2023/04/21 更新

写真a

ヨシハラ マサト
吉原 雅人
YOSHIHARA Masato
所属
医学部附属病院 卒後臨床研修・キャリア形成支援センター 病院助教
職名
病院助教

学位 1

  1. 博士(医学) ( 2020年3月   名古屋大学 ) 

 

論文 60

  1. DDIT4 Facilitates Lymph Node Metastasis via the Activation of NF-κB Pathway and Epithelial-Mesenchymal Transition.

    Lin X, Yoshikawa N, Liu W, Matsukawa T, Nakamura K, Yoshihara M, Koya Y, Sugiyama M, Tamauchi S, Ikeda Y, Yokoi A, Shimizu Y, Kajiyama H

    Reproductive sciences (Thousand Oaks, Calif.)     2023年4月

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    記述言語:英語   出版者・発行元:Reproductive Sciences  

    This study was aimed to identify a novel metastasis-promoting molecule and elucidate its functional and prognostic roles in cervical cancer. DDIT4 (DNA-damage-inducible transcript 4), a hypoxia-inducible gene, was identified by analyzing multiple microarray databases. The correlation between DDIT4 expression in immunohistochemistry and clinicopathological characteristics in the public database and our cohort was evaluated by statistical analysis. Transwell® assay and wound-healing assay to determine cell migration and invasion were performed. DDIT4 was knocked down using siRNA or lentiviral vectors. The potential downstream pathways of DDIT4 were explored and verified by a gene set enrichment analysis and western blotting. The in vivo metastatic capability was determined with the use of an intraperitoneal injection mouse model. In the analysis of the public database and our cohort, DDIT4 high expression was significantly related to short overall survival and lymph node metastasis in patients with early-stage cervical cancer. The knockdown of DDIT4 attenuated the migration and invasion activity of tumor cells in vitro and reduced the expression of epithelial–mesenchymal transition (EMT)-related proteins and the NF-κB pathway in cervical cancer cells. DDIT4 also promoted tumor progression in the mouse model. Our results indicate that DDIT4 can be a prognostic indicator in cervical cancer and promote lymph node metastasis, augmenting malignancy via the EMT and NF-kB pathways.

    DOI: 10.1007/s43032-023-01230-y

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  2. Novel therapeutic strategies targeting UCP2 in uterine leiomyosarcoma.

    Nagao Y, Yokoi A, Yoshida K, Sugiyama M, Watanabe E, Nakamura K, Kitagawa M, Asano-Inami E, Koya Y, Yoshihara M, Tamauchi S, Shimizu Y, Ikeda Y, Yoshikawa N, Kato T, Yamamoto Y, Kajiyama H

    Pharmacological research   189 巻   頁: 106693   2023年3月

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    記述言語:英語   出版者・発行元:Pharmacological Research  

    Uterine leiomyosarcoma (ULMS) is a malignant stromal tumor arising from the myometrium with a poor prognosis and very limited response to current chemotherapy. This study aimed to identify novel targets for ULMS through a three-step screening process using a chemical library consisting of 1271 Food and Drug Administration-approved drugs. First, we evaluated their inhibitory effects on ULMS cells and identified four candidates: proscillaridin A, lanatoside C, floxuridine, and digoxin. Then, we subcutaneously or orthotopically transplanted SK-UT-1 cells into mice to establish mouse models. In vivo analyses showed that proscillaridin A and lanatoside C exerted a superior antitumor effect. The results of mRNA sequencing showed that uncoupling protein 2 (UCP2) was suppressed in the sirtuin signaling pathway, increasing reactive oxygen species (ROS) and inducing cell death. Moreover, the downregulation of UCP2 induced ROS and suppressed ULMS cell growth. Furthermore, analyses using clinical samples showed that UCP2 expression was significantly upregulated in ULMS tissues than in myoma tissues both at the RNA and protein levels. These findings suggested that UCP2 is a potential therapeutic target and can contribute to the development of novel therapeutic strategies in patients with ULMS.

    DOI: 10.1016/j.phrs.2023.106693

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  3. Disabled-2 (DAB2): A Key Regulator of Anti- and Pro-Tumorigenic Pathways

    Price Zoe K., Lokman Noor A., Yoshihara Masato, Kajiyama Hiroaki, Oehler Martin K., Ricciardelli Carmela

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   24 巻 ( 1 )   2023年1月

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    記述言語:英語   出版者・発行元:International Journal of Molecular Sciences  

    Disabled-2 (DAB2), a key adaptor protein in clathrin mediated endocytosis, is implicated in the regulation of key signalling pathways involved in homeostasis, cell positioning and epithelial to mesenchymal transition (EMT). It was initially identified as a tumour suppressor implicated in the initiation of ovarian cancer, but was subsequently linked to many other cancer types. DAB2 contains key functional domains which allow it to negatively regulate key signalling pathways including the mitogen activated protein kinase (MAPK), wingless/integrated (Wnt) and transforming growth factor beta (TGFβ) pathways. Loss of DAB2 is primarily associated with activation of these pathways and tumour progression, however this review also explores studies which demonstrate the complex nature of DAB2 function with pro-tumorigenic effects. A recent strong interest in microRNAs (miRNA) in cancer has identified DAB2 as a common target. This has reignited an interest in DAB2 research in cancer. Transcriptomics of tumour associated macrophages (TAMs) has also identified a pro-metastatic role of DAB2 in the tumour microenvironment. This review will cover the broad depth literature on the tumour suppressor role of DAB2, highlighting its complex relationships with different pathways. Furthermore, it will explore recent findings which suggest DAB2 has a more complex role in cancer than initially thought.

    DOI: 10.3390/ijms24010696

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  4. A case of non-immune hydrops fetalis with maternal mirror syndrome diagnosed by trio-based exome sequencing: An autopsy case report and literature review

    Tano Sho, Kotani Tomomi, Yoshihara Masato, Nakamura Noriyuki, Matsuo Seiko, Ushida Takafumi, Imai Kenji, Ito Miharu, Oka Yasuyoshi, Sato Emi, Hayashi Shin, Ogi Tomoo, Kajiyama Hiroaki

    MOLECULAR GENETICS AND METABOLISM REPORTS   33 巻   頁: 100925   2022年12月

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    記述言語:英語   出版者・発行元:Molecular Genetics and Metabolism Reports  

    Non-immune hydrops fetalis (NIHF) indicates the risk for stillbirth. Although the causes vary and most NIHFs have no identifiable cause, recent advances in exome sequencing have increased diagnostic rates. We report a case of NIHF that developed into a giant cystic hygroma complicated by maternal mirror syndrome. Trio-based exome sequencing showed a de novo heterozygous missense variant in the RIT1 (NM_006912: c.246 T > G [p.F82L]). The RIT1 variants are known causative variants of Noonan syndrome (NS; OMIM #163950). The location of the RIT1 variants in the previously reported NS cases with NIHF or/and maternal mirror syndrome was mainly in the switch II region, including the present case. While a further accumulation of cases is needed, exome sequencing, which can identify the variant type in detail, might help predict the phenotype and severity of NIHF.

    DOI: 10.1016/j.ymgmr.2022.100925

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  5. Optimal annual body mass index change for preventing spontaneous preterm birth in a subsequent pregnancy

    Tano Sho, Kotani Tomomi, Ushida Takafumi, Yoshihara Masato, Imai Kenji, Nakano-Kobayashi Tomoko, Moriyama Yoshinori, Iitani Yukako, Kinoshita Fumie, Yoshida Shigeru, Yamashita Mamoru, Kishigami Yasuyuki, Oguchi Hidenori, Kajiyama Hiroaki

    SCIENTIFIC REPORTS   12 巻 ( 1 ) 頁: 17502   2022年10月

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    記述言語:英語   出版者・発行元:Scientific Reports  

    Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality. Although PTB is known to recur, interpregnancy preventive strategies for PTB have not been established to date. Annual BMI change can serve as a specific target value for preventing obstetric complications during interpregnancy care/counseling. This value can also account for age-related weight gain (0.2 kg/m2/year). In a multicenter retrospective study, we investigated the optimal annual BMI change for preventing PTB recurrence using the data of individuals who had two singleton births from 2009 to 2019. The association between annual BMI change and spontaneous PTB (sPTB) was analyzed by separating cases of medically indicated PTB (mPTB) from those of sPTB. Previous history of sPTB was strongly associated with sPTB in the subsequent pregnancy (adjusted odds ratio [aOR], 12.7; 95% confidence interval [CI], 6.5–24.8). Increase in annual BMI was negatively associated with sPTB (aOR, 0.6; 95% CI 0.5–0.9). The sPTB recurrence rate was significantly lower in patients with an annual BMI change of ≥ 0.25 kg/m2/year than in those with an annual BMI change of < 0.25 kg/m2/year (7.7% vs. 35.0%, p = 0.011). Our findings suggest that age-related annual BMI gain between pregnancies may help prevent sPTB recurrence.

    DOI: 10.1038/s41598-022-22495-4

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  6. Regulation of Mesothelial Cell Fate during Development and Human Diseases

    Taniguchi Toshiaki, Tomita Hiroyuki, Kanayama Tomohiro, Mogi Kazumasa, Koya Yoshihiro, Yamakita Yoshihiko, Yoshihara Masato, Kajiyama Hiroaki, Hara Akira

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   23 巻 ( 19 )   2022年10月

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    記述言語:英語   出版者・発行元:International Journal of Molecular Sciences  

    Mesothelial cells (MCs) play a classic role in maintaining homeostasis in pleural, peritoneal, and pericardial cavities. MCs work as lubricants to reduce friction between organs, as regulators of fluid transport, and as regulators of defense mechanisms in inflammation. MCs can differentiate into various cells, exhibiting epithelial and mesenchymal characteristics. MCs have a high potential for differentiation during the embryonic period when tissue development is active, and this potential decreases through adulthood. The expression of the Wilms’ tumor suppressor gene (Wt1), one of the MC markers, decreased uniformly and significantly from the embryonic period to adulthood, suggesting that it plays a major role in the differentiation potential of MCs. Wt1 deletion from the embryonic period results in embryonic lethality in mice, and even Wt1 knockout in adulthood leads to death with rapid organ atrophy. These findings suggest that MCs expressing Wt1 have high differentiation potential and contribute to the formation and maintenance of various tissues from the embryonic period to adulthood. Because of these properties, MCs dynamically transform their characteristics in the tumor microenvironment as cancer-associated MCs. This review focuses on the relationship between the differentiation potential of MCs and Wt1, including recent reports using lineage tracing using the Cre-loxP system.

    DOI: 10.3390/ijms231911960

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  7. Who are the long-term survivors of recurrent ovarian carcinoma?: a retrospective analysis of a multicenter study

    Yoshihara Masato, Mogi Kazumasa, Kitami Kazuhisa, Uno Kaname, Iyoshi Shohei, Tano Sho, Fujimoto Hiroki, Miyamoto Emiri, Yoshikawa Nobuhisa, Emoto Ryo, Matsui Shigeyuki, Kajiyama Hiroaki

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   27 巻 ( 10 ) 頁: 1660 - 1668   2022年10月

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    記述言語:英語   出版者・発行元:International Journal of Clinical Oncology  

    Background: The aim of the present study was to investigate the incidence and hallmarks of long-term survivors of recurrent ovarian carcinoma (LTSROC) in a large-scale retrospective cohort of patients from a multicenter study group. Methods: We performed a regional multicenter retrospective study between January 1986 and September 2021 using clinical data collected under the central pathological review system. Patients who underwent surgery for primary OC at diagnosis and developed recurrent tumors after the initial treatment were included. We defined LTSROC as patients who survived for 5 years or longer after initial tumor recurrence and examined factors affecting the long-term survival of ROC and outcomes of LTSROC. Results: We collected information on patients with malignant ovarian tumors and finally 657 of them that developed ROC were included in the study population. Sixty-eight (10.4%) patients were LTSROC while 399 (60.7%) were short-term survivors of recurrent ovarian carcinoma. In a multivariate logistic regression analysis, negative ascites cytology [odds ratio (OR) 1.865; 95% CI 1.026–3.393; p = 0.041] and a recurrence-free interval (RFI) of 1 year or longer (OR 2.896; 95% CI 1.546–5.425; p < 0.001) were identified as independent factors associated with LTSROC. Approximately 80% of LTSROC presented with solitary recurrent tumors. Furthermore, more than 50% of LTSROC underwent tumor debulking surgery for the first recurrent tumor with or without chemotherapy. Conclusion: RFI of 1 year or longer and negative ascites cytology in the initial surgery were identified as independent predictive factors for LTSROC.

    DOI: 10.1007/s10147-022-02214-9

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  8. DEVELOPING OF A NOVEL THERAPEUTIC AGENT FOR FGR THROUGH DRUG REPOSITIONING

    Tano Sho, Kotani Tomomi, Ushida Takafumi, Nakamura Noriyuki, Iitani Yukako, Yoshihara Masato, Imai Kenji, Kajiyama Hiroaki

    PLACENTA   128 巻   頁: 124 - 124   2022年10月

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  9. Proton beam therapy for the isolated recurrence of endometrial cancer in para-aortic lymph nodes: a case report

    Uno Kaname, Yoshihara Masato, Tano Sho, Takeda Takehiko, Kishigami Yasuyuki, Oguchi Hidenori

    BMC WOMENS HEALTH   22 巻 ( 1 ) 頁: 375   2022年9月

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    記述言語:英語   出版者・発行元:BMC Women's Health  

    Background: Proton beam therapy penetrates tumor tissues with a highly concentrated dose. It is useful when normal structures are too proximate to the treatment target and, thus, may be damaged by surgery or conventional photon beam therapy. However, proton beam therapy has only been used to treat recurrent endometrial cancer in a few cases; therefore, its effectiveness remains unclear. Case presentation: We herein report a case of the isolated recurrence of endometrial cancer in the para-aortic lymph nodes in a 59-year-old postmenopausal woman that was completely eradicated by proton beam therapy. The patient was diagnosed with stage IIIC2 endometrial cancer and treated with 6 courses of doxorubicin (45 mg/m2) and cisplatin (50 mg/m2) in adjuvant chemotherapy. Fifteen months after the initial therapy, the isolated recurrence of endometrial cancer was detected in the para-aortic lymph nodes. The site of recurrence was just under the left renal artery. Due to the potential risks associated with left kidney resection due to the limited surgical space between the tumor and left renal artery, proton beam therapy was administered instead of surgery or conventional photon beam therapy. Following proton beam therapy, the complete resolution of the recurrent lesion was confirmed. No serious complications occurred during or after treatment. There have been no signs of recurrence more than 7 years after treatment. Conclusions: Proton beam therapy is a potentially effective modality for the treatment of recurrent endometrial cancer where the tumor site limits surgical interventions and the use of conventional photon beam therapy.

    DOI: 10.1186/s12905-022-01961-1

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  10. Hypoalbuminemia for the prediction of survival in patients with stage IVB cervical cancer

    Yoshikawa Nobuhisa, Yoshihara Masato, Tamauchi Satoshi, Ikeda Yoshiki, Yokoi Akira, Kajiyama Hiroaki

    PLOS ONE   17 巻 ( 9 ) 頁: e0273876   2022年9月

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    記述言語:英語   出版者・発行元:PLoS ONE  

    We evaluated the prognostic significance of malnutrition in patients with metastatic cervical cancer. In this study, we retrospectively analyzed the cases of 43 patients with stage IVB (FIGO2018) cervical cancer treated at our institute from December 2004 to December 2017. We determined the correlation between clinicopathological characteristics and survival by performing univariate and multivariate analyses. The serum albumin value at diagnosis was used as an index of malnutrition. The median follow-up period was 16.4 months (range, 0.9–91.4 months). On Kaplan-Meier analysis, the 1- and 2-year overall survival (OS) rates for all patients were 61.6% and 48.6%, respectively. The optimal serum albumin for predicting 1-year survival was 3.3 g/dL, as determined by the receiver operating characteristic curve to maximize the area under the curve. The OS of the patients with albumin >3.3 g/ dL (n = 28) was significantly better than that of the patients with albumin ≤3.3 g/dL (n = 15) (p = 0.004). The univariate and multivariate analyses revealed that pretreatment serum albumin and mode of primary treatment were significantly associated with survival in patients with stage IVB cervical cancer. Hypoalbuminemia was an unfavorable prognostic factor for patients with metastatic cervical cancer.

    DOI: 10.1371/journal.pone.0273876

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  11. Obesity contributes to the stealth peritoneal dissemination of ovarian cancer: a multi-institutional retrospective cohort study

    Iyoshi Shohei, Sumi Asami, Yoshihara Masato, Kitami Kazuhisa, Mogi Kazumasa, Uno Kaname, Fujimoto Hiroki, Miyamoto Emiri, Tano Sho, Yoshikawa Nobuhisa, Emoto Ryo, Matsui Shigeyuki, Kajiyama Hiroaki

    OBESITY   30 巻 ( 8 ) 頁: 1599 - 1607   2022年8月

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    記述言語:英語   出版者・発行元:Obesity  

    Objective: The clinical significance of a higher BMI on the prognosis of ovarian cancer remains controversial; therefore, a more detailed analysis is demanded. This study investigated the impact of BMI on peritoneum-specific recurrence to clarify the involvement of adipose tissue in the proliferation of cancer cells at sites of peritoneal dissemination. Methods: Among 4,730 patients with malignant ovarian tumors, 280 diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IIIC epithelial ovarian cancer and who underwent complete resection in the primary surgery were included in the present study. Results: There were 42, 201, and 37 women in the low, normal, and high BMI groups, respectively. Peritoneum-specific recurrence-free survival and overall survival were both significantly shorter in patients with a high BMI than in those with a normal BMI (p = 0.028 and 0.018, respectively). No significant differences were observed in the distribution of sites of recurrence between these two groups. A multivariate analysis identified obesity as an independent prognostic factor in addition to pT3 tumor staging and positive ascites cytology. Conclusions: Patients with a high BMI had a significantly worse prognosis than those with a normal BMI, and peritoneal adipose tissue may have contributed to this difference.

    DOI: 10.1002/oby.23497

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  12. Survival benefits of retroperitoneal lymphadenectomy for optimally-resected advanced ovarian high-grade serous carcinoma: a multi-institutional retrospective study

    Ikeda Yoshiki, Yoshihara Masato, Tamauchi Satoshi, Yokoi Akira, Yoshikawa Nobuhisa, Kajiyama Hiroaki

    JOURNAL OF GYNECOLOGIC ONCOLOGY   33 巻 ( 4 ) 頁: e40   2022年7月

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    記述言語:英語   出版者・発行元:Journal of Gynecologic Oncology  

    Objective: The survival benefits of retroperitoneal lymphadenectomy (RLNA) for epithelial ovarian cancer (EOC) remain controversial because clinical behaviors differ among subtypes. The purpose of the present study was to clarify whether RLNA increases the survival rate of advanced high-grade serous carcinoma (HGSC). Methods: This was a retrospective cohort analysis of 3,227 patients with EOC treated between 1986 and 2017 at 14 institutions. Among them, 335 patients with stage IIB-IV HGSC who underwent optimal cytoreduction (residual tumor of <1 cm) were included. Patients were divided into the RLNA group (n=170) and non-RLNA group (n=165). All pathological slides were assessed based on a central pathological review. Oncologic outcomes were compared between the two groups in the original and weighted cohorts adjusted with the inverse probability of treatment weighting. Results: The median observation period was 49.8 (0.5–241.5) months. Overall, 219 (65%) out of 335 patients had recurrence or progression, while 146 (44%) died of the disease. In the original cohort, RLNA was a significant prognostic factor for longer progression-free survival (PFS) (hazard ratio [HR]=0.741; 95% confidence interval [CI]=0.558–0.985) and overall survival (OS) (HR=0.652; 95% CI=0.459–0.927). In the weighted cohort in which all variables were well balanced as standardized differences decreased, RLNA was also a significant prognostic factor for more favorable oncologic outcomes (PFS, adjusted HR=0.742; 95% CI=0.613–0.899) and OS, adjusted HR=0.620; 95% CI=0.488–0.787). Conclusion: The present study demonstrated that RLNA for stage III-IV HGSC with no residual tumor after primary debulking surgery contributed to better oncologic outcomes.

    DOI: 10.3802/jgo.2022.33.e40

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  13. Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of the TGF-beta 1/thrombospondin-1 axis

    Kitami Kazuhisa, Yoshihara Masato, Tamauchi Satoshi, Sugiyama Mai, Koya Yoshihiro, Yamakita Yoshihiko, Fujimoto Hiroki, Iyoshi Shohei, Uno Kaname, Mogi Kazumasa, Ikeda Yoshiki, Yokoi Akira, Yoshikawa Nobuhisa, Nishino Kimihiro, Niimi Kaoru, Nawa Akihiro, Enomoto Atsushi, Kajiyama Hiroaki

    MATRIX BIOLOGY   109 巻   頁: 70 - 90   2022年5月

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    記述言語:英語   出版者・発行元:Matrix Biology  

    Ovarian cancer (OvCa), a lethal gynecological malignancy, disseminates to the peritoneum. Mesothelial cells (MCs) act as barriers in the abdominal cavity, preventing the adhesion of cancer cells. However, in patients with OvCa, they are transformed into cancer-associated mesothelial cells (CAMs) via mesenchymal transition and form a favorable microenvironment for tumors to promote metastasis. However, attempts for restoring CAMs to their original state have been limited. Here, we investigated whether inhibition of mesenchymal transition and restoration of MCs by vitamin D suppressed the OvCa dissemination in vitro and in vivo. The effect of vitamin D on the mutual association of MCs and OvCa cells was evaluated using in vitro coculture models and in vivo using a xenograft model. Vitamin D restored the CAMs, and thrombospondin-1 (component of the extracellular matrix that is clinically associated with poor prognosis and is highly expressed in peritoneally metastasized OvCa) was found to promote OvCa cell adhesion and proliferation. Mechanistically, TGF-β1 secreted from OvCa cells enhanced thrombospondin-1 expression in CAMs via Smad-dependent TGF-β signaling. Vitamin D inhibited mesenchymal transition in MCs and suppressed thrombospondin-1 expression via vitamin D receptor/Smad3 competition, contributing to the marked reduction in peritoneal dissemination in vivo. Importantly, vitamin D restored CAMs from a stabilized mesenchymal state to the epithelial state and normalized thrombospondin-1 expression in preclinical models that mimic cancerous peritonitis in vivo. MCs are key players in OvCa dissemination and peritoneal restoration and normalization of thrombospondin-1 expression by vitamin D may be a novel strategy for preventing OvCa dissemination.

    DOI: 10.1016/j.matbio.2022.03.003

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  14. Is cystectomy an option as conservative surgery for young patients with borderline ovarian tumor? A multi-institutional retrospective study

    Ikeda Yoshiki, Yoshihara Masato, Yoshikawa Nobuhisa, Tamauchi Satoshi, Yokoi Akira, Nishino Kimihiro, Niimi Kaoru, Kajiyama Hiroaki

    INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS   157 巻 ( 2 ) 頁: 437 - 443   2022年5月

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    記述言語:英語   出版者・発行元:International Journal of Gynecology and Obstetrics  

    Objective: To investigate the impact of cystectomy for borderline ovarian tumor (BOT) on tumor recurrence compared with salpingo-oophorectomy using inverse probability of treatment weighting (IPTW). Methods: A central pathologic review and a search of the medical records from 14 collaborating institutions from 1986 to 2017 identified 4708 women with a malignant ovarian neoplasm. Data for young women with Stage I BOT were extracted. To compare recurrence-free survival between the surgery groups, Cox regression analyses and the IPTW-adjusted Kaplan-Meier method were employed. Results: During a median follow-up of 62.0 (1.2–270.4) months, 10 of the 285 patients identified (3.5%) developed recurrence. In multivariate analysis, the practice of cystectomy was not a significant prognostic indicator of recurrence-free survival (hazard ratio [95% confidence interval] 1.276 [0.150–10.864]; P = 0.823). In the IPTW-adjusted cohort, the 5-year recurrence-free survival rates were 95.8% and 96.0% in patients receiving cystectomy and salpingo-oophorectomy, respectively (P = 0.378). Conclusion: If patients are selected appropriately, cystectomy in itself may not increase tumor recurrence in young women with early-stage BOT. A large-scale prospective clinical study is necessary to validate this finding.

    DOI: 10.1002/ijgo.13844

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  15. Metastatic Voyage of Ovarian Cancer Cells in Ascites with the Assistance of Various Cellular Components

    Uno Kaname, Iyoshi Shohei, Yoshihara Masato, Kitami Kazuhisa, Mogi Kazumasa, Fujimoto Hiroki, Sugiyama Mai, Koya Yoshihiro, Yamakita Yoshihiko, Nawa Akihiro, Kanayama Tomohiro, Tomita Hiroyuki, Enomoto Atsushi, Kajiyama Hiroaki

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   23 巻 ( 8 )   2022年4月

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    記述言語:英語   出版者・発行元:International Journal of Molecular Sciences  

    Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and has a unique metastatic route using ascites, known as the transcoelomic root. However, studies on ascites and contained cellular components have not yet been sufficiently clarified. In this review, we focus on the significance of accumulating ascites, contained EOC cells in the form of spheroids, and interaction with non-malignant host cells. To become resistant against anoikis, EOC cells form spheroids in ascites, where epithelial-to-mesenchymal transition stimulated by transforming growth factor-β can be a key pathway. As spheroids form, EOC cells are also gaining the ability to attach and invade the peritoneum to induce intraperitoneal metastasis, as well as resistance to conventional chemotherapy. Recently, accumulating evidence suggests that EOC spheroids in ascites are composed of not only cancer cells, but also non-malignant cells existing with higher abundance than EOC cells in ascites, including macrophages, mesothelial cells, and lymphocytes. Moreover, hetero-cellular spheroids are demonstrated to form more aggregated spheroids and have higher adhesion ability for the mesothelial layer. To improve the poor prognosis, we need to elucidate the mechanisms of spheroid formation and interactions with non-malignant cells in ascites that are a unique tumor microenvironment for EOC.

    DOI: 10.3390/ijms23084383

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  16. Crosstalk between foetal vasoactive peptide hormones and placental aminopeptidases regulates placental blood flow: Its significance in preeclampsia

    Yoshihara Masato, Mizutani Shigehiko, Matsumoto Kunio, Kato Yukio, Masuo Yusuke, Tano Sho, Mizutani Hidesuke, Kotani Tomomi, Mizutani Eita, Shibata Kiyosumi, Kajiyama Hiroaki

    PLACENTA   121 巻   頁: 32 - 39   2022年4月

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    記述言語:英語   出版者・発行元:Placenta  

    In pregnancy, placental circulation occurs through two independent circulation systems: foetoplacental and uterine (spiral artery)-placental lake. Crosstalk between the foetal peptide hormones, angiotensin II (A-II) and vasopressin (AVP), and their degrading placental aminopeptidases (APs), aminopeptidase A for A-II and placental leucine aminopeptidase for both AVP and oxytocin, primarily regulate placental circulation. On the other hand, placental circulation represents an arteriovenous shunt. In normal pregnancy, the blood pressure decreases, despite increased cardiac output and plasma volume, probably due to the arteriovenous shunt in the growing placenta. Actually, the foetal vasoactive hormones in the foetoplacental circulation are much higher than those in the maternal circulation throughout pregnancy. In normal pregnancy, AP activity derived from the placenta in maternal blood increases with gestation and placental growth. Foetal hypoxia increases the secretion of foetal both AVP and A-II. Although there is an increase in both AP activities in the maternal blood in normal pregnancy, their activities increase more than those in normal pregnancy during mild preeclampsia. However, both AP activities decline significantly compared than those in severe preeclampsia. This suggests that AP prevents leakage of increased foetal vasoactive hormones into the maternal blood in mild preeclampsia, and its protective role breaks down in severe preeclampsia, leading to a massive leak of the hormones into maternal circulation and consequent marked contraction of both the maternal vessels and the uterus. Consequently, AP activity in both placenta and maternal blood acts as the foeto-maternal barrier for foetal vasoactive hormones and thus contributes to the onset of preeclampsia.

    DOI: 10.1016/j.placenta.2022.02.016

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  17. Annual Body Mass Index Gain and Risk of Gestational Diabetes Mellitus in a Subsequent Pregnancy

    Tano Sho, Kotani Tomomi, Ushida Takafumi, Yoshihara Masato, Imai Kenji, Nakano-Kobayashi Tomoko, Moriyama Yoshinori, Iitani Yukako, Kinoshita Fumie, Yoshida Shigeru, Yamashita Mamoru, Kishigami Yasuyuki, Oguchi Hidenori, Kajiyama Hiroaki

    FRONTIERS IN ENDOCRINOLOGY   13 巻   頁: 815390   2022年3月

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    記述言語:英語   出版者・発行元:Frontiers in Endocrinology  

    Introduction: Weight change during the interpregnancy is related to gestational diabetes mellitus (GDM) in the subsequent pregnancy. In interpregnancy care/counseling, the timeframe for goal setting is important, while the timing of the next conception is unpredictable and preventing age-related body weight gain is difficult. This study aimed to investigate the association between annual weight gain during the interpregnancy, which provide clearer timeframe, and GDM in subsequent pregnancies. Methods: This multicenter retrospective study was conducted by collecting data on two pregnancies of the same women in 2009–2019. The association between annual BMI gain and GDM during the subsequent pregnancy was examined. Results: This study included 1,640 pregnant women. A history of GDM [adjusted odds ratio (aOR), 26.22; 95% confidence interval (CI), 14.93–46.07] and annual BMI gain (aOR, 1.48; 95% CI, 1.22–1.81) were related to GDM during the subsequent pregnancy. In the women with a pre-pregnant BMI of <25.0 kg/m2 and without GDM during the index pregnancy, an annual BMI gain of ≥0.6 kg/m2/year during the interpregnancy were associated with GDM in subsequent pregnancies; however, in the other subgroups, it was not associated with GDM in subsequent pregnancies. Conclusions: For women with a pre-pregnant BMI of <25.0 kg/m2 and without GDM during the index pregnancy, maintaining an annual BMI gain of <0.6 kg/m2/year may prevent GDM during the subsequent pregnancy.

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  18. Is adjuvant chemotherapy necessary for young women with early-stage epithelial ovarian cancer who have undergone fertility-sparing surgery?: a multicenter retrospective analysis

    Ikeda Yoshiki, Yoshihara Masato, Yoshikawa Nobuhisa, Yokoi Akira, Tamauchi Satoshi, Nishino Kimihiro, Niimi Kaoru, Kajiyama Hiroaki

    BMC WOMENS HEALTH   22 巻 ( 1 ) 頁: 80   2022年3月

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    記述言語:英語   出版者・発行元:BMC Women's Health  

    Objective: In young patients with early-stage epithelial ovarian carcinoma (EOC) who were received fertility-sparing surgery (FSS), the role of adjuvant chemotherapy is unclear. Here, we performed a multicenter study using inverse probability of treatment weighting (IPTW) to explore the effect of chemotherapy on patients’ survival. Methods: Between 1987 and 2015, a retrospective study was carried out, including 1183 patients with stage I EOC. Among them, a total of 101 women with stage I EOC who underwent FSS were investigated, including 64 and 37 patients with or without adjuvant chemotherapy, respectively. Oncologic outcomes were compared between the two arms using original and IPTW cohorts. Results: During 62.6 months (median) of follow-up, recurrence was noted in 11 (17.2%) women in the chemotherapy arm and 6 (16.2%) patients in the observation arm. In the unweighted cohort, the 5-year overall and recurrence-free survival (OS/RFS) rates of chemotherapy and observation arms were 86.3/80.8 and 90.2/79.8%, respectively. There was no significant difference between the two groups {Log-rank: P = 0.649 (OS)/P = 0.894 (RFS)}. In the IPTW cohort after adjusting for various clinicopathologic covariates, we also failed to identify a difference in RFS/OS between the two groups {RFS (chemotherapy vs. observation), HR: 0.501 (95% CI 0.234–1.072), P = 0.075: OS (chemotherapy vs. observation), HR: 0.939 (95% CI 0.330–2.669), P = 0.905}. Conclusions: Even after adjusting clinicopathologic covariates, performing adjuvant chemotherapy may not improve the oncologic outcome in young patients who have undergone FSS.

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  19. Significance of platinum distribution to predict platinum resistance in ovarian cancer after platinum treatment in neoadjuvant chemotherapy

    Uno Kaname, Yoshikawa Nobuhisa, Tazaki Akira, Ohnuma Shoko, Kitami Kazuhisa, Iyoshi Shohei, Mogi Kazumasa, Yoshihara Masato, Koya Yoshihiro, Sugiyama Mai, Tamauchi Satoshi, Ikeda Yoshiki, Yokoi Akira, Kikkawa Fumitaka, Kato Masashi, Kajiyama Hiroaki

    SCIENTIFIC REPORTS   12 巻 ( 1 ) 頁: 4513   2022年3月

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    記述言語:英語   出版者・発行元:Scientific Reports  

    Most patients with ovarian cancer experience recurrence and develop resistance to platinum-based agents. The diagnosis of platinum resistance based on the platinum-free interval is not always accurate and timely in clinical settings. Herein, we used laser ablation inductively coupled plasma mass spectrometry to visualize the platinum distribution in the ovarian cancer tissues at the time of interval debulking surgery after neoadjuvant chemotherapy in 27patients with advanced high-grade serous ovarian cancer. Two distinct patterns of platinum distribution were observed. Type A (n = 16): platinum accumulation at the adjacent stroma but little in the tumor; type B (n = 11): even distribution of platinum throughout the tumor and adjacent stroma. The type A patients treated post-surgery with platinum-based adjuvant chemotherapy showed significantly shorter periods of recurrence after the last platinum-based chemotherapy session (p = 0.020) and were diagnosed with “platinum-resistant recurrence”. Moreover, type A was significantly correlated with worse prognosis (p = 0.031). Post-surgery treatment with non-platinum-based chemotherapy could be effective for the patients classified as type A. Our findings indicate that the platinum resistance can be predicted prior to recurrence, based on the platinum distribution; this could contribute to the selection of more appropriate adjuvant chemotherapy, which may lead to improves prognoses.

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  20. Adjuvant taxane plus platinum chemotherapy for stage I ovarian clear cell carcinoma with complete surgical staging: are more than three cycles necessary?

    Ukai Mayu, Suzuki Shiro, Yoshihara Masato, Yokoi Akira, Yoshikawa Nobuhisa, Kajiyama Hiroaki, Kikkawa Fumitaka

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   27 巻 ( 3 ) 頁: 609 - 618   2022年3月

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    記述言語:英語   出版者・発行元:International Journal of Clinical Oncology  

    Background: Previous studies on adjuvant chemotherapy for patients with ovarian clear cell carcinoma (OCCC) have included a limited number of Asian patients with surgical stage I OCCC, despite differences in OCCC survival by race and stage. The aim of this study was to estimate the survival effect of the number of cycles of adjuvant taxane plus carboplatin chemotherapy in Asian patients with surgical stage I OCCC. Methods: We retrospectively identified 227 patients with surgical stage I OCCC at 14 institutions from 1995 to 2017. Kaplan–Meier analysis and Cox proportional hazard regression with inverse probability of treatment weighting (IPTW) adjustment were performed to evaluate overall survival (OS) and recurrence-free survival (RFS) in patients receiving ≤ 3 and 4–6 cycles of taxane plus platinum adjuvant chemotherapy. Results: Eighty-nine and 138 patients received ≤ 3 and 4–6 cycles of adjuvant chemotherapy, respectively. There was no between-group difference in OS or RFS with or without IPTW adjustment. In Cox proportional hazards analysis, 4–6 cycles of adjuvant chemotherapy were not associated with improved OS (HR 1.090; 95% CI 0.518–2.291; p = 0.821) or RFS (HR 1.144; 95% CI 0.619–2.114; p = 0.669) compared to ≤ 3 cycles, even with IPTW adjustment. Subgroup analysis in different substages of stage I OCCC showed that the number of cycles of adjuvant chemotherapy had no impact on OS or RFS. Conclusion: Three or fewer cycles of taxane plus carboplatin chemotherapy may be a reasonable treatment regime for patients with surgical staging I OCCC.

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  21. Factors associated with response to compression-based physical therapy for secondary lower limb lymphedema after gynecologic cancer treatment: a multicenter retrospective study

    Yoshihara Masato, Kitamura Kaoru, Tsuru Satoko, Shimono Ryoko, Sakuda Hiromi, Mayama Michinori, Tano Sho, Uno Kaname, Ukai Mayu Ohno, Kishigami Yasuyuki, Oguchi Hidenori, Hirota Akio

    BMC CANCER   22 巻 ( 1 ) 頁: 25   2022年1月

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    記述言語:英語   出版者・発行元:BMC Cancer  

    Background: Lower limb lymphedema (LLL) is one of the most refractory and debilitating complications related to gynecological cancer treatment. We investigated factors associated with response to compression-based physical therapy (CPT) for secondary LLL after gynecologic cancer treatment. Methods: We performed a multicenter retrospective study using the records of seven medical institutions from 2002 and 2014. Patients who developed LLL after gynecological cancer treatment were included. Limb volumes were calculated from the lengths of the limb circumferences at four points. All participants underwent compression-based physical therapy for LLL. Factors, including MLD, indicative of circumference reductions in LLL were determined. Results: In total, 1,034 LLL met the required criteria of for the study. A multivariate linear regression analysis identified age; body mass index (BMI); endometrial cancer; radiotherapy; and initial limb circumference as significant independent prognostic factors related to improvement in LLL. In analysis of covariance for improvement in LLL adjusted by the initial limb circumference and stratified by BMI and radiotherapy, patients with BMI 28 kg/m2 or higher and receiving radiation rarely responded to CPT. Conclusions: Improvements in the lower limb circumference correlated with clinical histories and physical characteristics, which may be used as independent prognostic factors for successful CPT for LLL after gynecological cancer treatment.

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  22. Placental Leucine Aminopeptidase as a Potential Specific Urine Biomarker for Invasive Ovarian Cancer

    Matsukawa Tetsuya, Mizutani Shigehiko, Matsumoto Kunio, Kato Yukio, Yoshihara Masato, Kajiyama Hiroaki, Shibata Kiyosumi

    JOURNAL OF CLINICAL MEDICINE   11 巻 ( 1 )   2022年1月

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    記述言語:英語   出版者・発行元:Journal of Clinical Medicine  

    Background: A non-invasive and sensitive biomarker for the detection of ovarian cancer (OvCa) is lacking. We aim to investigate if urinary placental leucine aminopeptidase (P-LAP) can serve as a reliable biomarker for OvCa. Methods: P-LAP activity was measured using a LAP assay kit (Serotech Co., Ltd., Sapporo, Japan) in the urine of 22 patients with benign or borderline malignant ovarian tumors and 18 patients with OvCa. In this assay, L-methionine was added at 20 mM because P-LAP is functional, but other aminopeptidases are inhibited at this dose of L-methionine. Results: The mean urinary P-LAP activity was significantly higher in the OvCa group than in the benign or borderline malignant tumor group. When the cut-off value of P-LAP was determined as 11.00 U/L, its sensitivity and specificity for differentiating invasive cancer were 77.8% and 95.5%, respectively. Conclusion: Although the usefulness of this test should be confirmed in a larger cohort of cases and controls, our study is the first to highlight the importance of urinary P-LAP as a biomarker for OvCa.

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  23. Impact of perioperative use of GnRH agonist or dienogest on ovarian reserve after cystectomy for endometriomas: a randomized controlled trial

    Muraoka Ayako, Osuka Satoko, Yabuki Atsushi, Bayasula, Yoshihara Masato, Tanaka Hideaki, Sonehara Reina, Miyake Natsuki, Murakami Mayuko, Yoshita Sayako, Nakanishi Natsuki, Nakamura Tomoko, Goto Maki, Iwase Akira, Kajiyama Hiroaki

    REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY   19 巻 ( 1 ) 頁: 179   2021年12月

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    記述言語:英語   出版者・発行元:Reproductive Biology and Endocrinology  

    Background: Ovarian endometrioma is a common gynecological disease that is often treated with surgery or hormonal treatment. Ovarian cystectomy, a surgical procedure for ovarian endometrioma, can result in impaired ovarian reserve. Methods: We conducted a randomized controlled trial to evaluate the efficacy of hormonal treatment [gonadotropin-releasing hormone agonist (GnRHa) or dienogest (DNG)] for preserving ovarian reserve after cystectomy for ovarian endometrioma. The primary endpoint was the level of serum Anti-Müllerian hormone (AMH) as a marker of ovarian reserve. Results: Before and after laparoscopic surgery, 22 patients in the GnRHa group and 27 patients in the DNG group were administered hormonal treatment for a total of 4 months. After 1-year follow-up, >60% of the patients in the DNG group retained over 70% of their pretreatment AMH levels, whereas no patient in the GnRHa group retained their AMH levels after cystectomy (P < 0.01). Interleukin-6 (IL-6) is a key cytokine involved in inflammation. Compared with the GnRHa group, patients in the DNG group had lower IL-6 levels at the end of treatment. Conclusions: Our data revealed that DNG is more effective than GnRHa in preserving ovarian reserve after cystectomy of ovarian endometrioma. This is achieved through the reduction of the inflammatory response during the perioperative period and other endometriosis-related inflammatory reactions. Trial registration: The registration number of this trial is UMIN-CTR, UMIN000018569, registered 6 August 2015, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021492, and Japan Registry of Clinical Trials, jRCTs041180140, registered 29 March 2019, https://jrct.niph.go.jp/en-latest-detail/jRCTs041180140. This randomized controlled trial was conducted in accordance with the CONSORT guidelines.

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  24. Clinical effects of cervical conization with positive margins in cervical cancer

    Nagao Yukari, Yokoi Akira, Yoshida Kosuke, Sumi Masanori, Yoshihara Masato, Tamauchi Satoshi, Ikeda Yoshiki, Yoshikawa Nobuhisa, Nishino Kimihiro, Niimi Kaoru, Kajiyama Hiroaki

    SCIENTIFIC REPORTS   11 巻 ( 1 ) 頁: 23288   2021年12月

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    記述言語:英語   出版者・発行元:Scientific Reports  

    Radical surgery after cervical conization is a common approach for the treatment of cervical cancer. In some cases, disease progression is observed after positive margins at conization, but the effect of conization on disease progression remains unclear. Thus, the aim of this study was to investigate the clinical outcomes of positive margins at conization in cervical cancer. A total of 101 patients who underwent cervical conization before radical hysterectomy and pelvic lymph node dissection were considered eligible by reviewing medical records. The association between the positive margins and patient outcomes, including subsequent lymph node metastasis, was evaluated. The rate of lymphovascular space invasion (LVSI) positivity at radical surgery was significantly higher in patients with positive margins (p = 0.017) than in those with negative margins, although there was no significant difference in the rate of pelvic lymph node metastasis (p = 0.155). Moreover, there was no significant difference in the overall survival or progression-free survival between the two groups (p = 0.332 and 0.200, respectively). A positive margin at conization presented no significant prognostic disadvantage; thus, diagnostic conization is one of the most suitable treatment options for early-stage cervical cancer that is difficult to accurately assess.

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  25. Pro-tumoral behavior of omental adipocyte-derived fibroblasts in tumor microenvironment at the metastatic site of ovarian cancer

    Iyoshi Shohei, Yoshihara Masato, Nakamura Kae, Sugiyama Mai, Koya Yoshihiro, Kitami Kazuhisa, Uno Kaname, Mogi Kazumasa, Tano Sho, Tomita Hiroyuki, Kajiwara Keiji, Taki Masayasu, Yamaguchi Shigehiro, Nawa Akihiro, Kajiyama Hiroaki

    INTERNATIONAL JOURNAL OF CANCER   149 巻 ( 11 ) 頁: 1961 - 1972   2021年12月

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    記述言語:英語   出版者・発行元:International Journal of Cancer  

    Adipocyte-rich omentum offers “good soil” for disseminating ovarian cancer (OvCa), contributing to therapeutic difficulty. However, little is understood about the association between adipocytes and tumor growth at peritoneal dissemination site. Herein, we report the induction of adipocyte dedifferentiation by OvCa cells and pro-tumorigenic effects of resulted adipocyte-derived fibroblasts. We confirmed that malignant ascites promoted the dedifferentiation of the primary human adipocytes obtained from surgical omental specimen into omental adipocyte-derived fibroblast (O-ADF) that possess both mesenchymal stem cell and myofibroblast-like features. This promotion of dedifferentiation by malignant ascites was blocked by addition of Wnt signaling inhibitor. The effects of dedifferentiated adipocytes in proliferation and migration of OvCa cells were analyzed with in vitro coculturing experimental models and in vivo mice model, and we demonstrated that OvCa cell lines showed enhanced proliferative characteristics, as well as increased migratory abilities upon coculturing with O-ADF. Additionally, exogenous transforming growth factor-β1 augmented desmoplastic morphological change of O-ADF, leading to higher proliferative ability. Our results suggest that OvCa cells promote dedifferentiation of peritoneal adipocytes by activating Wnt/β-catenin signaling, and generated O-ADFs exhibit pro-tumoral hallmarks.

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  26. Recent Insights into Human Endometrial Peptidases in Blastocyst Implantation via Shedding of Microvesicles

    Yoshihara Masato, Mizutani Shigehiko, Kato Yukio, Matsumoto Kunio, Mizutani Eita, Mizutani Hidesuke, Fujimoto Hiroki, Osuka Satoko, Kajiyama Hiroaki

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   22 巻 ( 24 )   2021年12月

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    記述言語:英語   出版者・発行元:International Journal of Molecular Sciences  

    Blastocyst implantation involves multiple interactions with numerous molecules expressed in endometrial epithelial cells (EECs) during the implantation window; however, there is limited information regarding the molecular mechanism underlying the crosstalk. In blastocysts, fibronectin plays a major role in the adhesion of various types of cells by binding to extracellular matrix proteins via the Arg-Gly-Asp (RGD) motif. In EECs, RGD-recognizing integrins are important bridging receptors for fibronectin, whereas the non-RGD binding of fibronectin includes interactions with dipeptidyl peptidase IV (DPPIV)/cluster of differentiation (CD) 26. Fibronectin may also bind to aminopeptidase N (APN)/CD13, and in the endometrium, these peptidases are present in plasma membranes and lysosomal membranes. Blastocyst implantation is accompanied by lysosome exocytosis, which transports various peptidases and nutrients into the endometrial cavity to facilitate blastocyst implantation. Both DPPIV and APN are released into the uterine cavity via shedding of microvesicles (MVs) from EECs. Recently, extracellular vesicles derived from endometrial cells have been proposed to act on trophectoderm cells to promote implantation. MVs are also secreted from embryonal stem cells and may play an active role in implantation. Thus, crosstalk between the blastocyst and endometrium via extracellular vesicles is a new insight into the fundamental molecular basis of blastocyst implantation.

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  27. Long-term post-recurrence survival outcomes in young women receiving fertility-sparing surgery for epithelial ovarian cancer

    Shigeyama Munehisa, Yoshihara Masato, Kitami Kazuhisa, Mogi Kazumasa, Uno Kaname, Iyoshi Shohei, Tano Sho, Yoshikawa Nobuhisa, Kajiyama Hiroaki

    EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY   267 巻   頁: 221 - 225   2021年12月

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    記述言語:英語   出版者・発行元:European Journal of Obstetrics and Gynecology and Reproductive Biology  

    Objective: The aim of this study was to investigate long-term post-recurrence survival outcomes in young women receiving fertility-sparing surgery (FSS) to verify the feasibility of the limited surgery for epithelial ovarian cancer (OvCa). Study design: We performed a regional multicenter retrospective study from January 1986 and March 2020, using clinical data corrected under the central pathological review system. Patients with recurrent tumor after surgery for stage I epithelial OvCa, aged equal or younger than 45 years were included for this study. We evaluated effect of FSS regarding long-term post-recurrence survival with statistical adjustment of propensity score-based method. Results: With the Kaplan–Meier method, original and adjusted survival curves were estimated for recurrence-after survival of patients with (n = 14) and without FSS (n = 26). Median time to disease-specific death was 18.6 months. In both original and adjusted cohorts, there were no significant difference between the two groups (log rank test; P > 0.05). Hazard ratio of disease-specific death was 1.264 (95% confidence interval, 0.563–2.836; P = 0.570) in original and 1.354 (95% confidence interval, 0.702–2.611; P = 0.366) in adjusted population. This result indicated that patients with FSS was not associated with poorer prognosis for recurrence-after survival than those without. When comparing patients not receiving FSS, patients receiving FSS with recurrence at spared ovary followed not significantly different survival outcome as well as those with extra-ovarian recurrence. Conclusion: There was no significant difference of long-term post-recurrence survival outcomes between patients of epithelial OvCa with and without FSS in young women of reproductive age.

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  28. Annual body mass index gain and risk of hypertensive disorders of pregnancy in a subsequent pregnancy

    Tano Sho, Kotani Tomomi, Ushida Takafumi, Yoshihara Masato, Imai Kenji, Nakano-Kobayashi Tomoko, Moriyama Yoshinori, Iitani Yukako, Kinoshita Fumie, Yoshida Shigeru, Yamashita Mamoru, Kishigami Yasuyuki, Oguchi Hidenori, Kajiyama Hiroaki

    SCIENTIFIC REPORTS   11 巻 ( 1 ) 頁: 22519   2021年11月

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    記述言語:英語   出版者・発行元:Scientific Reports  

    Weight gain during interpregnancy period is related to hypertensive disorders of pregnancy (HDP). However, in interpregnancy care/counseling, the unpredictability of the timing of the next conception and the difficulties in preventing age-related body weight gain must be considered while setting weight management goals. Therefore, we suggest considering the annual change in the body mass index (BMI). This study aimed to clarify the association between annual BMI changes during the interpregnancy period and HDP risk in subsequent pregnancies. A multicenter retrospective study of data from 2009 to 2019 examined the adjusted odds ratio (aOR) of HDP in subsequent pregnancies. The aORs in several annual BMI change categories were also calculated in the subgroups classified by HDP occurrence in the index pregnancy. This study included 1,746 pregnant women. A history of HDP (aOR, 16.76; 95% confidence interval [CI], 9.62 − 29.22), and annual BMI gain (aOR, 2.30; 95% CI, 1.76 − 3.01) were independent risk factors for HDP in subsequent pregnancies. An annual BMI increase of ≥ 1.0 kg/m2/year was related to HDP development in subsequent pregnancies for women without a history of HDP. This study provides data as a basis for interpregnancy care/counseling, but further research is necessary to validate our findings and confirm this relationship.

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  29. Heat Shock Protein 105 as an Immunotherapeutic Target for Patients With Cervical Cancer

    Nosaka Kazuto, Suzuki Shiro, Yoshikawa Toshiaki, Shimomura Manami, Kitami Kazuhisa, Yoshida Kosuke, Yoshihara Masato, Kikkawa Fumitaka, Nakatsura Tetsuya, Kajiyama Hiroaki

    ANTICANCER RESEARCH   41 巻 ( 10 ) 頁: 4741 - 4751   2021年10月

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    記述言語:英語   出版者・発行元:Anticancer Research  

    Background/Aim: Heat shock protein 105 (HSP105) is overexpressed in various cancers, but not in normal tissues. We investigated the expression levels of HSP105 in cervical cancer and the efficacy of immunotherapy targeting HSP105. Materials and Methods: Previously, we established human leukocyte antigen-A∗02:01 (HLA-A2) restricted HSP105 peptide-specific cytotoxic T lymphocyte (CTL) clones from a colorectal cancer patient vaccinated with an HSP105 peptide. Herein, we evaluated the expression of HSP105 in cervical cancer and cervical intraepithelial neoplasia. Moreover, we tested the effectiveness of an HLAA2-restricted HSP105 peptide-specific CTL clone against cervical cancer cell lines. Results: HSP105 was expressed in 95% (19/20) of examined cervical cancer tissues. Moreover, the HSP105 peptide-specific CTL clone recognized HSP105- and HLA-A∗02:01-positive cervical cancer cell lines and also showed that cytotoxicity against the cervical cancer cell lines depends on HSP105 peptide and HLA class I restricted manners. Conclusion: HSP105 could be an effective target for immunotherapy in patients with cervical cancer.

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  30. Impact of incomplete surgery and adjuvant chemotherapy for the intraoperative rupture of capsulated stage I epithelial ovarian cancer: a multi-institutional study with an in-depth subgroup analysis

    Yoshihara Masato, Tamauchi Satoshi, Iyoshi Shohei, Kitami Kazuhisa, Uno Kaname, Mogi Kazumasa, Kajiyama Hiroaki

    JOURNAL OF GYNECOLOGIC ONCOLOGY   32 巻 ( 5 ) 頁: e66   2021年9月

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    記述言語:英語   出版者・発行元:Journal of gynecologic oncology  

    OBJECTIVE: The aim of the present study was to examine the effects of incomplete surgery and adjuvant chemotherapy on the prognosis of patients with intraoperative rupture of capsulated stage I epithelial ovarian cancer (OvCa). METHODS: A regional retrospective study was conducted between 1986 and 2019. Among 4,730 patients with malignant ovarian tumors, 534 women with International Federation of Gynecology and Obstetrics stage IA and IC1 epithelial OvCa were eligible. Differences in survival outcomes were examined between patients with stage IA and IC1 tumors and the effects of uterine preservation, complete-staging lymphadenectomy, and adjuvant chemotherapy were investigated by an in-depth subgroup analysis. To analyze therapeutic effects, baseline imbalances were adjusted using propensity score (PS). RESULTS: The prognosis of patients with stage IC1 tumors was worse than those with stage IA. Surgical spill did not affect the site of recurrence. In the PS-adjusted subgroup analysis, uterine preservation (hazard ratio [HR]=1.669; 95% confidence interval [CI]=1.052-2.744), incomplete-staging lymphadenectomy (HR=1.689; 95% CI=1.211-2.355), and the omission of adjuvant chemotherapy (HR=3.729; 95% CI=2.090-6.653) significantly increased the HR of recurrence for patients with stage IC1 tumors compared to those with stage IA tumors. Adjuvant chemotherapy decreased the impact of rupture with uterine preservation (HR=0.159; 95% CI=0.230-1.168) or incomplete-staging lymphadenectomy (HR=0.987; 95% CI=0.638-1.527). CONCLUSION: The present results suggest intraoperative rupture of capsulated stage I epithelial OvCa is associated with a poor prognosis. When chemotherapy is given for patients receiving incomplete surgery, there is no longer an increased risk of recurrence observed with the rupture.

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  31. A large-scale multi-institutional study evaluating prognostic aspects of positive ascites cytology and effects of therapeutic interventions in epithelial ovarian cancer

    Yoshihara Masato, Emoto Ryo, Kitami Kazuhisa, Iyoshi Shohei, Uno Kaname, Mogi Kazumasa, Tano Sho, Yoshikawa Nobuhisa, Matsui Shigeyuki, Kajiyama Hiroaki

    SCIENTIFIC REPORTS   11 巻 ( 1 ) 頁: 15154   2021年7月

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    記述言語:英語   出版者・発行元:Scientific Reports  

    Positive ascites cytology is a strong prognostic factor in patients with early-stage ovarian cancer (OvCa). However, limited information is currently available on the impact of positive ascites cytology on patient prognoses under each clinical background. We herein investigated the comprehensive impact of positive ascites cytology on patients with epithelial OvCa and the effectiveness of additional therapeutic interventions, including complete staging surgery and chemotherapy. Among 4730 patients with malignant ovarian neoplasms, retrospectively identified in multiple institutions, 1906 with epithelial OvCa were included. In the investigation of its effects on clinical factors using a multivariate analysis, positive ascites cytology correlated with a poor prognosis. Positive ascites cytology had a significantly worse prognosis than those with negative cytology in all subgroups except for patients with stage IV tumors and a mucinous histology. Chemotherapy may be effective in reducing the negative impact of positive ascites cytology on the prognosis of patients in terms of progression-free and overall survivals, while complete staging surgery did not improve the prognosis of patients with positive ascites cytology. Collectively, our findings suggested that positive ascites cytology had a negative impact on the prognosis of patients with epithelial OvCa, but not those with stage IV tumors or a mucinous histology.

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  32. Significance of Concurrent Chemoradiotherapy as Primary Treatment in Patients with Metastatic Cervical Cancer.

    Hattori S, Yoshikawa N, Mogi K, Yoshida K, Yoshihara M, Tamauchi S, Ikeda Y, Yokoi A, Nishino K, Niimi K, Suzuki S, Kajiyama H

    Current oncology (Toronto, Ont.)   28 巻 ( 3 ) 頁: 1663 - 1672   2021年4月

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    記述言語:英語   出版者・発行元:Current Oncology  

    DOI: 10.3390/curroncol28030155

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  33. Does complete-staging lymphadenectomy improve survival outcomes in stage I endometrioid epithelial ovarian carcinoma? A multi-institutional retrospective study with propensity score-weighted analysis

    Yoshihara Masato, Tamauchi Satoshi, Iyoshi Shohei, Kitami Kazuhisa, Uno Kaname, Tano Sho, Matsui Shigeyuki, Kajiyama Hiroaki

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   51 巻 ( 3 ) 頁: 387 - 392   2021年3月

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    記述言語:日本語   出版者・発行元:Japanese Journal of Clinical Oncology  

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  34. Ovarian Cancer-Associated Mesothelial Cells: Transdifferentiation to Minions of Cancer and Orchestrate Developing Peritoneal Dissemination

    Mogi Kazumasa, Yoshihara Masato, Iyoshi Shohei, Kitami Kazuhisa, Uno Kaname, Tano Sho, Koya Yoshihiro, Sugiyama Mai, Yamakita Yoshihiko, Nawa Akihiro, Tomita Hiroyuki, Kajiyama Hiroaki

    CANCERS   13 巻 ( 6 ) 頁: 1 - 13   2021年3月

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    記述言語:日本語   出版者・発行元:Cancers  

    DOI: 10.3390/cancers13061352

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  35. Relationship between vaginal group B streptococcus colonization in the early stage of pregnancy and preterm birth: a retrospective cohort study

    Tano Sho, Ueno Takuji, Mayama Michinori, Yamada Takuma, Takeda Takehiko, Uno Kaname, Yoshihara Masato, Ukai Mayu, Suzuki Teppei, Kishigami Yasuyuki, Oguchi Hidenori

    BMC PREGNANCY AND CHILDBIRTH   21 巻 ( 1 ) 頁: 141   2021年2月

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    記述言語:日本語   出版者・発行元:BMC Pregnancy and Childbirth  

    DOI: 10.1186/s12884-021-03624-9

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  36. Establishment of a patient-derived xenograft model and cell line of malignant transformation of mature cystic teratoma of the ovary

    Tamauchi Satoshi, Suzuki Shiro, Xuboya Chang, Yoshihara Masato, Yoshida Kosuke, Ikeda Yoshiki, Yoshikawa Nobuhisa, Kajiyama Hiroaki, Kikkawa Fumitaka

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   47 巻 ( 2 ) 頁: 713 - 719   2021年2月

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    記述言語:日本語   出版者・発行元:Journal of Obstetrics and Gynaecology Research  

    DOI: 10.1111/jog.14596

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  37. Reduced response to controlled ovarian stimulation after radical trachelectomy: A pitfall of fertility-sparing surgery for cervical cancer

    Tamauchi Satoshi, Kajiyama Hiroaki, Osuka Satoko, Moriyama Yoshinori, Yoshihara Masato, Kikkawa Fumitaka

    INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS   154 巻 ( 1 ) 頁: 162 - 168   2021年1月

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    記述言語:日本語   出版者・発行元:International Journal of Gynecology and Obstetrics  

    DOI: 10.1002/ijgo.13529

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  38. Streptococcal toxic shock syndrome induced by group a streptococcus with the emm28 genotype that developed after a uterine cancer test

    Yamaba Y., Takakuwa O., Ida C., Saito M., Kawae D., Yoshihara M., Kunii E., Imaeda K., Tatsuno I., Hasegawa T., Akita K.

    Internal Medicine   60 巻 ( 21 ) 頁: 3481 - 3483   2021年

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    出版者・発行元:Internal Medicine  

    A 69-year-old woman without pre-existing disease visited our hospital due to general malaise, diarrhea, and arthralgia 3 days after a uterine cancer test. We diagnosed her with sepsis of unknown focus and started treatment immediately, but she died 20 hours after the first visit due to multi-organ failure and septic shock. Later, group A streptococcus was detected from the blood culture, and streptococcal toxic shock syndrome (STSS) was diagnosed. The strain had the emm28 genotype and a mutation in csrR with increased NADase activity. These virulence factors were considered to be related to STSS development in this patient.

    DOI: 10.2169/internalmedicine.6290-20

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  39. Microphthalmia-Associated Transcription Factor-Dependent Melanoma Cell Adhesion Molecule Activation Promotes Peritoneal Metastasis of Ovarian Cancer

    Kitami Kazuhisa, Yoshihara Masato, Koya Yoshihiro, Sugiyama Mai, Iyoshi Shohei, Uno Kaname, Mogi Kazumasa, Tano Sho, Fujimoto Hiroki, Nawa Akihiro, Kikkawa Fumitaka, Kajiyama Hiroaki

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   21 巻 ( 24 ) 頁: 1 - 15   2020年12月

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    記述言語:日本語   出版者・発行元:International Journal of Molecular Sciences  

    DOI: 10.3390/ijms21249776

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  40. Does uterine preservation affect survival outcomes of patients with stage I ovarian sex cord-stromal cell tumours? A multi-institutional study

    Yoshihara Masato, Tamauchi Satoshi, Iyoshi Shohei, Kitami Kazuhisa, Uno Kaname, Yoshikawa Nobuhisa, Ikeda Yoshiki, Kawai Michiyasu, Nagasaka Tetsuro, Kajiyama Hiroaki

    EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY   254 巻   頁: 52 - 56   2020年11月

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    記述言語:日本語   出版者・発行元:European Journal of Obstetrics and Gynecology and Reproductive Biology  

    DOI: 10.1016/j.ejogrb.2020.09.009

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  41. Adjusted multiple gases in the plasma flow induce differential antitumor potentials of plasma-activated solutions

    Nakamura Kae, Yoshikawa Nobuhisa, Yoshihara Masato, Ikeda Yoshiki, Higashida Akihiro, Niwa Akihiro, Jindo Takahiro, Tanaka Hiromasa, Ishikawa Kenji, Mizuno Masaaki, Toyokuni Shinya, Hori Masaru, Kikkawa Fumitaka, Kajiyama Hiroaki

    PLASMA PROCESSES AND POLYMERS   17 巻 ( 10 )   2020年10月

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    記述言語:日本語   出版者・発行元:Plasma Processes and Polymers  

    DOI: 10.1002/ppap.201900259

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  42. Follicular dendritic cell sarcoma of the uterine cervix: a case report

    Nakamura Takuto, Yoshihara Masato, Tamauchi Satoshi, Kajiyama Hiroaki, Kikkawa Fumitaka

    BMC WOMENS HEALTH   20 巻 ( 1 ) 頁: 182   2020年8月

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    記述言語:日本語   出版者・発行元:BMC Women's Health  

    DOI: 10.1186/s12905-020-01045-y

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  43. Impact of uterus-preserving surgery on Stage I primary mucinous epithelial ovarian carcinoma: A multi-institutional study with propensity score-weighted analysis

    Yoshihara Masato, Kajiyama Hiroaki, Tamauchi Satoshi, Iyoshi Shohei, Yokoi Akira, Suzuki Shiro, Kawai Michiyasu, Nagasaka Tetsuro, Takahashi Kunihiko, Matsui Shigeyuki, Kikkawa Fumitaka

    INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS   150 巻 ( 2 ) 頁: 177 - 183   2020年8月

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    記述言語:日本語   出版者・発行元:International Journal of Gynecology and Obstetrics  

    DOI: 10.1002/ijgo.13244

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  44. Filopodia play an important role in the trans-mesothelial migration of ovarian cancer cells

    Yoshihara Masato, Yamakita Yoshihiko, Kajiyama Hiroaki, Senga Takeshi, Koya Yoshihiro, Yamashita Mamoru, Nawa Akihiro, Kikkawa Fumitaka

    EXPERIMENTAL CELL RESEARCH   392 巻 ( 2 ) 頁: 112011   2020年7月

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    記述言語:日本語   出版者・発行元:Experimental Cell Research  

    DOI: 10.1016/j.yexcr.2020.112011

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  45. Risk factors for late-onset lower limb lymphedema after gynecological cancer treatment: A multi-institutional retrospective study

    Yoshihara Masato, Shimono Ryoko, Tsuru Satoko, Kitamura Kaoru, Sakuda Hiromi, Oguchi Hidenori, Hirota Akio

    EJSO   46 巻 ( 7 ) 頁: 1334 - 1338   2020年7月

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    記述言語:日本語   出版者・発行元:European Journal of Surgical Oncology  

    DOI: 10.1016/j.ejso.2020.01.033

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  46. Ovarian cancer-associated mesothelial cells induce acquired platinum-resistance in peritoneal metastasis via the FN1/Akt signaling pathway

    Yoshihara Masato, Kajiyama Hiroaki, Yokoi Akira, Sugiyama Mai, Koya Yoshihiro, Yamakita Yoshihiko, Liu Wenting, Nakamura Kae, Moriyama Yoshinori, Yasui Hiroaki, Suzuki Shiro, Yamamoto Yusuke, Ricciardelli Carmela, Nawa Akihiro, Shibata Kiyosumi, Kikkawa Fumitaka

    INTERNATIONAL JOURNAL OF CANCER   146 巻 ( 8 ) 頁: 2268 - 2280   2020年4月

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    記述言語:日本語   出版者・発行元:International Journal of Cancer  

    DOI: 10.1002/ijc.32854

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  47. Is standard radical surgery necessary for elderly patients with early-stage epithelial ovarian carcinoma? similar to Propensity score matched analysis similar to

    Kajiyama Hiroaki, Yoshihara Masato, Tamauchi Satoshi, Yoshikawa Nobuhisa, Niimi Kaoru, Suzuki Shiro, Shibata Kiyosumi, Kikkawa Fumitaka

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   50 巻 ( 4 ) 頁: 411 - 418   2020年4月

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    記述言語:日本語   出版者・発行元:Japanese Journal of Clinical Oncology  

    DOI: 10.1093/jjco/hyz194

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  48. Reasons for previous Cesarean deliveries impact a woman's independent decision of delivery mode and the success of trial of labor after Cesarean.

    Uno K, Mayama M, Yoshihara M, Takeda T, Tano S, Suzuki T, Kishigami Y, Oguchi H

    BMC pregnancy and childbirth   20 巻 ( 1 ) 頁: 170   2020年3月

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    記述言語:英語  

    DOI: 10.1186/s12884-020-2833-2

    PubMed

  49. Prognostic impact of pelvic and para-aortic lymphadenectomy on clinically-apparent stage I primary mucinous epithelial ovarian carcinoma: a multi-institutional study with propensity score-weighted analysis

    Yoshihara Masato, Kajiyama Hiroaki, Tamauchi Satoshi, Iyoshi Shohei, Yokoi Akira, Suzuki Shiro, Kawai Michiyasu, Nagasaka Tetsuro, Takahashi Kunihiko, Matsui Shigeyuki, Kikkawa Fumitaka

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   50 巻 ( 2 ) 頁: 145 - 151   2020年2月

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    記述言語:日本語   出版者・発行元:Japanese Journal of Clinical Oncology  

    DOI: 10.1093/jjco/hyz163

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  50. The role of additional hysterectomy after concurrent chemoradiation for patients with locally advanced cervical cancer

    Yoshida Kosuke, Kajiyama Hiroaki, Yoshihara Masato, Tamauchi Satoshi, Ikeda Yoshiki, Yoshikawa Nobuhisa, Nishino Kimihiro, Niimi Kaoru, Suzuki Shiro, Kikkawa Fumitaka

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   25 巻 ( 2 ) 頁: 384 - 390   2020年2月

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    記述言語:日本語   出版者・発行元:International Journal of Clinical Oncology  

    DOI: 10.1007/s10147-019-01551-6

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  51. Prognostic factors and effects of fertility-sparing surgery in women of reproductive age with ovarian clear-cell carcinoma: a propensity score analysis

    Yoshihara Masato, Kajiyama Hiroaki, Tamauchi Satoshi, Suzuki Shiro, Takahashi Kunihiko, Matsui Shigeyuki, Kikkawa Fumitaka

    JOURNAL OF GYNECOLOGIC ONCOLOGY   30 巻 ( 6 ) 頁: e102   2019年11月

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    記述言語:日本語   出版者・発行元:Journal of Gynecologic Oncology  

    DOI: 10.3802/jgo.2019.30.e102

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  52. Fertility-Sparing surgery for young women with ovarian endometrioid carcinoma: a multicenteric comparative study using inverse probability of treatment weighting.

    Kajiyama H, Yoshihara M, Tamauchi S, Yoshikawa N, Suzuki S, Kikkawa F

    European journal of obstetrics & gynecology and reproductive biology: X   4 巻   頁: 100071   2019年10月

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    記述言語:英語   出版者・発行元:European Journal of Obstetrics and Gynecology and Reproductive Biology: X  

    DOI: 10.1016/j.eurox.2019.100071

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  53. Relationship between preexisting mental disorders and prognosis of gynecologic cancers: A case-control study

    Tamauchi Satoshi, Kajiyama Hiroaki, Moriyama Yoshinori, Yoshihara Masato, Ikeda Yoshiki, Yoshikawa Nobuhisa, Nishino Kimihiro, Niimi Kaoru, Suzuki Shiro, Kikkawa Fumitaka

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   45 巻 ( 10 ) 頁: 2082 - 2087   2019年10月

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    記述言語:日本語   出版者・発行元:Journal of Obstetrics and Gynaecology Research  

    DOI: 10.1111/jog.14053

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  54. Does postoperative prophylactic irradiation of para-aortic lymph nodes reduce the risk of recurrence in uterine cervical cancer with positive pelvic lymph nodes?

    Yoshida Kosuke, Kajiyama Hiroaki, Yoshihara Masato, Ikeda Yoshiki, Yoshikawa Nobuhisa, Nishino Kimihiro, Utsumi Fumi, Niimi Kaoru, Suzuki Shiro, Kikkawa Fumitaka

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   24 巻 ( 5 ) 頁: 567 - 574   2019年5月

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    記述言語:日本語   出版者・発行元:International Journal of Clinical Oncology  

    DOI: 10.1007/s10147-018-1376-2

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  55. Endometriosis and cancer

    Kajiyama Hiroaki, Suzuki Shiro, Yoshihara Masato, Tamauchi Satoshi, Yoshikawa Nobuhisa, Niimi Kaoru, Shibata Kiyosumi, Kikkawa Fumitaka

    FREE RADICAL BIOLOGY AND MEDICINE   133 巻   頁: 186 - 192   2019年3月

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    記述言語:日本語   出版者・発行元:Free Radical Biology and Medicine  

    DOI: 10.1016/j.freeradbiomed.2018.12.015

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  56. PAI-1 secreted from metastatic ovarian cancer cells triggers the tumor-promoting role of the mesothelium in a feedback loop to accelerate peritoneal dissemination

    Peng Yang, Kajiyama Hiroaki, Yuan Hong, Nakamura Kae, Yoshihara Masato, Yokoi Akira, Fujikake Kayo, Yasui Hiroaki, Yoshikawa Nobuhisa, Suzuki Shiro, Senga Takeshi, Shibata Kiyosumi, Kikkawa Fumitaka

    CANCER LETTERS   442 巻   頁: 181 - 192   2019年2月

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    記述言語:日本語   出版者・発行元:Cancer Letters  

    DOI: 10.1016/j.canlet.2018.10.027

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  57. Reproductive outcomes of 105 malignant ovarian germ cell tumor survivors: a multicenter study

    Tamauchi Satoshi, Kajiyama Hiroaki, Yoshihara Masato, Ikeda Yoshiki, Yoshikawa Nobuhisa, Nishino Kimihiro, Utsumi Fumi, Niimi Kaoru, Suzuki Shiro, Kikkawa Fumitaka

    AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY   219 巻 ( 4 ) 頁: 385.e1 - 385.e7   2018年10月

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    記述言語:日本語   出版者・発行元:American Journal of Obstetrics and Gynecology  

    DOI: 10.1016/j.ajog.2018.07.021

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  58. The possible existence of occult metastasis in patients with ovarian clear-cell carcinoma who underwent complete resection without any residual tumours.

    Kajiyama H, Suzuki S, Yoshihara M, Nishino K, Yoshikawa N, Utsumi F, Niimi K, Mizuno M, Kawai M, Oguchi H, Mizuno K, Yamamuro O, Nagasaka T, Shibata K, Kikkawa F

    Oncotarget   9 巻 ( 5 ) 頁: 6298 - 6307   2018年1月

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    記述言語:英語   出版者・発行元:Oncotarget  

    DOI: 10.18632/oncotarget.23921

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  59. A novel mechanism of neovascularization in peritoneal dissemination via cancer-associated mesothelial cells affected by TGF-beta derived from ovarian cancer

    Fujikake Kayo, Kajiyama Hiroaki, Yoshihara Masato, Nishino Kimihiro, Yoshikawa Nobuhisa, Utsumi Fumi, Suzuki Shiro, Niimi Kaoru, Sakata Jun, Mitsui Hiroko, Shibata Kiyosumi, Senga Takeshi, Kikawa Fumitaka

    ONCOLOGY REPORTS   39 巻 ( 1 ) 頁: 193 - 200   2018年1月

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    記述言語:日本語   出版者・発行元:Oncology Reports  

    DOI: 10.3892/or.2017.6104

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  60. Factors influencing brain natriuretic peptide levels in healthy pregnant women.

    Mayama M, Yoshihara M, Uno K, Tano S, Takeda T, Ukai M, Kishigami Y, Oguchi H

    International journal of cardiology   228 巻   頁: 749 - 753   2017年2月

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    記述言語:英語  

    DOI: 10.1016/j.ijcard.2016.11.111

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▼全件表示

講演・口頭発表等 20

  1. Visualization of platinum resistance through mapping trace elements

    Uno Kaname, Yoshikawa Nobuhisa, Yoshihara Masato, Tazaki Kei, Kato Masashi, Kitami Kazuhisa, Iyoshi Shohei, Tamauchi Satoshi, Sugiyama Mai, Koya Yoshihiro, Kajiyama Hiroaki

    CANCER SCIENCE  2021年2月 

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    記述言語:日本語  

  2. The role of chrXq27.3 miRNA cluster in advanced ovarian clear cell carcinoma

    Yoshida Kosuke, Yokoi Akira, Yoshihara Masato, Tamauchi Satoshi, Yoshikawa Nobuhisa, Nishino Kimihiro, Niimi Kaoru, Kikkawa Fumitaka, Kajiyama Hiroaki

    CANCER SCIENCE  2021年2月 

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    記述言語:日本語  

  3. The impact of chemokine in the peritoneal metastatic niche composed of ovarian cancer and peritoneal mesothelial cells

    Yasui Hiroaki, Kajiyama Hiroaki, Yoshihara Masato, Sugiyama Mai, Kikkawa Fumitaka

    CANCER SCIENCE  2018年1月 

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    記述言語:日本語  

  4. REDUCED RESPONSE TO CONTROLLED OVARIAN STIMULATION AFTER RADICAL TRACHELECTOMY

    Tamauchi S., Kajiyama H., Osuka S., Moriyama Y., Yoshihara M., Iyoshi S., Yoshida K., Ikeda Y., Yoshikawa N., Nishino K., Niimi K., Suzuki S., Kikkawa F.

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER  2019年11月 

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    記述言語:日本語  

  5. PROPENSITY SCORE ADJUSTED ANALYSIS OF PROPHYLACTIC IRRADIATION TO PARA-AORTIC LYMPH NODE AFTER RADICAL HYSTERECTOMY FOR UTERINE CERVICAL CANCER.

    Yoshida K., Yoshihara M., Ikeda Y., Yoshikawa N., Nishino K., Utumi F., Niimi K., Suzuki S., Kajiyama H., Kikkawa F.

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER  2018年9月 

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    記述言語:日本語  

  6. PRIMA-1MET INDUCES APOPTOSIS THROUGH ACCUMULATION OF INTRACELLULAR REACTIVE OXYGEN SPECIES IRRESPECTIVE OF P53 STATUS AND CHEMO-SENSITIVITY IN EPITHELIAL OVARIAN CANCER CELLS

    Yoshikawa N., Shimizu Y., Yoshihara M., Nakamura K., Suzuki S., Kajiyama H., Kikkawa F.

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER  2017年11月 

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    記述言語:日本語  

  7. PELVIC EXENTERATION IN PATIENTS WITH RECURRENT OR ADVANCED GYNECOLOGIC MALIGNANCIES

    Takuto N., Shimizu Y., Yoshihara M., Nakamura K., Yoshikawa N., Suzuki S., Kajiyama H., Kikkawa F.

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER  2017年11月 

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    記述言語:日本語  

  8. Notch signaling enhances the mutual association with epithelial ovarian cancer and mesothelial cells

    Sugiyama Mai, Yoshihara Masato, Koya Yoshihiro, Yokoi Akira, Ryu Buntei, Kikkawa Fumitaka, Kajiyama Hiroaki

    CANCER SCIENCE  2018年12月 

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    記述言語:日本語  

  9. MITF contributes to cell migration/invasion in ovarian carcinoma cells

    Koya Yoshihiro, Ryu Buntei, Sugiyama Mai, Yoshihara Masato, Senga Takeshi, Nawa Akihiro, Kikkawa Fumitaka, Kajiyama Hiroaki

    CANCER SCIENCE  2018年12月 

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    記述言語:日本語  

  10. Mesothelial cells create invasion frontier in peritoneal metastasis of epithelial ovarian cancer

    Iyoshi Shohei, Kajiyama Hiroaki, Yoshihara Masato, Yamakita Yoshihiko, Sugiyama Mai, Koya Yoshihiro, Ryu Buntei, Kikkawa Fumitaka

    CANCER SCIENCE  2018年12月 

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    記述言語:日本語  

  11. Luteolin suppresses Ovarian Cancer progression via decrease the expression of VRK1

    Chang Xuboya, Kajiyama Hiroaki, Yoshikawa Nobuhisa, Yokoi Akira, Tamauchi Satoshi, Yoshihara Masato

    CANCER SCIENCE  2021年2月 

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    記述言語:日本語  

  12. Intra-tumoral polarity induced by Notch signaling can be a novel therapeutic target for advanced ovarian cancer

    Yoshihara Masato, Sugiyama Mai, Koya Yoshihiro, Iyoshi Shohei, Kitami Kazuhisa, Uno Kaname, Mogi Kazumasa, Tano Sho, Tamauchi Satoshi, Yokoi Akira, Yoshikawa Nobuhisa, Nawa Akihiro, Kajiyama Hiroaki

    CANCER SCIENCE  2021年2月 

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    記述言語:日本語  

  13. How do peritoneal mesothelial cells on adipose tissue attract ovarian cancer cells?

    Mogi Kazumasa, Yoshihara Masato, Kitami Kazuhisa, Iyoshi Shohei, Uno Kaname, Tano Sho, Sugiyama Mai, Koya Yoshihiro, Tamauchi Satoshi, Yokoi Akira, Yoshikawa Nobuhisa, Nawa Akihiro, Kajiyama Hiroaki

    CANCER SCIENCE  2021年2月 

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    記述言語:日本語  

  14. EVALUATING THE LONG TERM PROGNOSTIC FACTOR AND THE ROLE OF CYTOREDUCTION IN THE OVERALL POPULATION OF PATIENTS WITH CLINICAL AND SURGICAL STAGE IV ENDOMETRIAL CARCINOMA

    Shimizu Y., Kajiyama H., Suzuki S., Yoshikawa N., Nakamura K., Yoshihara M., Tamauchi S., Yoshida K., Kikkawa F.

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER  2017年11月 

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    記述言語:日本語  

  15. ESTABLISHMENT AND CHARACTERISATION OF PATIENT-DERIVED XENOGRAFT MODELS FOR MALIGNANT GYNECOLOGIC TUMORS

    Suzuki S., Tamauchi S., Shimizu Y., Yoshihara M., Nakamura K., Yoshikawa N., Kajiyama H., Kikkawa F.

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER  2017年11月 

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    記述言語:日本語  

  16. Carcinoma-associated mesothelial cells promote dissemination and platinum resistance in epithelial ovarian cancer.

    Yoshihara Masato, Kajiyama Hiroaki, Sugiyama Mai, Yasui Hiroaki, Koya Yoshihiro, Yamakita Yoshihiko, Ryu Buntei, Yokoi Akira, Yamamoto Yusuke, Kikkawa Fumitaka

    CANCER SCIENCE  2018年1月 

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    記述言語:日本語  

  17. Cancer-associated mesothelial cells as a potential therapeutic target in epithelial ovarian cancer

    Yoshihara Masato, Kajiyama Hiroaki, Sugiyama Mai, Koya Yoshihiro, Ryu Buntei, Yokoi Akira, Yamamoto Yusuke, Kikkawa Fumitaka

    CANCER SCIENCE  2018年12月 

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    記述言語:日本語  

  18. Anti-tumor effect of 9-oxo-10,12-ODA on human cervical cancer cells

    Koya Yoshihiro, Sugiyama Mai, Yoshihara Masato, Shibata Kiyosumi, Nawa Akihiro, Kajiyama Hiroaki

    CANCER SCIENCE  2021年2月 

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    記述言語:日本語  

  19. ALTERATION OF THE TUMOR MICROENVIRONMENT BY NOTCH SINGNALING ENHANCES THE MUTUAL ASSOCIATION WITH EPITHELIAL OVARIAN CANCER AND MESOTHELIAL CALLS

    Yoshihara M., Kajiyama H., Sugiyama M., Kikkawa F.

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER  2017年11月 

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    記述言語:日本語  

  20. Active vitamin D inhibits mesothelial-mesenchymal-transition accelerating peritoneal dissemination in ovarian cancer

    Kitami Kazuhisa, Yoshihara Masato, Sugiyama Mai, Koya Yoshihiro, Iyoshi Shohei, Uno Kaname, Mogi Kazumasa, Tamauchi Satoshi, Yokoi Akira, Yoshikawa Nobuhisa, Nawa Akihiro, Kajiyama Hiroaki

    CANCER SCIENCE  2021年2月 

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    記述言語:日本語  

▼全件表示

科研費 6

  1. 進行卵巣癌の病勢制御を目的とした腹膜マトリソームの機能・構造解明と新規治療標的化

    研究課題/研究課題番号:21KK0296  2022年 - 2024年

    科学研究費助成事業  国際共同研究加速基金(国際共同研究強化(A))

    吉原 雅人

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    担当区分:研究代表者 

    配分額:15600000円 ( 直接経費:12000000円 、 間接経費:3600000円 )

    腹膜播種を伴う進行卵巣癌に対する有効な治療法は未だに確立されておらず、腫瘍の病勢を制御することで難治性を打破する新たな治療戦略が期待される。本研究課題では腹膜中皮細胞を特異的に標識する遺伝子改変実験動物モデルを用いて、卵巣癌腹膜播種における細胞外基質の総体である腹膜マトリソームを、オーストラリア・アデレード大学との国際共同研究により解明することを目的とする。最先端のプロテオミクス分析機器および解析技術を有する同施設の手法を用いて、基課題の目的である進行卵巣癌の病勢制御を、腹膜マトリソームを標的として発展させ、腹膜という宿主環境の再生による卵巣癌新規治療戦略の開発を試みる。

  2. 腹水中ペプチド・デグラドミクスに注目した進行卵巣癌に対する腹腔内環境戦略の創生

    研究課題/研究課題番号:21KK0157  2021年10月 - 2025年3月

    科学研究費助成事業  国際共同研究加速基金(国際共同研究強化(B))

    梶山 広明, 吉原 雅人, 佐藤 綾人, 横井 暁, 小屋 美博

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    担当区分:研究分担者 

    悪性腹水中のジペプチジルペプチダーゼ酵素群を主としたペプチドバランスを、新規の質量分析手法であるTMT-TAILS法を用いたデグラドミクス解析によって明らかにする。また、腹腔内環境を構成する宿主細胞が、腫瘍の「味方」に至る腫瘍側誘導メカニズムに焦点をあて、腹膜中皮、脂肪細胞、および腫瘍随伴マクロファージといった免疫細胞などにおける包括的な機能解析を、「卵巣癌-腹膜間の細胞コミュニケーション」の観点から行う。さらに、アミノペプチダーゼ阻害剤による卵巣癌進行抑制効果を、実験動物モデルを用いて検証し、治療応用への可能性を模索する。
    卵巣癌は診断時に極めて多くの症例で腹膜播種を伴っており、予後不良の主要な因子となっている。よい植物が育つにはよい“種”とよい“土壌”が必要である様に、卵巣癌の癌性腹膜炎の克服には、卵巣癌(種)だけではなく腹膜環境(土壌)を一体として捉える必要がある。腹膜腔という閉鎖的空間において、腹水は癌細胞と宿主細胞との間の相互作用が生じる媒体であり、反応の場でもある。本課題では、腹腔内全体を一つの生態的環境(エコシステム)と見なし、「卵巣癌-腹膜間の細胞コミュニケーション」をつなぐ主要な媒体である悪性腹水中のペプチドバランスに着目した新規卵巣癌腹膜進展の機序解明を目的とする。そして、フライブルグ大学分子医学研究所及び病理部に所属するOliver Schilling博士との国際共同研究の上、悪性腹水中のジペプチジルペプチダーゼ酵素群を主としたペプチドバランスを明らかとするために、TMT-TAILS法を用いて、N-ターミノームを網羅的探索することで、癌性腹膜炎化に対する寄与の大きい基質を見出すデグラドミクス解析を行う。さらに、腹腔内エコシステムにおける卵巣癌細胞と宿主細胞としての腹膜中皮細胞や脂肪細胞とが織りなす相互作用を標的として、進行卵巣癌の癌性腹膜炎化に至る新規メカニズムを解明する。最終的に、卵巣癌における腹膜環境の正常化に焦点にあてたジペプチジルペプチダーゼ阻害剤を治療応用につなげるべく、臨床上の活用を目指す。
    <BR>
    本年度は、ジョイントディグリープログラムの一環として独・フライブルク大学附属病院外科系病理部に大学院生1名が留学中であり、卵巣癌悪性腹水の大規模プロテオミクス解析を行った。その結果、新たに3つの腹水分子型サブタイプを同定するとともに、数種の新規予後マーカーを同定した。これらの成果は今後の卵巣癌個別化医療の発展に寄与するものと考えられ、現在論文として報告準備中である。
    本年度の研究により、以下の内容に関する成果を挙げることができたと考える。卵巣癌は腹水を介して腹腔内に直接播種することが知られ、腹水中には癌細胞だけでなく、免疫細胞をはじめとする非腫瘍細胞も多数存在し、これらの細胞からプロテアーゼやその基質となるサイトカインが放出されることが知られているが、腹水中におけるタンパク分解シグナルの詳細について検討した報告はない。本研究ではこれまでに、高悪性度漿液性卵巣癌(HGSOC)91例から採取した悪性腹水を用いて、データ非依存解析(DIA)法による大規模プロテオミクス解析を行い、悪性腹水のプロテオームシグネチャーを評価するとともに、バイオマーカー候補の探索を行った。その結果、ECM、ECM, tissue-leakage, coagulationをそれぞれキータームとする3つの異なるサブグループを同定し、各サブグループ間で蛋白分解活性が有意に異なることを確認した。また、Cox proportional hazards model by componentwise likelihood based boosting (CoxBoost法)を用いて、予後に関連するバイオマーカー候補を抽出し、得られた分子群のエンリッチメント解析から、凝固・補体活性化が予後と相関することを確認した。これらの結果からプロテオームリソースとしての腹水の有用性が示唆された。本研究内容から得られた複数の候補遺伝子を用いて、卵巣癌実験モデル動物を使用した検証実験を行い、これらを統合した内容の論文の作成準備をしている。
    社会状況により渡欧時期を調整し、研究代表者が現地における悪性腹水の品質チェックとアミノペプチダーゼを用いた酵素反応実験を含むデータ分析やデグラドミクス解析を、Oliver Schilling博士とともに行う予定を計画する。現地にて実施できない内容に関しては、webミーティングを介して指導を行う。また当初からの標的である腹水中に存在する免疫細胞に対して、腹水が抑制的あるいは促進的に作用するかを、原因となる特異的物質とともに同定することで、腹腔内エコシステムにおける卵巣癌細胞の悪性化プロセスの解明と腹膜環境の正常化を目指した研究基盤の確立を目指す。

  3. 腹腔内細胞コミュニケーションが誘導するオカルト播種の休眠維持環境構築のメカニズム

    研究課題/研究課題番号:21K19562  2021年7月 - 2024年3月

    科学研究費助成事業  挑戦的研究(萌芽)

    梶山 広明, 吉原 雅人, 横井 暁, 芳川 修久

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    担当区分:研究分担者 

    本課題は腹腔内微小環境における癌関連腹膜中皮細胞に注目して、腹腔内オカルト播種の休眠の機能および維持メカニズムを追究する研究である。休眠の維持に関する解析項目に「腫瘍-CAMのNotchシグナル」や免疫回避の第一歩として「SDF-1α制御-腫瘍関連マクロファージ」との関連を取り入れた斬新かつ挑戦的な研究である。本課題で得られた知見によって腹膜全体をターゲットとした包括的治療戦略の策定や新規バイオマーカーの同定を目指す。特に腹膜は面積的に広範囲であるため、標的にしえた場合の治療及びQOL改善の効果も大きいと考えられる。さらに本研究は卵巣癌に限らず癌性腹膜炎を形成しうる他癌にも応用可能となりうる。
    現在、腹膜播種に対する有効な治療法は確立されているとはいえず、比較的、腹膜播種の発生が多いとされる卵巣癌、大腸癌、および胃癌の腹膜進展に関する分子生物学的機序については未だ不明な点が多い。よい植物が育つにはよい“種”とよい“土壌”が必要であり、腹膜播種の克服には、癌(種)だけではなく腹膜微小環境(土壌)も一体化して考える必要がある。本研究では、「土壌」となる“腫瘍の手先”にさせられた本来生体防御的であった腹膜中皮{癌関連腹膜中皮細胞: Cancer-associated peritoneal mesothelial cell:(CAM)}により、よい「種」としての腹腔内微小環境ストレスに抵抗性を有する生存能力の高い卵巣癌細胞の成立過程を検証し、CAMがどのようなメカニズムで腫瘍細胞の休眠や進化を助け、既存の抗腫瘍薬からの攻撃回避に機能しているかを解明することを最大の研究目的とした。
    <BR>
    これまでの研究成果により、CAMに発現するNotchリガンドの一つであるDLL3を介して、一部の卵巣癌細胞にNotchシグナルが誘導されることが判明した。Notch陽性となった卵巣癌細胞は、幹細胞形質を獲得し、細胞周期の遅延や低栄養耐性などの休眠様の状態を呈することを解明した。さらにNotch陽性卵巣癌細胞はNotch陰性細胞から出現し、一方でNotch陰性卵巣癌細胞はNotch陽性細胞からも出現することが明らかとなった。またNotch陽性細胞は代謝変容を引き起こし、プラチナ製剤などへのストレス抵抗性を獲得している機序を明らかにした。これらの結果を統合することで、CAMが腹膜において卵巣癌細胞にNotchシグナルを誘導し、腹腔内微小環境におけるストレス抵抗性を獲得することで、既存の抗腫瘍薬からの攻撃回避に機能していることを突き止めた。これらの成果をもとに、現在論文を作成し投稿を予定している。
    本年度の研究により、以下の内容に関する成果を挙げることができたと考える。
    <BR>
    卵巣癌腹膜播種実験モデルを樹立し、腹膜中皮細胞との共培養で生じる癌細胞の変化を解析したところ、Notchシグナルの関与が同定された。一方、マウス腹腔内に移植された卵巣癌細胞では、皮下移植と比較してNotchシグナルが有意に誘導されることが判明した。さらに、卵巣癌腹膜播種臨床検体において、一部の癌細胞のみにNotchシグナルの亢進が見られることを発見した。すなわち、卵巣癌の腹膜播種巣において、Notchシグナルを介した相互作用により癌細胞間に極性が生じ、腫瘍内不均一性が誘導されていることが判明した。続いて、強制発現系を用いたNotch優位細胞株を樹立したところ、増殖能の低下と細胞周期の遅延を認め、代謝変容を示唆する結果がプロテオーム解析により導き出された。これらの結果より、卵巣癌腹膜播種巣において、癌細胞間の極性により生じたNotchシグナルが亢進した細胞では、休眠や幹細胞様の性質を獲得し、治療抵抗性を誘導していると考えられた。一方で、γセクレターゼ阻害剤を、腹膜中皮細胞と卵巣癌細胞の共培養による腹膜播種実験モデル、卵巣癌腹膜播種マウスモデルに使用したところ、双方で有意な癌細胞増殖や腫瘍形成の低下が見られた。これらの結果より、卵巣癌腹膜播種巣において、Notchシグナルを介した癌細胞の極性が腫瘍内不均一性を創出していると考えられた。さらに、Notchシグナルを標的としたγセクレターゼ活性制御は、進行卵巣癌における新規治療戦略となる可能性が示された。
    <BR>
    また同様の細胞間クロストークを展開する卵巣癌や絨毛細胞などにおける同様のメカニズムの検証や手法の展開を図り、総説の作成や予備実験結果に基づく報告も行った。
    本年度に得られた結果を、より具体的な成果へと昇華させるべく研究を推し進める。卵巣癌において腹膜誘導性のNotch依存性腫瘍内不均一性が、主に代謝変容に基づく細胞運命のダイナミクスを生み出し、卵巣癌腹膜播種の進展を促進することが示されたことから、治療抵抗性の腹膜転移のこれらのメカニズムを標的としたγセクレターゼ阻害を含む候補物質などにより、卵巣癌の病勢制御を担うに新規戦略の開発を目指す。加えてトランスレーショナルなアプローチを用いて基礎・臨床横断的な医学研究を推進し、腹腔内全体を一つの包括的環境基軸と見なした研究を継続していく。

  4. 進行卵巣癌の病勢制御を目指した癌関連中皮細胞の機能解析と腹膜再生治療の開発

    研究課題/研究課題番号:21K16788  2021年4月 - 2024年3月

    若手研究

    吉原 雅人

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    担当区分:研究代表者 

    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

  5. 卵巣癌細胞を貪食した腹膜中皮細胞による抗腫瘍免疫抑制の機序解明と再賦活化法の検討

    研究課題/研究課題番号:21K09492  2021年4月 - 2024年3月

    科学研究費助成事業  基盤研究(C)

    小屋 美博, 梶山 広明, 吉原 雅人

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    担当区分:研究分担者 

    卵巣癌は半数以上が進行期で発見され、婦人科系悪性腫瘍の中で最も死亡数の多い疾患であり、増悪の一因として、腹膜播種という転移様式が挙げられる。腹膜播種は、腹腔内に飛散した卵巣癌細胞が、腹膜の広い範囲に渡って細かく点在している状態である為、手術での完全切除はほぼ不可能である。従って、腹膜播種を抑制、制御することが、卵巣癌の予後を改善する鍵となる。本研究では、中皮細胞と卵巣癌の関係に注目し、中皮細胞が卵巣癌細胞を貪食し、宿主の腫瘍免疫を制御することで卵巣癌の進展に寄与する機構を解明する。さらに、癌細胞を貪食した中皮細胞を標的として、宿主腫瘍免疫の再賦活化を目指した新規治療候補物質の探索を試みる。
    腹腔内の最大の構成要素である中皮細胞は、貪食能を有している。近年、bystanderではあるがアマチュアの貪食細胞の重要性が、神経損傷をはじめ様々な分野で報告されている。本課題では、(1)腹膜中皮細胞の卵巣癌細胞に対する貪食機能の解析を行い、(2)その結果、腹膜中皮細胞にどの様な変化が生じるのかを評価する。(3)そして、その変化が腫瘍微小環境へどのような影響を及ぼすのかを明らかにし、(4)宿主の腫瘍免疫を再賦活化する方法の探索を行う。
    令和3年度は、(1)及び(2)を中心に遂行した。中皮細胞の追跡が可能なマウスに、同系の蛍光標識をしたマウス卵巣癌細胞株の腹腔内移入することにより、同系腹膜播種モデルを構築し中皮細胞による癌細胞の貪食能を評価した(in vivo)。不死化したマウス由来中皮細胞と同系のアポトーシス誘導マウス卵巣癌細胞を共培養し、貪食性中皮細胞をFACSにより分取し、蛍光顕微鏡により貪食を観察した(in vitro)。また、分取した貪食性中皮細胞からRNAを抽出し、免疫関連遺伝子の発現を定量的PCRにより解析した。
    これらの結果、中皮細胞はin vivoおよびin vitroにおいてアポトーシス状態のマウス卵巣癌細胞を貪食することが判明した。また、定量的PCR解析では、免疫関連遺伝子の有意な発現変化が確認された。免疫抑制誘導分子の発現が増加し、一方、免疫共刺激遺伝子の発現が減少していた。これらの結果から、中皮細胞は貪食作用を持ち、貪食した中皮細胞は免疫抑制を誘導する性質があることが示され、卵巣癌細胞の宿主免疫系からの逃避に寄与している可能性が示唆された。
    マウス由来中皮細胞から貪食した中皮細胞を分取するのに、中皮細胞とマウス卵巣癌細胞をそれぞれ蛍光標識する必要がある。その蛍光色素の組合せ、条件の最適化に時間がかかったため。
    動物実験施設の改築に伴い、動物実験計画に一部遅延が生じた為。
    (1)、(2)の詳細な解析を実施する。特に、(2)においてプロテオーム、トランスオミクス解析を実施し、貪食した中皮細胞において、どのような変化が生じているかを明らかにする。(3)の 動物モデルでの解析を進める。貪食したマウス中皮細胞を同系マウスに接種し免疫を行う。その後、マウス卵巣癌細胞を移入し、癌細胞の増殖や宿主の抗腫瘍免疫を評価する。(4)において、必要となる評価系の構築を進める。

  6. アディポペリトクロストークに基づく卵巣癌腹膜進展に関する学際的研究基盤の創成

    研究課題/研究課題番号:20H03824  2020年4月 - 2023年3月

    科学研究費助成事業  基盤研究(B)

    梶山 広明, 芳川 修久, 柴田 清住, 吉原 雅人

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    担当区分:研究分担者 

    ① 卵巣癌関連腹膜中皮・脱分化脂肪細胞―卵巣癌を1つのユニットとして捉えた上で卵巣癌の悪性化・腹膜進展機構の包括的解明を目指す。また、悪性腹水のメタボローム解析・エクソソーム解析を用いて、脂肪細胞からADMCにいたる誘導因子を解明する。癌細胞の膜脂質供給メカニズムの解明を行う。
    ② ADMCが卵巣癌関連腹膜中皮(CAM)や腫瘍関連マクロファージと協調して、腫瘍細胞の局所免疫回避や休眠維持、腹腔内進展をもたらすメカニズム解明する。
    ③ 新規蛍光プローブによる定量的脱分化評価システムを用いて、化合物ライブラリーから脱分化阻害剤の探索を行い、播種巣周囲の腹膜微小環境に着目した新規治療戦略を探求する。
    本課題では、腹腔内全体を一つの包括的環境基軸と見なし、腹膜中皮-脂肪(土壌)-卵巣癌(種)を1つのユニットとして捉えた上でその相互作用に着目し、卵巣癌の悪性化・腹膜進展機構を解明することを目的としている。
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    本年度の研究成果において、独自の天井培養法によって大網から脱分化脂肪由来間葉系細胞(ADSC)が有する卵巣癌悪性化への影響を調べ、卵巣癌細胞の増殖の促進及び卵巣癌細胞の遊走能亢進、in vivo での腫瘍形成能の増大が誘導されることを、in vivo imaging system (IVIS)を用いた実験系により示すことに成功し、一連の成果をもとに論文化を行い、International Journal of Cancerに採択された。一方で、本研究の過程において、卵巣癌腹膜播種モデル動物を詳細に観察する際に、卵巣癌細胞が脂肪細胞の近傍に効率的に接着する所見を得た。これは脂肪細胞の直上に存在する腹膜中皮細胞に卵巣癌細胞がより接着しやすい傾向にあることを示唆していることから、同部位の電子顕微鏡による評価や、網羅的発現分子解析を行い、卵巣癌接着の標的となりうる候補物質を複数同定した。
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    また、進行卵巣癌の腹膜微小環境において卵巣癌関連腹膜中皮細胞(ovarian cancer-associated mesothelial cells: OCAM)が卵巣癌の進展に深く寄与することをこれまでに同定しているが、正常腹膜中皮細胞がOCAMへと変貌する過程を抑制する候補物質としてcalcitriol(ビタミンD)が有望であることを実証し、本研究内容にて制作した論文が国際雑誌Matrix biologyに採択された。これらの成果を背景に、本研究課題の目的である、腹腔内を包括的環境と捉えた腹膜中皮-脂肪-卵巣癌というユニットを解釈し、治療標的とすることを目指していく。
    本年度の研究により、以下の項目に該当する内容に関する成果を挙げることができたと考える。
    ①卵巣癌関連腹膜中皮細胞―脱分化脂肪細胞―卵巣癌を1つのユニットとして捉えた上で卵巣癌の悪性化・腹膜進展機構の包括的解明を目指す、②ADSCが卵巣癌関連腹膜中皮細胞(OCAM)や腫瘍関連マクロファージと協調して、腫瘍細胞の局所免疫回避や休眠維持、腹腔内進展をもたらすメカニズム解明する: 上述の通り、ADSCにより、卵巣癌細胞に遊走能、in vivo での腫瘍形成能の増大が誘導されることを各種実験系により示すことに成功し、一連の成果をもとに論文化を行い、国際雑誌International Journal of Cancerに採択された。
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    また本研究の過程において、卵巣癌腹膜播種モデル動物を詳細に観察する際に、卵巣癌細胞が脂肪細胞の近傍に効率的に接着する所見を得ることができた。これは、脂肪細胞の直上に存在する腹膜中皮細胞に卵巣癌細胞がより接着しやすい傾向にあることを示唆している。すなわち、脂肪細胞に近接する腹膜中皮細胞と、脂肪細胞に近接しない腹膜中皮細胞との間には、生理的な構造が異なっている可能性が考えられる。こうした所見を局所レベルで詳細に観察することを目的とし、同部位の電子顕微鏡による評価や、網羅的発現分子解析を行い、卵巣癌接着の標的となりうる候補物質を複数同定した。さらに正常腹膜中皮細胞がOCAMへと変貌する過程を抑制する候補物質としてcalcitriol(ビタミンD)が有望であることを実証し、本研究内容にて制作した論文が国際雑誌Matrix biologyに採択された。
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    また昨年度に引き続き、卵巣癌患者の臨床情報を後方視的に探索し、腹膜播種の増悪に関与する環境因子の同定を、患者背景から推論する疫学的研究を並行して行い、さらに複数の論文報告を行った。
    本年度に得られた結果を、より具体的な成果へと昇華させるべく研究を推し進める。また、当初の目的である、新規蛍光プローブによる定量的脱分化評価システムの確立と、化合物ライブラリーから脱分化阻害剤の探索及び、播種巣周囲の腹膜微小環境に着目した新規治療戦略の探求を継続して行う。さらに、OCAMやADSCを標的とした治療候補物質の探究をケミカルライブラリーやドラッグライブラリーを用いて検証し、臨床応用を見据えた研究基盤の確立も目指す。加えて引き続きトランスレーショナルなアプローチを用いて基礎・臨床横断的な医学研究を推進し、腹腔内全体を一つの包括的環境基軸と見なした研究を継続して行く。

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