperative 5-fluorouracil-based CRT was started. At 25 d after the start of CRT, the patient developed a typical fever. Computed tomography revealed rectal perforation, and he underwent emergency sigmoid colostomy. At 12 d after the surgery, the remaining CRT was completed according to the original plan. The histopathological findings after radical operation revealed a wide field of tumor necrosis and fibrosis without lymph node metastasis. We share this case as important evidence for the treatment of LARC perforation in the midst of preoperative CRT.
- Published
- 2017
36. Intraepithelial CD163
- Author
-
Manabu, Shigeoka, Yu-Ichiro, Koma, Takayuki, Kodama, Mari, Nishio, Masaya, Akashi, and Hiroshi, Yokozaki
- Subjects
Antigens, CD ,Biopsy ,Macrophages ,Antigens, Differentiation, Myelomonocytic ,Humans ,Receptors, Cell Surface ,Leukoplakia, Oral ,Early Detection of Cancer ,Retrospective Studies ,Tongue Neoplasms - Abstract
Oral leukoplakia has mixed and differing histopathological features, and it is thus difficult to reach an accurate histological diagnosis of oral leukoplakia based on a local biopsy alone. We recently demonstrated the significance of CD163Twenty-six patients with tongue leukoplakia who underwent a histological examination by both a preoperative local biopsy and consecutive total excision were enrolled. We evaluated clinicopathological factors and the expression of CD163Seventeen patients (diagnostic-agreement group) were diagnosed with squamous intraepithelial lesion based on both the biopsy and the excision. Nine patients (diagnostic-discrepancy group) were diagnosed with invasive cancer by excision, although invasive cancer was not observed in their biopsy specimens. Compared to the diagnostic-agreement group, the diagnostic-discrepancy group had more tongue leukoplakia with non-homogenous or high numbers of intraepithelial CD163The evaluation of intraepithelial CD163
- Published
- 2019
37. Collaboration of cancer‐associated fibroblasts and tumour‐associated macrophages for neuroblastoma development
- Author
-
Noriyuki Nishimura, Daiichiro Hasegawa, Hiroshi Yokozaki, Okito Hashimoto, Tomoko Yanai, Yoshiyuki Kosaka, Yu-ichiro Koma, and Makiko Yoshida
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Stromal cell ,Carcinogenesis ,Biology ,N-Myc Proto-Oncogene Protein ,Pathology and Forensic Medicine ,Neuroblastoma ,03 medical and health sciences ,0302 clinical medicine ,Cancer-Associated Fibroblasts ,Antigens, CD ,Cell Line, Tumor ,medicine ,Humans ,Macrophage ,Cell Proliferation ,CD68 ,Macrophages ,Ganglioneuroblastoma ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,medicine.disease ,Coculture Techniques ,CXCL2 ,030104 developmental biology ,030220 oncology & carcinogenesis ,Leukocytes, Mononuclear - Abstract
Neuroblastoma is the most common extracranial solid tumour in children and is histologically classified by its Schwannian stromal cells. Although having fewer Schwannian stromal cells is generally associated with more aggressive phenotypes, the exact roles of other stromal cells (mainly macrophages and fibroblasts) are unclear. Here, we examined 41 cases of neuroblastoma using immunohistochemistry for the tumour-associated macrophage (TAM) markers CD68, CD163, and CD204, and a cancer-associated fibroblast (CAF) marker, alpha smooth muscle actin (αSMA). Each case was assigned to low/high groups on the basis of the number of TAMs or three groups on the basis of the αSMA-staining area for CAFs. Both the number of TAMs and the area of CAFs were significantly correlated with clinical stage, MYCN amplification, bone marrow metastasis, histological classification, histological type, and risk classification. Furthermore, TAM settled in the vicinity of the CAF area, suggesting their close interaction within the tumour microenvironment. We next determined the effects of conditioned medium of a neuroblastoma cell line (NBCM) on bone marrow-derived mesenchymal stem cells (BM-MSCs) and peripheral blood mononuclear cell (PBMC)-derived macrophages in vitro. The TAM markers CD163 and CD204 were significantly up-regulated in PBMC-derived macrophages treated with NBCM. The expression of αSMA by BM-MSCs was increased in NBCM-treated cells. Co-culturing with CAF-like BM-MSCs did not enhance the invasive ability but supported the proliferation of tumour cells, whereas tumour cells co-cultured with TAM-like macrophages had the opposite effect. Intriguingly, TAM-like macrophages enhanced not only the invasive abilities of tumour cells and BM-MSCs but also the proliferation of BM-MSCs. CXCL2 secreted from TAM-like macrophages plays an important role in tumour invasiveness. Taken together, these results indicate that PBMC-derived macrophages and BM-MSCs are recruited to a tumour site and activated into TAMs and CAFs, respectively, followed by the formation of favourable environments for neuroblastoma progression. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
- Published
- 2016
38. NCAM- and FGF-2-mediated FGFR1 signaling in the tumor microenvironment of esophageal cancer regulates the survival and migration of tumor-associated macrophages and cancer cells
- Author
-
Yu-ichiro Koma, Hiroshi Yokozaki, Noriaki Arai, Yoshihiro Kakeji, Manabu Shigeoka, Nobuhisa Takase, Naoki Urakawa, Hiroaki Akiyama, and Mari Nishio
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Pathology ,Esophageal Neoplasms ,Macrophage ,Esophageal cancer ,FGF-2 ,Fibroblast growth factor ,0302 clinical medicine ,Cell Movement ,Medicine ,NCAM ,Neural Cell Adhesion Molecules ,Middle Aged ,Phenotype ,Tumor microenvironment ,Oncology ,030220 oncology & carcinogenesis ,CYR61 ,Carcinoma, Squamous Cell ,Female ,Fibroblast Growth Factor 2 ,RNA Interference ,Esophageal Squamous Cell Carcinoma ,Signal Transduction ,Macrophage colony-stimulating factor ,medicine.medical_specialty ,Stromal cell ,Cell Survival ,Tumor-associated macrophage ,Transfection ,03 medical and health sciences ,Cell Line, Tumor ,Paracrine Communication ,Humans ,Receptor, Fibroblast Growth Factor, Type 1 ,Aged ,business.industry ,Macrophages ,Fibroblast growth factor receptor 1 ,FGFR1 ,030104 developmental biology ,Culture Media, Conditioned ,Cancer research ,Neural cell adhesion molecule ,Phosphatidylinositol 3-Kinase ,Stromal Cells ,business ,Proto-Oncogene Proteins c-akt - Abstract
Tumor-associated macrophages (TAMs) have important roles in the angiogenesis and tumor immunosuppression of various cancers, including esophageal squamous cell carcinomas (ESCCs). To elucidate the roles of TAMs in ESCCs, we compared the gene expression profiles between human peripheral blood monocyte-derived macrophage-like cells (Macrophage_Ls) and Macrophage_Ls stimulated with conditioned medium of the TE series human ESCC cell line (TECM) (TAM_Ls) using cDNA microarray analysis. Among the highly expressed genes in TAM_Ls, we focused on neural cell adhesion molecule (NCAM). NCAM knockdown in TAM_Ls revealed a significant decrease of migration and survival via a suppression of PI3K-Akt and fibroblast growth factor receptor 1 (FGFR1) signaling. Stimulation by TECM up-regulated the level of FGFR1 in Macrophage_Ls. Recombinant human fibroblast growth factor-2 (rhFGF-2) promoted the migration and survival of TAM_Ls and TE-cells through FGFR1 signaling. Our immunohistochemical analysis of 70 surgically resected ESCC samples revealed that the up-regulated FGF-2 in stromal cells, including macrophages, was associated with more aggressive phenotypes and a high number of infiltrating M2 macrophages. These findings may indicate a novel role of NCAM- and FGF-2-mediated FGFR1 signaling in the tumor microenvironment of ESCCs.
- Published
- 2016
39. CD163+ Foamy Macrophages Are Associated with the Morphogenesis of Oral Verruciform Xanthoma through Angiogenesis by VEGF Expression: An Immunohistochemical Study
- Author
-
Yu-ichiro Koma, Takayuki Kodama, Hiroshi Yokozaki, Manabu Shigeoka, Masaya Akashi, and Mari Nishio
- Subjects
Pathology ,medicine.medical_specialty ,endocrine system ,Angiogenesis ,Macrophage polarization ,foamy macrophage ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,angiogenesis ,0302 clinical medicine ,medicine ,Macrophage ,oral verruciform xanthoma ,General Dentistry ,Verruciform xanthoma ,Lamina propria ,business.industry ,CD68 ,030206 dentistry ,medicine.disease ,VEGF ,Vascular endothelial growth factor ,lcsh:RK1-715 ,medicine.anatomical_structure ,surgical procedures, operative ,chemistry ,030220 oncology & carcinogenesis ,lcsh:Dentistry ,CD163 ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
Oral verruciform xanthoma (OVX) is an uncommon benign lesion that is characterized histologically by the accumulation of several foamy macrophages in the lamina propria papillae. The pathogenesis of OVX has not been completely elucidated, although the significance of macrophage polarization (M1, tumor suppression, and M2, tumor promotion) and the contribution of M2 macrophages to angiogenesis are well established. This study investigated the role of foamy macrophages in OVX, with a focus on angiogenesis. Four patients who underwent surgical excision or total excisional biopsy for OVXs were enrolled in this study. We evaluated the expression of the macrophage markers CD68 (broad) and CD163 (M2) and the CD34-positive microvessel density (MVD) of OVXs. The foamy macrophages of all patients exhibited positivity to CD68 and CD163. We evaluated the MVD and the expression of the vascular endothelial growth factor (VEGF) based on histological architecture. The MVD of all OVX cases was significantly higher than that of the corresponding normal epithelia. Interestingly, the MVD of verrucous-type OVX cases was higher than that of the other type. VEGF was expressed on foamy macrophages in all cases. Overall, the foamy macrophages expressing CD163 were associated with the morphogenesis of OVX through the process of angiogenesis by VEGF expression.
- Published
- 2020
40. Polypoid leiomyosarcoma of the esophagus treated by endoscopic submucosal dissection
- Author
-
Hidetaka Tsumura, Toshiko Sakuma, Masahiro Tsuda, Aya Sakai, Hogara Nishisaki, Yoshinobu Yamamoto, Kazutoshi Tobimatsu, Masayuki Mano, Hiroaki Sawai, Takanori Hirose, Yu-ichiro Koma, Ikuya Miki, Takeshi Sakamoto, Hideto Inokuchi, Takuya Mimura, and Saeko Kushida
- Subjects
Leiomyosarcoma ,Pathology ,medicine.medical_specialty ,Muscularis mucosae ,medicine.diagnostic_test ,business.industry ,Gastroenterology ,Dissection (medical) ,medicine.disease ,Dysphagia ,Metastasis ,medicine.anatomical_structure ,Submucosa ,Biopsy ,medicine ,Radiology, Nuclear Medicine and imaging ,Esophagus ,medicine.symptom ,business - Abstract
We report a rare case of polypoid leiomyosarcoma of the esophagus that was treated by endoscopic submucosal dissection (ESD). A 63-year-old man with complaints of progressive dysphagia was referred to Hyogo Cancer Center for treatment of esophageal tumor. Esophagoscopy revealed a polypoid tumor 25 mm in diameter on the left side of the upper esophagus. Despite several biopsy specimens, the diagnosis could not be confirmed. Computed tomography showed a protruded, homogeneously enhancing mass in the upper esophagus, but no lymph node enlargement or metastasis. After 1.5 months, the esophagogram showed a filling defect 47 mm in diameter in the upper esophagus. Given this rapid tumor growth, en bloc resection was done by ESD for therapeutic diagnosis. After this treatment, the tumor seemed to grow larger, showing a short stalk and occupying the esophageal lumen. Histopathologically, the tumor comprised pleomorphic spindle cells with mitosis. Tumor invasion involved the lumina propria mucosae and contact with the muscularis mucosae, but not involving the submucosa. Immunohistochemical examination showed positive staining for smooth muscle actin and HHF35, but negative for desmin, caldesmon, CD34, c-kit, DOG1, ALK, S-100 protein and cytokeratin. These histopathological findings were compatible with a diagnosis of esophageal leiomyosarcoma derived from the muscularis mucosae.
- Published
- 2015
41. Cyr61 promotes CD204 expression and the migration of macrophages via MEK/ERK pathway in esophageal squamous cell carcinoma
- Author
-
Mari Nishio, Nobuhisa Takase, Soken Utsunomiya, Hiroshi Yokozaki, Naoki Urakawa, Takahide Komori, Yu-ichiro Koma, Yoshihiro Kakeji, Hiroaki Akiyama, and Manabu Shigeoka
- Subjects
MAPK/ERK pathway ,Male ,Cancer Research ,Esophageal Neoplasms ,Angiogenesis ,MAP Kinase Signaling System ,macrophage ,Biology ,Cell Movement ,Cell Line, Tumor ,tumor microenvironment ,Humans ,Radiology, Nuclear Medicine and imaging ,esophageal cancer ,Cancer Biology ,Aged ,Aged, 80 and over ,Tumor microenvironment ,Macrophages ,Scavenger Receptors, Class A ,Cell migration ,Middle Aged ,digestive system diseases ,Gene Expression Regulation, Neoplastic ,CD204 ,Oncology ,Cell culture ,CYR61 ,Cancer cell ,Cancer research ,Carcinoma, Squamous Cell ,Monocytic leukemia ,Cyr61 ,Female ,Esophageal Squamous Cell Carcinoma ,Cysteine-Rich Protein 61 - Abstract
Tumor-associated macrophages (TAMs) are known to be involved in the progression of various human malignancies. We previously demonstrated that CD204 was a useful marker for TAMs contributing to the angiogenesis, progression, and prognosis of human esophageal squamous cell carcinoma (ESCC). We also showed that conditioned media of ESCC cell lines induced CD204 expression in THP-1 human monocytic leukemia cells. Here, we performed a cDNA microarray analysis between THP-1 cells stimulated with TPA (macrophage [MΦ]-like THP-1 cells) treated with and without conditioned medium of ESCC cell line to clarify the molecular characteristics of TAMs in ESCC. From the microarray data, we discovered that Cyr61 was induced in CD204-positive-differentiated THP-1 cells (TAM-like THP-1 cells). In the ESCC microenvironment, not only cancer cells but also TAMs expressed Cyr61. Interestingly, the expression levels of Cyr61 showed a significant positive correlation with the number of CD204-positive macrophages in ESCCs by immunohistochemistry. Recombinant human Cyr61 (rhCyr61) promoted cell migration and induced the expression of CD204 along with the activation of the MEK/ERK pathway in MΦ-like THP-1 cells. Pretreatment with a MEK1/2 inhibitor significantly inhibited not only the Cyr61-mediated migration but also the CD204 expression in the MΦ-like THP-1 cells. These results suggest that Cyr61 may contribute to the expression of CD204 and the promotion of cell migration via the MEK/ERK pathway in TAMs in the ESCC microenvironment.
- Published
- 2015
42. Amelanotic primary malignant melanoma of the esophagus: report of a case treated with minimally invasive esophagectomy and adjuvant chemotherapy
- Author
-
Yasuhiro Fujino, Masahiro Tominaga, Taro Oshikiri, Kentaro Kawasaki, Shingo Kanaji, Masahiro Tsuda, Masayuki Mano, Yu-ichiro Koma, and Hogara Nishisaki
- Subjects
medicine.medical_specialty ,Chemotherapy ,business.industry ,Dacarbazine ,Melanoma ,medicine.medical_treatment ,Gastroenterology ,medicine.disease ,Metastasis ,Surgery ,medicine.anatomical_structure ,Esophagectomy ,medicine ,Radiology ,Stage (cooking) ,Esophagus ,business ,Lymph node ,medicine.drug - Abstract
Amelanotic primary malignant melanoma of the esophagus (PMME) is extremely rare. We report a case of amelanotic PMME that was accurately diagnosed and subsequently treated by radical resection with adjuvant chemotherapy. A 69-year-old woman was admitted to our hospital because of dysphagia. Endoscopic examination revealed a tumor without pigmentation in the upper thoracic esophagus, and melanosis in the lower thoracic esophagus. Tumor biopsy showed proliferation of malignant spindle cells with conspicuous nucleoli. Immunohistochemically, the tumor cells were positive for melanosomes (HMB45). The tumor was diagnosed as PMME. Positron emission tomography and computed tomography showed accumulation of the tracer only in the primary lesion. The preoperative diagnosis according to the extent of the tumor, whether cancer cells have spread to lymph nodes, and whether metastasis has occurred (TNM) classification was malignant melanoma in the upper third of the esophagus, T2N0M0 stage IIA. The patient underwent minimally invasive video assisted esophagectomy in the prone position with three-field lymph node dissection. On the resected specimen, the malignant cells were positive for HMB45, KIT, and melan-A. Masson-Fontana staining demonstrated no melanin pigmentation. The patient was diagnosed with amelanotic PMME and received adjuvant chemotherapy, consisting of dacarbazine, nimustine, cisplatin, and tamoxifen. The patient showed no systemic metastasis, and is alive 18 months after the operation with no evidence of recurrence.
- Published
- 2012
43. Pulmonary large cell neuroendocrine carcinoma exhibiting extensive pagetoid spread in the bronchial epithelium: A case report
- Author
-
Masahiro Yoshimura, Shinya Tane, Daisuke Hokka, Hiroyuki Ogawa, Yu-ichiro Koma, Shunsuke Tauchi, Kazuya Uchino, Yugo Tanaka, and Yoshimasa Maniwa
- Subjects
Cancer Research ,Bronchus ,Pathology ,medicine.medical_specialty ,Lung ,business.industry ,Articles ,Large cell neuroendocrine carcinoma of the lung ,medicine.disease ,Primary tumor ,pagetoid spread ,lung cancer ,medicine.anatomical_structure ,Oncology ,Pagetoid ,Carcinoma ,Medicine ,business ,Lung cancer ,large cell neuroendocrine carcinoma ,Pathological - Abstract
Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive malignant tumor, which was proposed as a novel type of neuroendocrine tumor in 1991. Although it is categorized as a non-small cell lung carcinoma, the precise pathological condition is unknown due to its rare occurrence. The present study outlines the case of a patient presenting with an LCNEC that exhibited pagetoid spread from the region of the primary tumor to the bronchial epithelium (distance, >30 mm). The pagetoid spread was unconfirmed preoperatively, however, was identified by intraoperative rapid diagnosis. This caused us to suffer the perioperative decision of additional resection and resulted in an incomplete resection, as suture of the bronchus was not possible. Pagetoid spread, which is often apparent in the breast, presents as a rare pattern of infiltration of cancer cells when a massive carcinoma is identified beneath the intraepithelial spread. Although preoperative diagnosis of pagetoid spread is difficult due to its rarity and undefined clinical features, it is important for surgeons and pathologists treating lung cancer patients to be aware of potential pagetoid spread in the thoracic region.
- Published
- 2014
44. Constitutive suppression of PRL-3 inhibits invasion and proliferation of gastric cancer cell in vitro and in vivo
- Author
-
Hirotaka Kato, Shuho Semba, Yu-ichiro Koma, Hiroshi Yokozaki, Kazuyoshi Yanagihara, and Yasuko Matsukawa
- Subjects
endocrine system ,Small interfering RNA ,Time Factors ,Mice, Nude ,Biology ,Transfection ,Pathology and Forensic Medicine ,Metastasis ,Mice ,In vivo ,Cell Movement ,Stomach Neoplasms ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,RNA, Messenger ,Molecular Biology ,Cell Proliferation ,Gene knockdown ,Mice, Inbred BALB C ,Cell growth ,Carcinoma ,Liver Neoplasms ,Cancer ,Cell Biology ,General Medicine ,medicine.disease ,Molecular biology ,Neoplasm Proteins ,Tumor Burden ,Gene Expression Regulation, Neoplastic ,Tumor progression ,Cancer cell ,Female ,RNA Interference ,Protein Tyrosine Phosphatases ,hormones, hormone substitutes, and hormone antagonists - Abstract
Objective: Overexpression of phosphatase of regenerating liver-3 (PRL-3) has been implicated in tumor progression and metastasis of gastric carcinoma. Here we examined what alterations occur in the phenotype of gastric cancer cells in vitro and in vivo when PRL-3 expression is knocked down. Methods: We constructed a small interfering RNA (siRNA)-expressing vector which stably interfered with PRL-3 expression and was transfected into SH101-P4 cells, which express the highest PRL-3 mRNA levels among 13 gastric cancer cell lines. The new SH101-P4 subclones, in which PRL-3 was stably reduced, were established and their in vitro growth, motility and abilities of liver metastasis from the injected spleen were analyzed in vivo. Results: PRL-3 knockdown effectively suppressed invasion and growth of SH101-P4 cells in vitro. Liver metastasis in vivo was significantly decreased when PRL-3 expression was suppressed. The primary tumor size in the injected spleen tended to be smaller in PRL-3 knockdown clones than in the controls. These findings suggest that PRL-3 expression may contribute not only to the establishment of metastasis but also to the growth of primary foci of human gastric cancer. Therefore, PRL-3 may be one of the target molecules in gastric cancer therapy.
- Published
- 2010
45. Utility of Gd-EOB-DTPA-Enhanced MRI in Diagnosing Small Hepatocellular Carcinoma
- Author
-
Yoshitake Hayashi, Taisuke Nakajima, Kenji Ando, Susumu Imoto, Ryo Nishikawa, Masatoshi Kudo, Soo Ryang Kim, Yu-ichiro Koma, Katsumi Fukuda, Toshiyuki Matsuoka, and Keiji Mita
- Subjects
Pathology ,medicine.medical_specialty ,Cirrhosis ,Published: July 2009 ,Ultrasound ,Atypia ,Medicine ,lcsh:RC799-869 ,Gd-EOB-DTPA-enhanced MRI ,medicine.diagnostic_test ,business.industry ,Gastroenterology ,Well-differentiated hepatocellular carcinoma ,Magnetic resonance imaging ,Hypervascularity ,Hepatitis C ,CT during arteriography ,medicine.disease ,CT during arterial portography ,Hepatocellular carcinoma ,lcsh:Diseases of the digestive system. Gastroenterology ,Small hepatocellular carcinoma ,business ,Nuclear medicine ,Well Differentiated Hepatocellular Carcinoma ,Hepatocyte function - Abstract
We describe an 8-mm hepatocellular carcinoma (HCC) with hepatitis C virus-related cirrhosis in a 74-year-old woman. Ultrasound (US) revealed an 8-mm hyperechoic nodule in segment 6 of the liver. Contrast-enhanced computed tomography (CT) and US revealed no hypervascularity in the early phase and no washout in the late phase and the Kupffer phase, respectively. CT during arteriography revealed no hypervascularity and CT during arterial portography disclosed no perfusion defect. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) revealed no hypervascularity in the early phase, but disclosed a defect in the hepatobiliary phase. Histologically, the nodule was diagnosed as well-differentiated HCC characterized by more than two-fold the cellularity of the non-tumorous area, with a high nuclear:cytoplasmic ratio, increased cytoplasmic eosinophilia, fatty change, and slight cell atypia with an irregular thin trabecular pattern. Our case demonstrates the utility of Gd-EOB-DTPA-enhanced MRI in the diagnosis of small HCC.
- Published
- 2009
46. SgIGSF is a novel biliary–epithelial cell adhesion molecule mediating duct/ductule development
- Author
-
Tohru Tsujimura, Ayuko Sato, Yuji Nishikawa, Kazuhiro Ohnuma, Katsuhiko Enomoto, Hiroshi Yokozaki, Yu-ichiro Koma, Akihiko Ito, and Ikuyo Ohnuma
- Subjects
Pathology ,medicine.medical_specialty ,Cell Adhesion Molecules, Neuronal ,Immunoglobulins ,Cell Communication ,Biology ,Mice ,Cytokeratin ,medicine ,Animals ,Humans ,Cells, Cultured ,Keratin-19 ,Hepatology ,Cell adhesion molecule ,Bile duct ,Tumor Suppressor Proteins ,Cell Adhesion Molecule-1 ,Membrane Proteins ,Epithelial Cells ,Intercellular adhesion molecule ,Molecular biology ,Rats, Inbred F344 ,Epithelium ,Liver Regeneration ,Rats ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Gene Expression Regulation ,Biliary tract ,Hepatocyte ,Immunohistochemistry ,Bile Ducts ,Cell Adhesion Molecules - Abstract
Spermatogenic immunoglobulin superfamily (SgIGSF) is an intercellular adhesion molecule of the nectin-like family. While screening its tissue distribution, we found that it was expressed in fetal liver but not adult liver. In the present study, we examined which cells in developing and regenerating liver express SgIGSF via immunohistochemistry and Western blot analysis. In developing mouse liver, SgIGSF expression was transiently upregulated at perinatal ages and was restricted to the lateral membrane of biliary epithelial cells (BECs). In regenerating rat livers from the 2-acetylaminofluorene/partial hepatectomy model, SgIGSF was detected exclusively in oval cells that aligned in ductal and trabecular patterns by the second week posthepatectomy. In human livers, fetal and newborn bile ducts and cirrhotic bile ductules were clearly positive for SgIGSF, whereas disease-free adult bile ducts were negative. To investigate the role of SgIGSF in bile duct/ductule formation, we used an in vitro model in which rat hepatocyte aggregates embedded in collagen gels containing insulin and epidermal growth factor extend epithelial sheets and processes in the first week and form ductules within a month. The process and ductular cells were continuously positive for SgIGSF and cytokeratin 19, a BEC marker. When the aggregate culture was started in the presence of a function-blocking anti-SgIGSF antibody, the number of epithelial processes per aggregate was reduced by 80%. Conclusion: We propose that SgIGSF is a novel and functional BEC adhesion molecule that is expressed for a limited time during active bile duct/ductule formation. (HEPATOLOGY 2007;45:684–694.)
- Published
- 2007
47. Software-assisted morphometric and phenotype analyses of human peripheral blood monocyte-derived macrophages induced by a microenvironment model of human esophageal squamous cell carcinoma
- Author
-
Hiroshi Yokozaki, Nobuhisa Takase, Noriaki Arai, Manabu Shigeoka, Yu-ichiro Koma, Naoki Urakawa, Yumi Ichihara, and Mari Nishio
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Esophageal Neoplasms ,CD14 ,Cellular differentiation ,Cell ,Antigens, Differentiation, Myelomonocytic ,Receptors, Cell Surface ,Biology ,Immunofluorescence ,Monocytes ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,stomatognathic system ,Antigens, CD ,Cell Line, Tumor ,medicine ,Image Processing, Computer-Assisted ,Tumor Microenvironment ,Humans ,skin and connective tissue diseases ,Interleukin 4 ,Tumor microenvironment ,medicine.diagnostic_test ,Macrophages ,Scavenger Receptors, Class A ,Cell Differentiation ,General Medicine ,030104 developmental biology ,medicine.anatomical_structure ,Phenotype ,Cell culture ,030220 oncology & carcinogenesis ,Culture Media, Conditioned ,Carcinoma, Squamous Cell ,Esophageal Squamous Cell Carcinoma ,Interleukin-4 ,CD163 ,Software - Abstract
Human macrophages play important roles in tumor promotion and are called tumor-associated macrophages (TAMs). We previously demonstrated that human esophageal squamous cell carcinomas (ESCCs) contain TAMs and that these TAMs tend to have tumor-supporting features. Here we exposed human macrophages to conditioned media of TE-series human ESCC cell lines (TECMs) to generate an ESCC extracellular stimuli-influenced TAM model. CD14(+) peripheral blood monocytes (PBMos) from healthy donors were treated with M-CSF and with additional IL-4 or TECM exposure. Morphological changes of the cells and the induction of CD163/CD204 proteins were detected in the TECM-exposed model TAMs by immunofluorescence. A software-assisted immunofluorescent cell image analysis showed increased CD163/CD204 positivity in the model TAMs and a weak to moderate positive correlation between the cytoplasmic area and the sum fluorescent intensity of CD204. Morphological changes of the cells were significantly reflected by several cytomorphometric parameters. PBMos were elongated with M-CSF treatment, then enlarged with TECM exposure. The cytoplasmic aspect ratio was decreased by M-CSF treatment and slightly increased by TECM exposure. The nuclear-cytoplasmic ratio decreased during the whole process of cell differentiation. This system is useful for quantitative assessments of TAM-like morphological changes of macrophages and the induction of CD163/CD204 in a model ESCC microenvironment.
- Published
- 2015
48. Polypoid leiomyosarcoma of the esophagus treated by endoscopic submucosal dissection
- Author
-
Yoshinobu, Yamamoto, Hogara, Nishisaki, Yu-ichiro, Koma, Hiroaki, Sawai, Aya, Sakai, Takuya, Mimura, Saeko, Kushida, Hidetaka, Tsumura, Takeshi, Sakamoto, Kazutoshi, Tobimatsu, Ikuya, Miki, Toshiko, Sakuma, Masahiro, Tsuda, Masayuki, Mano, Takanori, Hirose, and Hideto, Inokuchi
- Subjects
Leiomyosarcoma ,Male ,Mucous Membrane ,Time Factors ,Esophageal Neoplasms ,Biopsy, Needle ,Middle Aged ,Immunohistochemistry ,Risk Assessment ,Polyps ,Treatment Outcome ,Humans ,Minimally Invasive Surgical Procedures ,Esophagoscopy ,Deglutition Disorders ,Tomography, X-Ray Computed ,Follow-Up Studies - Abstract
We report a rare case of polypoid leiomyosarcoma of the esophagus that was treated by endoscopic submucosal dissection (ESD). A 63-year-old man with complaints of progressive dysphagia was referred to Hyogo Cancer Center for treatment of esophageal tumor. Esophagoscopy revealed a polypoid tumor 25 mm in diameter on the left side of the upper esophagus. Despite several biopsy specimens, the diagnosis could not be confirmed. Computed tomography showed a protruded, homogeneously enhancing mass in the upper esophagus, but no lymph node enlargement or metastasis. After 1.5 months, the esophagogram showed a filling defect 47 mm in diameter in the upper esophagus. Given this rapid tumor growth, en bloc resection was done by ESD for therapeutic diagnosis. After this treatment, the tumor seemed to grow larger, showing a short stalk and occupying the esophageal lumen. Histopathologically, the tumor comprised pleomorphic spindle cells with mitosis. Tumor invasion involved the lumina propria mucosae and contact with the muscularis mucosae, but not involving the submucosa. Immunohistochemical examination showed positive staining for smooth muscle actin and HHF35, but negative for desmin, caldesmon, CD34, c-kit, DOG1, ALK, S-100 protein and cytokeratin. These histopathological findings were compatible with a diagnosis of esophageal leiomyosarcoma derived from the muscularis mucosae.
- Published
- 2014
49. The Spermatogenic Ig Superfamily/Synaptic Cell Adhesion Molecule Mast-Cell Adhesion Molecule Promotes Interaction with Nerves
- Author
-
Yukihiko Kitamura, Hiroshi Yokozaki, Tadahide Furuno, Akihiko Ito, Kenji Watabe, Yu-ichiro Koma, John Bienenstock, and Mamoru Nakanishi
- Subjects
Superior cervical ganglion ,Neurite ,Cell Adhesion Molecules, Neuronal ,Immunology ,Cell ,Immunoglobulins ,Bone Marrow Cells ,Mice, Transgenic ,Cell Communication ,Superior Cervical Ganglion ,Biology ,Mice ,Piperidines ,Cell Adhesion ,Neurites ,medicine ,Animals ,Immunology and Allergy ,Mast Cells ,Cells, Cultured ,Neurons ,Stem Cell Factor ,Cell adhesion molecule ,Tumor Suppressor Proteins ,Cell Adhesion Molecule-1 ,Membrane Proteins ,Transfection ,Mast cell ,Coculture Techniques ,Cell biology ,Mice, Inbred C57BL ,Proto-Oncogene Proteins c-kit ,medicine.anatomical_structure ,Cell culture ,Mice, Inbred CBA ,NIH 3T3 Cells ,Cell Adhesion Molecules ,Homeostasis - Abstract
Nerve-mast cell interaction is involved in both homeostatic and pathologic regulations. The molecules that sustain this association have not been identified. Because synaptic cell adhesion molecule (SynCAM), alternatively named spermatogenic Ig superfamily (SgIGSF), is expressed on both nerves and mast cells and because it binds homophilically, this molecule may be a candidate. To examine this possibility, mast cells with or without SgIGSF/SynCAM were cocultured with superior cervical ganglion neurons that express SgIGSF/SynCAM, and the number of mast cells attached to neurites was counted. The attachment of mast cells with SgIGSF/SynCAM, i.e., bone marrow-derived mast cells (BMMC) from wild-type mice, was inhibited dose-dependently by blocking Ab to SgIGSF/SynCAM. Mast cells without SgIGSF/SynCAM, i.e., BMMC from microphthalmia transcription factor-deficient mice and BMMC-derived cell line IC-2 cells, were defective in attachment to neurite, and transfection with SgIGSF/SynCAM normalized this. When the nerves were specifically activated by scorpion venom, one-quarter of the attached IC-2 cells mobilized Ca2+ after a few dozen seconds, and ectopic SgIGSF/SynCAM doubled this proportion. At points of contact between neurites and wild-type BMMC, SgIGSF/SynCAM was locally concentrated in both neurites and BMMC. SgIGSF/SynCAM on mast cells appeared to predominantly mediate attachment and promote communication with nerves.
- Published
- 2005
50. Number of Mast Cells in the Peritoneal Cavity of Mice
- Author
-
Keisuke Oboki, Tomohiko Wakayama, Yukihiko Kitamura, Yu-ichiro Koma, Tomoko Jippo, Eiichi Morii, M. Lynn Lamoreux, Akihiko Ito, and Shoichi Iseki
- Subjects
Pathology ,medicine.medical_specialty ,biology ,Cell adhesion molecule ,Ratón ,Mast cell ,Immunoglobulin E ,Microphthalmia-associated transcription factor ,Molecular biology ,Pathology and Forensic Medicine ,Peritoneal cavity ,medicine.anatomical_structure ,medicine ,biology.protein ,Antibody ,Cell adhesion - Abstract
The mi (microphthalmia) locus of mice encodes a transcription factor, MITF. B6-tg/tg mice that do not express any MITF have white coats and small eyes. Moreover, the number of mast cells decreased to one-third that of normal control (+/+) mice in the skin of B6-tg/tg mice. No mast cells were detectable in the stomach, mesentery, and peritoneal cavity of B6-tg/tg mice. Cultured mast cells derived from B6-tg/tg mice do not express a mast cell adhesion molecule, spermatogenic immunoglobulin superfamily (SgIGSF). To obtain in vivo evidence for the correlation of nonexpression of SgIGSF with decrease in mast cell number, we used another MITF mutant, B6-mivit/mivit mice that have a mild phenotype, ie, black coat with white patches and eyes of normal size. B6-mivit/mivit mice had a normal number of mast cells in the skin, stomach, and mesentery, but the number of peritoneal mast cells decreased to one-sixth that of +/+ mice. Cultured mast cells and peritoneal mast cells of B6-mivit/mivit mice showed a reduced but apparently detectable level of SgIGSF expression, demonstrating the parallelism between mast cell number and expression level of SgIGSF. The number of peritoneal mast cells appeared to be influenced by MITF through transcription of SgIGSF.
- Published
- 2004
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