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Molecular Pathology and Novel Clinical Therapy for Uterine

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Molecular Pathology and Novel Clinical Therapy for Uterine ANTICANCER RESEARCH 36 : 4997-5008 (2016) doi:10.21873/anticanres.11068 Review Molecular Pathology and Novel Clinical Therapy for Uterine Leiomyosarcoma TAKUMA HAYASHI 1,2 , MIKI KAWANO 2,3 , TOMOYUKI ICHIMURA 4, KOICHI IDA 1, HIROFUMI ANDO 1, DORIT ZHARHARY 5, YAE KANAI 6, HIROYUKI ABURATANI 7, SUSUMU TONEGAWA 8, TANRI SHIOZAWA 1, NOBUO YAEGASHI 9 and IKUO KONISHI 10 1Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Nagano, Japan; 2Department of Medical Technology, International University of Health and Welfare, Chiba, Japan; 3Department of Health Science, Kyushu University Graduate School of Medicine, Fukuoka, Japan; 4Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka, Japan; 5SIGMA-Aldrich Israel, Rehovot, Israel; 6Pathology Division, Keio University School of Medicine, Tokyo, Japan; 7The Cancer System Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan; 8Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, U.S.A.; 9Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Miyagi, Japan; 10 National Hospital Organization Kyoto Medical Centre, Kyoto, Japan Abstract. Patients with uterine leiomyosarcoma (LMS) disease prevalence of ~37% by 12 months of age. Furthermore, typically present with vaginal bleeding, pain, and a pelvic a recent report showed the loss of ability to induce PSMB9/ β1 i mass, with atypical presentations of hypercalcemia and expression, that is up-regulated by interferon- γ ( IFN γ), in eosinophilia also being reported. Radiographic evaluation with human uterine LMS tissues. Here, we reviewed human uterine combined positron-emission tomography/computed LMS for genetic mutations in the IFN γ signal cascade, and tomography may assist in diagnosis and surveillance in women found serious mutations in three genes, Janus activated kinase with uterine LMS; these are commonly used with stage and 1 (JAK1), signal transducer and activator of transcription 1 tumour grade as prognostic indicators and a recently (STAT1) and PSMB9/ β1 i promoter regions. Moreover, developed risk-assessment index to predict disease-specific molecular experiments demonstrated differential expression of survival. Recent studies have shown that the addition of cyclin E and P27/KIP1, that regulate cell-cycle G 1 arrest via adjuvant therapy after surgical management does not seem to PSMB9/ β1 i expression. The discovery of this mutational improve survival, and ovarian preservation does not appear to activation of a key cell-signalling pathway may provide new negatively impact outcome. Experimentally, it is noteworthy targets for diagnostic approaches and therapeutic intervention. that proteasome subunit beta 9 (PSMB9)/ β1 i-deficient mice exhibit spontaneous development of uterine LMS, with a Uterine mesenchymal tumours have been traditionally divided into benign leiomyomas (LMA) and malignant leiomyosarcomas (LMS), based on cytological atypia, mitotic activity, and other criteria. Globally, uterine LMSs, which are This article is freely accessible online. some of the most common neoplasms in the female genital tract, are relatively rare mesenchymal tumours, having an Correspondence to: Takuma Hayashi, Department of Medical estimated annual incidence of approximately one per 160,000 Technology, International University of Health and Welfare, 4-6, women (1). They account for approximately one-third of Kozunomori, Narita, Chiba, Japan. Tel: +81 263372719, e-mail: [email protected] uterine sarcomas and 1.3% of all uterine malignancies, and are considered aggressive malignancies, with a 5-year Key Words: Uterine leiomyosarcoma, PSMB9/ β1 i, IFN γ, cyclin E, survival rate of only 50% for patients with tumours confined review. to the uterus (2, 3). It is noteworthy that when adjusting for 0250-7005/2016 $2.00+.40 4997 ANTICANCER RESEARCH 36 : 4997-5008 (2016) stage and mitotic count, uterine LMS has a significantly dependent kinase inhibitor 1 (P21/CIP1); P27 kinase worse prognosis than carcinosarcoma (4). Generally, patients inhibitor protein 1 (P27/KIP1); cellular v-KIT Hardy- with uterine LMS present with vaginal bleeding, pain, and a Zuckerman 4 feline sarcoma viral oncogene homolog (c- pelvic mass. Although atypical presentations of uterine LMS KIT); mitogen-inducible gene-2 (MIG2); murine double with hypercalcemia or eosinophilia have been reported, these minute 2 (MDM2); tumour protein 53 (TP53); as well as clinical abnormalities are not considered initial risk factors human uterine LMS growth initiation factor, have all been for this disease (5, 6). compared to myometrium and reported, there is no scientific Since uterine LMS is resistant to chemotherapy and evidence to show that abnormal expression of these factors radiotherapy and surgical intervention is virtually the only directly correlates with the initiation and promotion of means of treatment, the development of an efficient adjuvant human uterine LMS (16-25). As such, the apoptotic and cell- therapy is expected to improve the prognosis of this disease (7- cycle regulatory protein expression profiles of human uterine 9). Matrix metallo-proteinases (MMPs), which degrade LMS are not yet useful for clinical prognostic purposes. components of the extracellular matrix, appear to participate in Previous reports have shown ATP-dependent proteasome tumour invasion and metastasis, and a trend towards prolonged function impairment in mice with a targeted disruption of disease-free survival has been seen in patients with MMP2- PSMB9/ β1 i. In a recent study, we report how Psmb9/ β1 i−/− negative tumours (10, 11). To the best of our knowledge, little mice are prone to the development of uterine neoplasms (12) is known regarding the biology of uterine LMS. Therefore, the (Figure 1). The percentage of animals with overt tumours risk factors that promote the initial development of uterine increases with age after 6 months, with a cumulative LMSs and regulate their growth in vivo remain poorly prevalence of disease in female mice of ~37% by 12 months understood. Earlier reports from our laboratory demonstrated of age and no apparent plateau at this late observation time. that proteasome beta subunit (PSMB)9/ β1 i-deficient mice LMS, which is the most common tumour of the uterus, was exhibit spontaneous development of uterine LMS (12). As observed in the female Psmb9/ β1 i−/− mice, but not in their such, defective PSMB9/ β1 i expression is likely to be one of parental C57BL/6 mice with the same genetic background the risk factors in the development of human uterine LMS, as (Figure 1). Histological examinations of the Psmb9/ β1 i−/− it is in PSMB9/ β1 i-deficient mice (13). Because there is no uterine tumours revealed the common characteristic effective therapy for unresectable uterine LMS, our research abnormalities seen in human uterine LMS: tumours lacked findings may lead to the development of specific molecular lymphoid infiltrates, which is a sign of immune recognition, therapies to treat this disease. and consisted of uniform elongated uterine smooth muscle cells arranged into bundles (Figure 1). The nuclei of the PSMB9/ β1 i-deficient Mice Exhibit tumour cells varied in size and shape, and mitosis was Spontaneous Development of Uterine LMS frequent. In contrast, the uterine smooth muscle cells of C57BL/6 mice were normal in appearance. Whereas relatively In light of significant effects achieved using antibody few Ki-67-positive cells, the proliferating cells of solid therapies directed against tumour-specific antigens, tumours, were observed in the basal cell layer of normal molecular targeting is regarded as a promising strategy for myometrium, most of the basal cells vividly expressed Ki-67 the treatment of malignant tumours (14). Although in Psmb9/ β1 i−/− mice. These histopathological examinations gynaecological cancer, for instance breast cancer and indicated abnormal proliferation of Psmb9/ β1 i−/− uterine endometrial carcinomas, are strongly promoted by female smooth muscle cells in the basal cell layer of normal hormones, the rates of oestrogen and progesterone receptor myometrium. Additionally in Psmb9/ β1 i−/− mice, proteasomal expression is reported to be significantly less in uterine LMS peptidase activity against hydrophobic and basic substrates, compared to the normal myometrium, and were found not to but not acidic substrates, was lower in the spleen and liver correlate with the promotion of initial disease development compared to wild-type mice. Differences in muscle and the or with overall survival (15). Since apoptotic mechanisms brain were not significant. Although flow cytometric analysis have also been implicated in many types of human cancer, showed no difference in the expression of major investigation of apoptotic and cell-cycle regulator histocompatibility complex (MHC) class I molecules, dysregulation in uterine LMS is required to identify immunological antigen-presenting cells from Psmb9/ β1 i−/− molecular pathways that could be involved in the mice were less able to stimulate T-cell hybridomas specific for development of this disease. Although the significant a nucleoprotein (NP) envelope antigen of an influenza A virus. differential expression of apoptotic and cell-cycle regulatory Psmb9/ β1 i−/− mice also had less than half of the wild-type factors, such as sexual hormone receptors (oestrogen levels of CD8-positive cytotoxic T-lymphocytes, and receptor and progesterone
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