Updated on 2024/03/29

写真a

 
IYOSHI Shohei
 
Organization
Institute for Advanced Research Designated assistant professor
Graduate School of Medicine Designated assistant professor
Title
Designated assistant professor
External link

Degree 2

  1. Doctor of Philosophy in Medical Science ( 2022.11   Nagoya University ) 

  2. Bachelor of Medical Doctor ( 2015.3   Nagoya University ) 

 

Papers 46

  1. An update of oncologic and obstetric outcomes of radical trachelectomy for early-stage cervical cancer: The need for further minimally invasive treatment

    Tamauchi, S; Iyoshi, S; Yoshihara, M; Yoshida, K; Ikeda, Y; Shimizu, Y; Yokoi, A; Niimi, K; Yoshikawa, N; Kajiyama, H

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   Vol. 50 ( 2 ) page: 175 - 181   2024.2

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  2. Mean platelet volume as a potential biomarker for survival outcomes in ovarian clear cell carcinoma

    Yoshikawa, N; Matsukawa, T; Hattori, S; Iyoshi, S; Yoshida, K; Yoshihara, M; Tamauchi, S; Shimizu, Y; Ikeda, Y; Yokoi, A; Niimi, K; Kawai, M; Kajiyama, H

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   Vol. 28 ( 12 ) page: 1680 - 1689   2023.12

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    Language:English   Publisher:International Journal of Clinical Oncology  

    Objective: This study aimed to explore the prognostic value of mean platelet volume (MPV) in patients with ovarian clear cell carcinoma (OCCC) and evaluate the predictive performance of a random forest model incorporating MPV and other key clinicopathological factors. Methods: A total of 204 patients with OCCC treated between January 2004 and December 2019 were retrospectively analyzed. Clinicopathological characteristics and preoperative laboratory data were collected, and survival outcomes were evaluated using the Kaplan–Meier method and Cox proportional hazards models. An optimal MPV cutoff was determined by receiver operating characteristic (ROC) curve analysis. A random forest model was then constructed using the identified independent prognostic factors, and its predictive performance was evaluated. Results: The ROC analysis identified 9.3 fL as the MPV cutoff value for predicting 2-year survival. The MPV-low group had lower 5-year overall survival and progression-free survival rates than the MPV-high group (p = 0.003 and p = 0.034, respectively). High MPV emerged as an independent prognostic factor (p = 0.006). The random forest model, incorporating the FIGO stage, residual tumors, peritoneal cytology, and MPV, demonstrated robust predictive performance (area under the curve: 0.905). Conclusion: MPV is a promising prognostic indicator in OCCC. Lower MPV correlated with worse survival rates, advocating its potential utility in refining patient management strategies. The commendable predictive performance of the random forest model, integrating MPV and other significant prognostic factors, suggests a pathway toward enhanced survival prediction, thereby warranting further research.

    DOI: 10.1007/s10147-023-02417-8

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  3. 9-oxo-ODAs suppresses the proliferation of human cervical cancer cells through the inhibition of CDKs and HPV oncoproteins

    Mogi, K; Koya, Y; Yoshihara, M; Sugiyama, M; Miki, R; Miyamoto, E; Fujimoto, H; Kitami, K; Iyoshi, S; Tano, S; Uno, K; Tamauchi, S; Yokoi, A; Shimizu, Y; Ikeda, Y; Yoshikawa, N; Niimi, K; Yamakita, Y; Tomita, H; Shibata, K; Nawa, A; Tomoda, Y; Kajiyama, H

    SCIENTIFIC REPORTS   Vol. 13 ( 1 ) page: 19208   2023.11

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    Mucosal human papillomavirus (HPV) subtypes 16 and 18 are causative agents of cervical cancer, a leading cause of cancer-related deaths among women worldwide. In Japan, eggplant calyx is a folk remedy used to treat common warts. 9-oxo-(10E,12E)-octadecadienoic acid, isolated from eggplant calyx, may have antitumor effects. This study investigated the antitumor effects of 9-oxo-(10E, 12Z)-octadecadienoic acid and 9-oxo-(10E,12E)-octadecadienoic acid (9-oxo-ODAs) on human cervical cancer cells. 9-oxo-ODAs suppressed the proliferation of human cervical cancer cell lines (HeLa, and SiHa) in a concentration-dependent manner (IC50 = 25–50 µM). FCM analysis revealed that 9-oxo-ODAs induced apoptosis. Transcriptome, proteomics, and enrichment analyses revealed that treatment with 9-oxo-ODAs significantly altered the cell cycle and p53 pathways and decreased cyclin-dependent kinase 1 (CDK1) protein expression. Real-time PCR analysis demonstrated that 9-oxo-ODAs reduced CDK1 mRNA expression in a concentration-dependent manner. In vitro, 9-oxo-ODAs reduced the HPV oncoprotein expression. In ex vivo human cervical cancer tissues, 9-oxo-ODAs decreased CDK1 expression and increased cleaved caspase 3, an apoptosis marker. Further, 9-oxo-ODAs showed the potential to suppressed metastatic formation and growth of cervical cancer in vivo. These findings suggest that 9-oxo-ODAs induce cell cycle arrest and apoptosis in HPV-positive human cervical cancer cells, and this process involves CDK1. Consequently, 9-oxo-ODAs may be potential therapeutic agents for cervical cancer.

    DOI: 10.1038/s41598-023-44365-3

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  4. Ovarian cancer: Novel mechanisms and therapeutic targets regarding the microenvironment in the abdominal cavity

    Yoshihara, M; Iyoshi, S; Mogi, K; Uno, K; Fujimoto, H; Miyamoto, E; Nomura, S; Kitami, K; Kajiyama, H

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   Vol. 49 ( 11 ) page: 2620 - 2628   2023.11

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    Language:English   Publisher:Journal of Obstetrics and Gynaecology Research  

    Ovarian cancer is an intractable disease that is mostly diagnosed at an advanced stage and has a high recurrence rate. The early development of characteristic peritoneal dissemination via ascites contributes to a poor prognosis. Based on the “seed and soil” theory, ovarian cancer is considered to form a disseminated tumor that interacts with the peritoneum; superficial mesothelial cells are structurally important. Thus far, we have reported that peritoneal mesothelial cells, which originally are ecological defenses, transform into ovarian cancer-associated mesothelial cells, which are allies of cancer. They are found to be actively involved in the formation of a friendly “soil” that promotes the survival of “seeds” of ovarian cancer cells. We also demonstrated that the progression of ovarian cancer and the induction of its refractory nature are partially mediated through competition and cooperation between ovarian cancer and mesothelial cells. We believe that it is necessary to shift the aim of treatment strategies from solely targeting cancer cells to focusing on the crosstalk between the surrounding environment and ovarian cancer, an approach that ultimately aims to achieve “coexistence” with cancer through disease control.

    DOI: 10.1111/jog.15756

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  5. 増大特集 代謝 Ⅲ.代謝とがん 肥満と卵巣がん

    伊吉 祥平, 吉原 雅人, 梶山 広明

    生体の科学   Vol. 74 ( 5 ) page: 458 - 459   2023.10

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    Publisher:株式会社医学書院  

    DOI: 10.11477/mf.2425201752

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  6. The sarcopenia index measured using the lumbar paraspinal muscle is associated with prognosis in endometrial cancer

    Uno, K; Yoshikawa, N; Kitami, K; Mori, S; Shibata, T; Iyoshi, S; Fujimoto, H; Mogi, K; Yoshihara, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Kato, K; Hoshiba, T; Oguchi, H; Kajiyama, H

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   Vol. 53 ( 10 ) page: 942 - 949   2023.10

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    Language:English   Publisher:Japanese Journal of Clinical Oncology  

    Objective: The number of type-II endometrial cancer patients has been increasing and the prognosis is not favorable. We aim to investigate whether sarcopenia index in any of several different muscles could serve as a novel biomarker of prognosis in patients with type-II endometrial cancer. Methods: We retrospectively investigated a total of 194 patients at four hospitals. Ninety patients were treated as derivation set and the other 104 patients as validation set. Using preoperative computed tomography images, we measured the horizontal cross-sectional area at the third lumbar spine level: the (i) psoas major, (ii) iliac and (iii) paraspinal muscle. The clinical information including recurrence-free survival and overall survival were retrospectively collected. These results were validated with external data sets of three hospitals. Results: The median values of the sarcopenia index (cm2/m2) ± standard deviation with the first data of 90 patients using the psoas, iliac and paraspinal muscle were 3.4 ± 1.0, 1.7 ± 0.6 and 12.6 ± 3.2, respectively. In univariate analyses, the sarcopenia indexes measured using the psoas or paraspinal muscle were associated with recurrence-free survival and overall survival. On the other hand, in multivariate analyses, only the sarcopenia index using paraspinal muscle was significantly related to recurrence-free survival (hazard ratio = 3.78, 95% confidence intervals = 1.29-5.97, P = 0.009) and overall survival (hazard ratio = 3.13, 95% confidence interval = 1.18-8.26, P = 0.022). Paraspinal sarcopenia index was also related to overall survival (hazard ratio = 3.74, 95% confidence interval = 1.31-10.72, P = 0.014) even in patients with advanced stage. Serum albumin was significantly correlated with the sarcopenia index (P = 0.012). Within the analysis of the validation set, sarcopenia index using paraspinal muscle was related to recurrence-free survival (hazard ratio = 2.06, P = 0.045) in multivariate analysis and recurrence-free survival (P = 0.009) in patients with advanced stage. Conclusions: The sarcopenia index using the paraspinal muscle, not psoas, could be a suitable index to predict recurrence-free survival and overall survival in patients with type-II endometrial cancer even in advanced stage.

    DOI: 10.1093/jjco/hyad086

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  7. The balance between fetal oxytocin and placental leucine aminopeptidase (P-LAP) controls human uterine contraction around labor onset

    Yoshihara, M; Mizutani, S; Matsumoto, K; Kato, Y; Masuo, Y; Harumasa, A; Iyoshi, S; Tano, S; Mizutani, H; Kotani, T; Mizutani, E; Shibata, K; Kajiyama, H

    EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY-X   Vol. 19   page: 100210   2023.9

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    Language:English   Publisher:European Journal of Obstetrics and Gynecology and Reproductive Biology: X  

    A fetal pituitary hormone, oxytocin which causes uterine contractions, increases throughout gestation, and its increase reaches 10-fold from week 32 afterward. Oxytocin is, on the other hand, degraded by placental leucine aminopeptidase (P-LAP) which exists in both terminal villi and maternal blood. Maternal blood P-LAP increases with advancing gestation under the control of non-genomic effects of progesterone, which is also produced from the placenta. Progesterone is converted to estrogen by CYP17A1 localized in the fetal adrenal gland and placenta at term. The higher oxytocin concentrations in the fetus than in the mother demonstrate not only fetal oxytocin production but also its degradation and/or inhibition of leakage from fetus to mother by P-LAP. Until labor onset, the pregnant uterus is quiescent possibly due to the balance between increasing fetal oxytocin and P-LAP under control of progesterone. A close correlation exists between the feto-placental and maternal units in the placental circulation, although the blood in the two circulations does not necessarily mix. Fetal maturation results in progesterone withdrawal via the CYP17A1 activation accompanied with fetal oxytocin increase. Contribution of fetal oxytocin to labor onset has been acknowledged through the recognition that the effect of fetal oxytocin in the maternal blood is strictly regulated by its degradation by P-LAP under the control of non-genomic effects of progesterone. In all senses, the fetus necessarily takes the initiative in labor onset.

    DOI: 10.1016/j.eurox.2023.100210

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  8. The prognostic impact of limited-staging surgery in patients with stage IA epithelial ovarian cancer: a multi-center study with a propensity score-adjusted analysis

    Miyamoto, E; Suzuki, H; Yoshihara, M; Mogi, K; Iyoshi, S; Uno, K; Fujimoto, H; Kitami, K; Tano, S; Emoto, R; Matsui, S; Kajiyama, H

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   Vol. 53 ( 8 ) page: 698 - 703   2023.7

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    Language:English   Publisher:Japanese Journal of Clinical Oncology  

    Objective: Complete-staging surgery is recommended for stage IA ovarian cancer, but may be omitted for various reasons, including the preservation of fertility and an advanced age. We herein investigated the prognostic impact of limited-staging surgery in patients with stage IA epithelial ovarian cancer. Methods: We retrospectively collected data on 4730 patients with malignant ovarian tumors from the databases of multiple institutions and ultimately included 293 with stage IA epithelial ovarian cancer. Limited-staging surgery was defined as one that did not involve hysterectomy, systematic retroperitoneal lymphadenectomy or the collection of ascites cytology. We used an inverse probability of treatment weighting analysis with propensity scores and estimated the hazard ratios of recurrence and death with limited-staging surgery. Results: In total, 176 out of 293 patients (39.9%) were assigned to the limited-staging surgery group. After propensity score adjustments, no significant differences were observed in recurrence-free survival or overall survival between the limited- and complete-staging surgery groups. Even in the subgroup analysis with age stratification, recurrence-free survival and overall survival were similar in the limited- and complete-staging surgery groups. Conclusions: The present results indicate the limited prognostic impact of limited-staging surgery for stage IA epithelial ovarian cancer.

    DOI: 10.1093/jjco/hyad039

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  9. CD271 contributes to progression of ovarian cancer via promoting cell migration and invasion

    Miyamoto, E; Koya, Y; Yoshihara, M; Sugiyama, M; Iyoshi, S; Kitami, K; Uno, K; Mogi, K; Fujimoto, H; Nawa, A; Kajiyama, H

    CANCER SCIENCE   Vol. 114   page: 364 - 364   2023.2

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  10. Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of TGF-β1/THBS1

    Kitami, K; Yoshihara, M; Yamakita, Y; Sugiyama, M; Koya, Y; Miyamoto, E; Fujimoto, H; Iyoshi, S; Uno, K; Mogi, K; Kato, K; Nawa, A; Enomoto, A; Kajiyama, H

    CANCER SCIENCE   Vol. 114   page: 1047 - 1047   2023.2

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  11. Notch signaling can be a new therapeutic target for advanced ovarian cancer

    Sugiyama, M; Yoshihara, M; Koya, Y; Kitami, K; Uno, K; Iyoshi, S; Mogi, K; Yokoi, A; Nakamura, K; Nawa, A; Kajiyama, H

    CANCER SCIENCE   Vol. 114   page: 2065 - 2065   2023.2

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  12. Mesothelial cells that phagocytosed ovarian cancer cells have enhanced signals that suppress antitumor immunity

    Koya, Y; Kitami, K; Yoshihara, M; Sugiyama, M; Mogi, K; Uno, K; Iyoshi, S; Fujimoto, H; Miyamoto, E; Nawa, A; Kajiyama, H

    CANCER SCIENCE   Vol. 114   page: 1224 - 1224   2023.2

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  13. Lineage tracing and functional analysis of ovarian cancer-associated mesothelial cells

    Mogi, K; Yoshihara, M; Taniguchi, T; Yamakita, Y; Miyamoto, E; Fujimoto, H; Kitami, K; Iyoshi, S; Uno, K; Sugiyama, M; Koya, Y; Tomita, H; Nawa, A; Kajiyama, H

    CANCER SCIENCE   Vol. 114   page: 1222 - 1222   2023.2

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  14. Impact of obesity and the role of dedifferentiated adipocytes upon peritoneal metastasis of ovarian cancer

    Iyoshi, S; Yoshihara, M; Nakamura, K; Sumi, A; Sugiyama, M; Koya, Y; Miyamoto, E; Fujimoto, H; Mogi, K; Uno, K; Kitami, K; Emoto, R; Matsui, S; Nawa, A; Kajiyama, H

    CANCER SCIENCE   Vol. 114   page: 978 - 978   2023.2

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  15. Establishing the novel experimental model of tumor-associated fibrosis for ovarian cancer's metastasis

    Fujimoto, H; Yoshihara, M; Yamakita, Y; Sugiyama, M; Koya, Y; Miyamoto, E; Mogi, K; Uno, K; Iyoshi, S; Kitami, K; Nawa, A; Kajiyama, H

    CANCER SCIENCE   Vol. 114   page: 1223 - 1223   2023.2

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  16. Follicle development and its prediction in patients with primary ovarian insufficiency: Possible treatments and markers to maximize the ability to conceive with residual follicles

    Osuka, S; Kasahara, Y; Iyoshi, S; Sonehara, R; Myake, N; Muraoka, A; Nakamura, T; Iwase, A; Kajiyama, H

    REPRODUCTIVE MEDICINE AND BIOLOGY   Vol. 22 ( 1 ) page: e12556   2023.1

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    Language:English   Publisher:Reproductive Medicine and Biology  

    Background: Primary ovarian insufficiency (POI) is characterized by the development of hypergonadotropic hypogonadism before 40 years of age and leads to intractable infertility. Although in vitro fertilization and embryo transfer with donated eggs enables pregnancy, not a few patients desire pregnancy using their oocytes. However, follicular development is rare and unpredictable in patients with POI. Thus, there is a need for treatments that promote the development of residual follicles and methods to accurately predict infrequent ovulation. Methods: This review discusses the effects of various treatments for obtaining eggs from POI patients. Furthermore, this study focused a potential marker for predicting follicular growth in patients with POI. Main Findings: Different treatments such as hormone-replacement therapy, dehydroepiandrosterone supplementation, platelet-rich plasma injection, and in vitro activation have shown varying degrees of effectiveness in retrieving oocytes from patients with POI. To predict follicle development in the cycle, elevated serum estradiol and reduced follicle-stimulating hormone (FSH) levels are important. However, these markers are not always reliable under continuous estradiol-replacement therapy. As a novel marker for predicting follicle growth, serum anti-Müllerian hormone (AMH) levels, measured using the picoAMH enzyme-linked immunosorbent assay, were found to predict follicle growth in patients and the cycle. Conclusion: This review highlights the challenges and available interventions for achieving pregnancy using a patient's oocytes in cases of POI. We believe that a combination of currently available treatments and prediction methods is the best strategy to enable patients with POI to conceive using their own eggs. Although AMH levels may predict follicle growth, further research is necessary to improve the chances of successful follicular development and conception in patients with POI.

    DOI: 10.1002/rmb2.12556

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

    Yoshihara, M; Mogi, K; Kitami, K; Uno, K; Iyoshi, S; Tano, S; Fujimoto, H; Miyamoto, E; Yoshikawa, N; Emoto, R; Matsui, S; Kajiyama, H

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   Vol. 27 ( 10 ) page: 1660 - 1668   2022.10

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    Language:English   Publisher: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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  18. Obesity contributes to the stealth peritoneal dissemination of ovarian cancer: a multi-institutional retrospective cohort study

    Iyoshi, S; Sumi, A; Yoshihara, M; Kitami, K; Mogi, K; Uno, K; Fujimoto, H; Miyamoto, E; Tano, S; Yoshikawa, N; Emoto, R; Matsui, S; Kajiyama, H

    OBESITY   Vol. 30 ( 8 ) page: 1599 - 1607   2022.8

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    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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  19. Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of the TGF-β1/thrombospondin-1 axis

    Kitami, K; Yoshihara, M; Tamauchi, S; Sugiyama, M; Koya, Y; Yamakita, Y; Fujimoto, H; Iyoshi, S; Uno, K; Mogi, K; Ikeda, Y; Yokoi, A; Yoshikawa, N; Nishino, K; Niimi, K; Nawa, A; Enomoto, A; Kajiyama, H

    MATRIX BIOLOGY   Vol. 109   page: 70 - 90   2022.5

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

    Uno, K; Iyoshi, S; Yoshihara, M; Kitami, K; Mogi, K; Fujimoto, H; Sugiyama, M; Koya, Y; Yamakita, Y; Nawa, A; Kanayama, T; Tomita, H; Enomoto, A; Kajiyama, H

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   Vol. 23 ( 8 )   2022.4

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

    Uno, K; Yoshikawa, N; Tazaki, A; Ohnuma, S; Kitami, K; Iyoshi, S; Mogi, K; Yoshihara, M; Koya, Y; Sugiyama, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Kikkawa, F; Kato, M; Kajiyama, H

    SCIENTIFIC REPORTS   Vol. 12 ( 1 ) page: 4513   2022.3

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    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.

    DOI: 10.1038/s41598-022-08503-7

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  22. Adipose-mesothelial crosstalk regulates peritoneal tumor microenvironment and accelerates metastasis of ovarian cancer

    Mogi, K; Yoshihara, M; Uno, K; Iyoshi, S; Kitami, K; Sugiyama, M; Koya, Y; Tamauchi, S; Yokoi, A; Yoshikawa, N; Nawa, A; Kajiyama, H

    CANCER SCIENCE   Vol. 113   page: 735 - 735   2022.2

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  23. Vitamin D inhibits mesothelial-mesenchymal-transition accelerating peritoneal dissemination in ovarian cancer via THBS1

    Kitami, K; Yoshihara, M; Sugiyama, M; Koya, Y; Yamakita, Y; Iyoshi, S; Uno, K; Mogi, K; Tamauchi, S; Yokoi, A; Yoshikawa, N; Nishino, K; Niimi, K; Nawa, A; Kajiyama, H

    CANCER SCIENCE   Vol. 113   page: 729 - 729   2022.2

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  24. Notch-dependent intra-tumoral heterogeneity mediates cell-fate dynamics and development of peritoneal dissemination

    Yoshihara, M; Sugiyama, M; Koya, Y; Iyoshi, S; Kitami, K; Uno, K; Mogi, K; Nawa, A; Kajiyama, H

    CANCER SCIENCE   Vol. 113   page: 1405 - 1405   2022.2

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  25. Notch signaling contributes to drug resistance acquisition through metabolic alteration in advanced ovarian cancer

    Sugiyama, M; Yoshihara, M; Koya, Y; Kitami, K; Uno, K; Iyoshi, S; Mogi, K; Yokoi, A; Nawa, A; Kajiyama, H

    CANCER SCIENCE   Vol. 113   page: 1280 - 1280   2022.2

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  26. NGFR contributes the malignancy of ovarian carcinoma cells

    Koya, Y; Sugiyama, M; Yoshihara, M; Kitami, K; Uno, K; Mogi, K; Iyoshi, S; Nawa, A; Kajiyama, H

    CANCER SCIENCE   Vol. 113   page: 1033 - 1033   2022.2

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

    Iyoshi, S; Yoshihara, M; Nakamura, K; Sugiyama, M; Koya, Y; Kitami, K; Uno, K; Mogi, K; Tano, S; Tomita, H; Kajiwara, K; Taki, M; Yamaguchi, S; Nawa, A; Kajiyama, H

    INTERNATIONAL JOURNAL OF CANCER   Vol. 149 ( 11 ) page: 1961 - 1972   2021.12

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

    Shigeyama, M; Yoshihara, M; Kitami, K; Mogi, K; Uno, K; Iyoshi, S; Tano, S; Yoshikawa, N; Kajiyama, H

    EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY   Vol. 267   page: 221 - 225   2021.12

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    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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  29. 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, M; Tamauchi, S; Iyoshi, S; Kitami, K; Uno, K; Mogi, K; Kajiyama, H

    JOURNAL OF GYNECOLOGIC ONCOLOGY   Vol. 32 ( 5 ) page: e66   2021.9

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

    Yoshihara, M; Emoto, R; Kitami, K; Iyoshi, S; Uno, K; Mogi, K; Tano, S; Yoshikawa, N; Matsui, S; Kajiyama, H

    SCIENTIFIC REPORTS   Vol. 11 ( 1 ) page: 15154   2021.7

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    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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  31. 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, M; Tamauchi, S; Iyoshi, S; Kitami, K; Uno, K; Tano, S; Matsui, S; Kajiyama, H

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   Vol. 51 ( 3 ) page: 387 - 392   2021.3

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    Background: We investigated the prognostic impact of complete-staging lymphadenectomy on patients with clinically apparent Stage I endometrioid epithelial ovarian carcinoma. Methods: We conducted a regional multi-institutional retrospective study between 1986 and 2018. Amongst 4897 patients with malignant ovarian tumours diagnosed under central pathological review, 259 women with Stage I endometrioid epithelial ovarian carcinoma were eligible. We evaluated differences in survival of patients with both pelvic and para-aortic lymphadenectomy (Group A) and those with only pelvic lymphadenectomy and/or clinical lymph node evaluation (Group B). To analyse the therapeutic effects, the baseline imbalance between patients with both pelvic and para-aortic lymphadenectomy and others was adjusted with an inverse probability of treatment weighting using propensity score involving independent clinical variables. Results: In total, 145 patients (56.0%) received both pelvic and para-aortic lymphadenectomy. With propensity score-based adjustment, estimated survival was better in Group A compared with that in Group B but not significant. Pelvic and para-aortic lymphadenectomy also led to no significant improvement of overall survival in most of the subgroups. However, point estimations of the hazard ratio for lymphadenectomy in patients with an age of 45 or younger (hazard ratio, 0.304; 95% confidence interval, 0.094-0.982), a Grade 1-2 (hazard ratio, 0.441; 95% confidence interval, 0.204-0.954) and T1c2-3 tumour (hazard ratio, 0.449; 95% confidence interval, 0.164-1.231) were better compared with those with the opposite characteristics. Conclusions: Complete-staging lymphadenectomy was not a significant prognostic factor in patients with Stage I endometrioid epithelial ovarian carcinoma, where we still need to explore appropriate candidate for the procedure.

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

    Mogi, K; Yoshihara, M; Iyoshi, S; Kitami, K; Uno, K; Tano, S; Koya, Y; Sugiyama, M; Yamakita, Y; Nawa, A; Tomita, H; Kajiyama, H

    CANCERS   Vol. 13 ( 6 ) page: 1 - 13   2021.3

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    Ovarian cancer has one of the poorest prognoses among carcinomas. Advanced ovarian cancer often develops ascites and peritoneal dissemination, which is one of the poor prognostic factors. From the perspective of the “seed and soil” hypothesis, the intra-abdominal environment is like the soil for the growth of ovarian cancer (OvCa) and mesothelial cells (MCs) line the top layer of this soil. In recent years, various functions of MCs have been reported, including supporting cancer in the OvCa microenvironment. We refer to OvCa-associated MCs (OCAMs) as MCs that are stimulated by OvCa and contribute to its progression. OCAMs promote OvCa cell adhesion to the peritoneum, invasion, and metastasis. Elucidation of these functions may lead to the identification of novel therapeutic targets that can delay OvCa progression, which is difficult to cure.

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

    Kitami, K; Yoshihara, M; Sugiyama, M; Koya, Y; Iyoshi, S; Uno, K; Mogi, K; Tamauchi, S; Yokoi, A; Yoshikawa, N; Nawa, A; Kajiyama, H

    CANCER SCIENCE   Vol. 112   page: 351 - 351   2021.2

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  34. Visualization of platinum resistance through mapping trace elements

    Uno, K; Yoshikawa, N; Yoshihara, M; Tazaki, K; Kato, M; Kitami, K; Iyoshi, S; Tamauchi, S; Sugiyama, M; Koya, Y; Kajiyama, H

    CANCER SCIENCE   Vol. 112   page: 906 - 906   2021.2

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

    Yoshihara, M; Sugiyama, M; Koya, Y; Iyoshi, S; Kitami, K; Uno, K; Mogi, K; Tano, S; Tamauchi, S; Yokoi, A; Yoshikawa, N; Nawa, A; Kajiyama, H

    CANCER SCIENCE   Vol. 112   page: 363 - 363   2021.2

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

    Mogi, K; Yoshihara, M; Kitami, K; Iyoshi, S; Uno, K; Tano, S; Sugiyama, M; Koya, Y; Tamauchi, S; Yokoi, A; Yoshikawa, N; Nawa, A; Kajiyama, H

    CANCER SCIENCE   Vol. 112   page: 341 - 341   2021.2

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

    Kitami, K; Yoshihara, M; Koya, Y; Sugiyama, M; Iyoshi, S; Uno, K; Mogi, K; Tano, S; Fujimoto, H; Nawa, A; Kikkawa, F; Kajiyama, H

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   Vol. 21 ( 24 ) page: 1 - 15   2020.12

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    Ovarian cancer (OvCa) is one of the leading causes of death due to its high metastasis rate to the peritoneum. Recurrent peritoneal tumors also develop despite the use of conventional platinum-based chemotherapies. Therefore, it is still important to explore the factors associated with peritoneal metastasis, as these predict the prognosis of patients with OvCa. In this study, we investigated the function of microphthalmia-associated transcription factor (MITF), which contributes to the development of melanoma, in epithelial ovarian cancer (OvCa). High MITF expression was significantly associated with a poor prognosis in OvCa. Notably, MITF contributed to the motility and invasion of OvCa cells, and specifically with their peri-mesothelial migration. In addition, MITF-positive cells expressed the melanoma cell adhesion molecule (MCAM/CD146), which was initially identified as a marker of melanoma progression and metastasis, and MCAM expression was regulated by MITF. MCAM was also identified as a significant prognostic factor for poor progression-free survival in patients with OvCa. Collectively, our results suggest that MITF is a novel therapeutic target that potentially promotes peritoneal metastasis of OvCa.

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

    Yoshihara, M; Tamauchi, S; Iyoshi, S; Kitami, K; Uno, K; Yoshikawa, N; Ikeda, Y; Kawai, M; Nagasaka, T; Kajiyama, H

    EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY   Vol. 254   page: 52 - 56   2020.11

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    Objective: Sex cord-stromal tumours of the ovary are relatively uncommon neoplasms that account for 3 % of all ovarian cancers. Uterine preservation with careful staging is achievable; however, conservative surgery remains controversial. This study examined the prognostic effects of uterine preservation in patients with stage I sex cord-stromal tumours. Study design: This retrospective cohort study was undertaken between January 1986 and February 2019, and the clinicopathological data of 4897 women with malignant ovarian tumours were collected. Seventy-seven patients with stage I sex cord-stromal tumours were eligible for inclusion. The characteristics and survival outcomes of these patients were examined. To investigate the prognostic effects of uterine-preserving surgery, baseline imbalances between patients with and without uterine-preserving surgery were adjusted using an inverse probability of treatment weighting with propensity scores composed of independent clinical variables. Results: The mean ages of patients in the uterine-preserving surgery and non-uterine-preserving surgery groups were 39.8 and 57.8 years, respectively. After inverse probability of treatment weighting adjustments, no significant differences in overall survival (p = 0.205) or recurrence-free survival (p=0.071) were observed between the uterine-preserving surgery and non-uterine-preserving surgery groups. Estimated 10-year overall survival rates were 98.7 % in the uterine-preserving surgery group and 95.9 % in the non-uterine-preserving surgery group, and 10-year recurrence-free survival rates were 87.2 % in the uterine-preserving surgery group and 78.2 % in the non-uterine-preserving surgery group. Uterine-preserving surgery did not significantly affect the site of tumour recurrence. Conclusion: Uterine-preserving surgery may be a feasible surgical option for patients with stage I sex cord-stromal tumours. Further research is needed to guarantee prognostic accuracy and develop effective therapeutic approaches for sex cord-stromal tumours.

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

    Yoshihara, M; Kajiyama, H; Tamauchi, S; Iyoshi, S; Yokoi, A; Suzuki, S; Kawai, M; Nagasaka, T; Takahashi, K; Matsui, S; Kikkawa, F

    INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS   Vol. 150 ( 2 ) page: 177 - 183   2020.8

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    Objective: To investigate the clinical characteristics of women with Stage I primary mucinous epithelial ovarian carcinoma (mEOC) and evaluate the impact of uterus-preserving surgery (UPS) in terms of survival prognosis. Methods: A regional multi-institutional retrospective study conducted between January 1986 and March 2017 by reviewing records of the Tokai Ovarian Tumor Study Group. Clinical and pathologic data and survival outcomes were assessed for women with Stage I primary mEOC. The baseline imbalance between women with and those without UPS was adjusted by an inverse probability of treatment weighting method using the propensity score (PS) of independent clinical variables. Results: Among 4730 women with malignant ovarian tumors, 185 had Stage I primary mEOC and were included in the study. The mean age was 47.6 years (range 12–87 years), and 56 (30.3%) women underwent UPS. After PS-based adjustment, women in the UPS group did not have a poorer prognosis regarding overall survival (P=0.776) or recurrence-free survival (P=0.683). Even after age stratification, there was no statistical difference in survival outcomes between the UPS and non-UPS groups. Conclusion: UPS was not associated with decreased survival and may be a treatment option for women with Stage I primary mEOC irrespective of age.

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  40. 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, M; Kajiyama, H; Tamauchi, S; Iyoshi, S; Yokoi, A; Suzuki, S; Kawai, M; Nagasaka, T; Takahashi, K; Matsui, S; Kikkawa, F

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   Vol. 50 ( 2 ) page: 145 - 151   2020.2

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    Background: The exact impact of full-staging lymphadenectomy on patients with primary mucinous epithelial ovarian carcinoma confined to the ovary is still unclear. In this study, we investigated the prognostic impact of lymphadenectomy covering both pelvic and para-aortic lymph nodes in patients with clinically-apparent stage I mucinous epithelial ovarian carcinoma, using data from multi-institutions under a central pathological review system and analyses with a propensity score-based method. Methods: We conducted a regional multi-institutional retrospective study between 1986 and 2017. Among 4730 patients with malignant ovarian tumors, a total of 186 women with mucinous epithelial ovarian carcinoma were eligible. We evaluated differences in survival outcomes between patients with both pelvic and para-aortic lymphadenectomy and those with only pelvic lymphadenectomy and/or clinical lymph node evaluation. To analyze the therapeutic effects, the baseline imbalance between patients with both pelvic and para-aortic lymphadenectomy and others was adjusted with an inverse probability of treatment weighting using propensity score involving independent clinical variables. Results: Fifty-five patients received both pelvic and para-aortic lymphadenectomy. With PS-based adjustment, both pelvic and para-aortic lymphadenectomy did not have additive effects regarding overall survival (P = 0.696) and recurrence-free survival (P = 0.978). Multivariate analysis similarly showed no significant impact of both pelvic and para-aortic lymphadenectomy on their prognosis. Conclusions: The effect of pelvic and para-aortic lymphadenectomy is limited for clinically-apparent stage I primary mucinous epithelial ovarian carcinoma as long as full peritoneal and clinical lymph node evaluations are conducted. The results of this study should be used as the basis for additional studies, including prospective trials.

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  41. 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   Vol. 29   page: A269 - A270   2019.11

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

    Iyoshi, S; Kajiyama, H; Yoshihara, M; Yamakita, Y; Sugiyama, M; Koya, Y; Ryu, B; Kikkawa, F

    CANCER SCIENCE   Vol. 109   page: 282 - 282   2018.12

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  43. Asymmetrical Distribution of Choline Phospholipids Revealed by Click Chemistry and Freeze-Fracture Electron Microscopy

    Iyoshi, S; Cheng, JL; Tatematsu, T; Takatori, S; Taki, M; Yamamoto, Y; Salic, A; Fujimoto, T

    ACS CHEMICAL BIOLOGY   Vol. 9 ( 10 ) page: 2217 - 2222   2014.10

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    Choline-containing phospholipids (Cho-PLs) are major components of all cellular membranes. We developed an electron microscopic technique to investigate the poorly understood problem of how Cho-PLs are distributed between membrane leaflets. Our method relies on generating freeze-fracture replicas of cells metabolically labeled with the choline analog, propargylcholine, followed by "click" reaction to conjugate biotin to propargylcholine head groups, and immunodetection of biotin with colloidal gold. Using this method in budding yeast, we found that, surprisingly, the Golgi and plasma membrane display a cytoplasmic leaflet-dominant asymmetry in Cho-PL distribution; in contrast, Cho-PLs are evenly distributed between the exoplasmic and cytoplasmic leaflets of other organelle membranes. In mammalian culture cells, the plasma membrane shows symmetrical Cho-PL distribution between leaflets, suggesting a fundamental difference between yeast and mammals. Our method should be expandable to other classes of lipids and will be useful for deciphering the mechanism responsible for generating lipid asymmetry in biological membranes. (Figure Presented)

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  44. Electron Microscopic Visualization of the Filament Binding Mode of Actin-Binding Proteins

    Ito, T; Hirayama, T; Taki, M; Iyoshi, S; Dai, SH; Takeda, S; Kimura-Sakiyama, C; Oda, T; Yamamoto, Y; Maéda, Y; Narita, A

    JOURNAL OF MOLECULAR BIOLOGY   Vol. 408 ( 1 ) page: 26 - 39   2011.4

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    A large number of actin-binding proteins (ABPs) regulate various kinds of cellular events in which the superstructure of the actin cytoskeleton is dynamically changed. Thus, to understand the actin dynamics in the cell, the mechanisms of actin regulation by ABPs must be elucidated. Moreover, it is particularly important to identify the side, barbed-end or pointed-end ABP binding sites on the actin filament. However, a simple, reliable method to determine the ABP binding sites on the actin filament is missing. Here, a novel electron microscopic method for determining the ABP binding sites is presented. This approach uses a gold nanoparticle that recognizes a histidine tag on an ABP and an image analysis procedure that can determine the polarity of the actin filament. This method will facilitate future study of ABPs. © 2011 Published by Elsevier Ltd.

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  45. Human Spire Interacts with the Barbed End of the Actin Filament

    Ito, T; Narita, A; Hirayama, T; Taki, M; Iyoshi, S; Yamamoto, Y; Maéda, Y; Oda, T

    JOURNAL OF MOLECULAR BIOLOGY   Vol. 408 ( 1 ) page: 18 - 25   2011.4

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    Spire is an actin nucleator that initiates actin polymerization at a specific place in the cell. Similar to the Arp2/3 complex, spire was initially considered to bind to the pointed end of the actin filament when it generates a new actin filament. Subsequently, spire was reported to be associated with the barbed end (B-end); thus, there is still no consensus regarding the end with which spire interacts. Here, we report direct evidence that spire binds to the B-end of the actin filament, under conditions where spire accelerates actin polymerization. Using electron microscopy, we visualized the location of spire bound to the filament by gold nanoparticle labeling of the histidine-tagged spire, and the polarity of the actin filament was determined by image analysis. In addition, our results suggest that multiple spires, linked through one gold nanoparticle, enhance the acceleration of actin polymerization. The B-end binding of spire provides the basis for understanding its functional mechanism in the cell. © 2011 Elsevier Ltd.

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  46. Synthesis of a new bifunctionalised fluorescent label and physical properties of the bound form on model peptide of troponin C

    Hirayama, T; Iyoshi, S; Taki, M; Maeda, Y; Yamamoto, Y

    ORGANIC & BIOMOLECULAR CHEMISTRY   Vol. 5 ( 13 ) page: 2040 - 2045   2007

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    A new bifunctional fluorescent label, BRos, was synthesised in order to monitor protein dynamics using fluorescence microscopy, and the photophysical properties were compared with those of bifunctionalised rhodamine, BRho. In a labelling experiment with a model peptide of troponin C, which regulates muscle contraction and relaxation, it was found that BRos was bound to the peptide through two linkages and provided a homogeneous compound, whereas BRho gave a pair of diastereomers having different physical properties in NMR and HPLC analyses. © The Royal Society of Chemistry.

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KAKENHI (Grants-in-Aid for Scientific Research) 2

  1. Interdisciplinary research toward the feto-maternal interface environmental strategies with targeted proteomics

    Grant number:23KK0157  2023.9 - 2027.3

    Grants-in-Aid for Scientific Research  Fund for the Promotion of Joint International Research (International Collaborative Research)

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    Authorship:Coinvestigator(s) 

  2. 臨床プロテオミクスとケミカルバイオロジーに基づいた進行卵巣癌の新規治療戦略の開発

    Grant number:23K19653  2023.8 - 2025.3

    科学研究費助成事業  研究活動スタート支援

    伊吉 祥平

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    Grant amount:\2860000 ( Direct Cost: \2200000 、 Indirect Cost:\660000 )

    本研究課題では、腹腔内において脂肪組織と悪性腹水が織りなす卵巣癌促進的土壌としての腹腔内エコシステムの本質に迫り、その治療標的化を目指す。具体的には新規超耐光性脂肪滴蛍光プローブと脂肪細胞モデルを用いた定量的な脂肪細胞脱分化評価システムを構築し、このアッセイ系により脱分化プロセスを抑制する候補物質を大規模化合物ライブラリーから探索する。更に、卵巣癌患者由来腹水の大規模コホートプロテオミクス解析から得られた知見に基づき、腹腔内への補体活性化阻害剤の投与が腹腔内微小環境改善に寄与する可能性についても検討を行う。