Molecular Approach to Uterine Leiomyosarcoma: LMP2-Deficient Mice as an Animal Model of Spontaneous Uterine Leiomyosarcoma

Uterine leiomyosarcoma (LMS) develops more often in the muscle tissue layer of the uterine body than in the uterine cervix. The development of gynecologic tumors is often correlated with female hormone secretion; however, the development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not yet known. Importantly, a diagnostic-biomarker which distinguishes malignant LMS from benign tumor leiomyoma (LMA) is yet to be established. Accordingly, it is necessary to analyze risk factors associated with uterine LMS, in order to establish a treatment method. LMP2-deficient mice spontaneously develop uterine LMS, with a disease prevalence of ~40% by 14 months of age. We found LMP2 expression to be absent in human LMS, but present in human LMA. Therefore, defective LMP2 expression may be one of the risk factors for LMS. LMP2 is a potential diagnostic-biomarker for uterine LMS, and may be targeted-molecule for a new therapeutic approach

Identification Of Novel Biomarker For Human Uterine Leiomyosarcoma

Sarcomas are neoplastic malignancies that typically arise in tissues of mesenchymal origin. The identification of novel molecular mechanisms leading to sarcoma formation and the establishment of new therapies has been hampered by several critical factors. Human uterine leiomyosarcoma (Ut-LMS) develops more frequently in the muscle tissue layer of the uterine body than in the uterine cervix. Although the development of gynecologic tumors is often correlated with the secretion of female hormones; that of human Ut-LMS does not and its risk factors remain unknown. Importantly, a diagnostic biomarker that can distinguish malignant Ut-LMS from benign tumor uterine leiomyoma (LMA) has yet to be established. Therefore the risk factor(s) associated with human Ut-LMS to establish a diagnosis and novel therapeutic method. Proteasome b-ring subunit LMP2/b1i-deficient mice spontaneously develop Ut-LMS, with a disease prevalence of ~40% by 14 months of age. We shown that LMP2/b1i expression was absent in human Ut-LMS, but present in other human uterine mesenchymal tumors including uterine LMA. Therefore, defective-LMP2/b1i expression may be one of the risk factors for human Ut-LMS. LMP2/b1i is a potential diagnostic biomarker for human Ut-LMS, and may be a targeted-molecule for a new therapeutic approach

Pathobiology of Human Uterine Leiomyosarcoma for Development of Novel Diagnosis and Clinical Therapy

Uterine sarcomas comprise a group of rare tumours with differing tumour pathobiology, natural history and response to clinical treatment. Diagnosis is often made following surgical treatment for presumed malignant mesenchymal tumours and benign tumours. Currently pre-operative diagnosis does not reliably distinguish between malignant mesenchymal tumours, Uterine Leiomyosarcoma (U-LMS) and benign tumours including Leiomyomas (LMA). U-LMS is the most common sarcoma but other subtypes include endometrial stromal sarcoma (low grade and high grade), undifferentiated uterine sarcoma and adeno sarcoma. Clinical trials have shown no definite survival benefit for adjuvant radiotherapy or chemotherapy, and have been hampered by the rarity and heterogeneity of these tumour types. There is a role of adjuvant treatment in carefully selected cases following multidisciplinary discussion at U-LMS reference centres. In patients with metastatic LMS then systemic chemotherapy can be considered. Accordingly, it is necessary to analyse risk factors associated with human U-LMS, in order to establish a treatment method. Proteasome β-subunit 9 (PSMB9)/β1i-deficient mice spontaneously develop U-LMS, with a disease prevalence of ~37% by 12 months of age. We found PSMB9/β1i expression to be absent in human U-LMS, but present in human LMA. Therefore, defective PSMB9/β1i expression may be one of the risk factors for human U-LMS. PSMB9/β1i is a potential diagnostic-biomarker for human U-LMS, and may be targeted-molecule for a new therapeutic approach. Keywords: PSMB9/β1i; Diagnosis; Mesenchymal tumour; Leiomyosarcoma; Leiomyom

Tumor Immunoediting, from T Cell-Mediated Immune Surveillance to Tumor-Escape of Uterine Leiomyosarcoma

The majority of smooth muscle tumors found in the uterus are benign, but uterine leiomyosarcomas (LMSs) are extremely malignant, with high rates of recurrence and metastasis. The development of gynecologic tumors is often correlated with female hormone secretion; however, the development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not clearly understood. The presentation of antigenic peptides by major histocompatibility complex (MHC) class I molecules is important for tumor rejection by cytotoxic T-lymphocytes (CTLs). Such antigenic peptides are generated as a result of the degradation of intracellular proteins by the proteasome pathway, a process that is influenced by the interferon (IFN)-γ-inducible low molecular mass polypeptide-2 (LMP2) subunit of the 20S proteasome. Homozygous deficient mice for LMP2 are now known to spontaneously develop uterine LMS. LMP2 expression is reportedly absent in human uterine LMS, but present in human myometrium. Further studies revealed a few infiltrating CD56+ NK cells in human uterine LMS tissues. This review aims at summarizing recent insights into the regulation of NK cell function and the T cell-mediated immune system as tumor immune surveillance, first attempts to exploit NK cell activation to improve immunity to tumors

The somatic mutations in Interferon-γ signal molecules in human uterine leiomyosarcoma

Human uterine leiomyosarcoma (U-LMS) is neoplastic malignancy that typically arises in tissues of mesenchymal origin. The identification of novel molecular mechanism leading to human U-LMS formation and the establishment of new therapies has been hampered by several critical points. We earlier reported that mice with a homozygous deficiency for proteasome beta subunit 9 (Psmb9)/β1i, an interferon (IFN)-γ inducible factor, spontaneously develop U-LMS. The use of research findings of the experiment with mouse model has been successful in increasing our knowledge and understanding of how alterations, in relevant oncogenic, tumour suppressive, and signaling pathways directly impact sarcomagenesis. The IFN-γ pathway is important for control of tumour growth and invasion and has been implicated in several malignant tumours. In this study, experiments with human tissues revealed a defective expression of PSMB9/β1i in human U-LMS that was traced to the IFN-γ pathway and the specific effect of somatic mutations of JANUS KINASE (JAK) 1 molecule or promoter region on the locus cording PSMB9/β1i gene. Understanding the molecular mechanisms of human U-LMS may lead to identification of new diagnostic candidates or therapeutic targets against human U-LMS

Diagnosis and Prognostication of Ductal Adenocarcinomas of the Pancreas Based on Genome-Wide DNA Methylation Profiling by Bacterial Artificial Chromosome Array-Based Methylated CpG Island Amplification

To establish diagnostic criteria for ductal adenocarcinomas of the pancreas (PCs), bacterial artificial chromosome (BAC) array-based methylated CpG island amplification was performed using 139 tissue samples. Twelve BAC clones, for which DNA methylation status was able to discriminate cancerous tissue (T) from noncancerous pancreatic tissue in the learning cohort with a specificity of 100%, were identified. Using criteria that combined the 12 BAC clones, T-samples were diagnosed as cancers with 100% sensitivity and specificity in both the learning and validation cohorts. DNA methylation status on 11 of the BAC clones, which was able to discriminate patients showing early relapse from those with no relapse in the learning cohort with 100% specificity, was correlated with the recurrence-free and overall survival rates in the validation cohort and was an independent prognostic factor by multivariate analysis. Genome-wide DNA methylation profiling may provide optimal diagnostic markers and prognostic indicators for patients with PCs

Genome-wide DNA methylation profiles in both precancerous conditions and clear cell renal cell carcinomas are correlated with malignant potential and patient outcome

To clarify genome-wide DNA methylation profiles during multistage renal carcinogenesis, bacterial artificial chromosome array-based methylated CpG island amplification (BAMCA) was performed. Non-cancerous renal cortex tissue obtained from patients with clear cell renal cell carcinomas (RCCs) (N) was at the precancerous stage where DNA hypomethylation and DNA hypermethylation on multiple bacterial artificial chromosome (BAC) clones were observed. By unsupervised hierarchical clustering analysis based on BAMCA data for their N, 51 patients with clear cell RCCs were clustered into two subclasses, Clusters AN (n = 46) and BN (n = 5). Clinicopathologically aggressive clear cell RCCs were accumulated in Cluster BN, and the overall survival rate of patients in Cluster BN was significantly lower than that of patients in Cluster AN. By unsupervised hierarchical clustering analysis based on BAMCA data for their RCCs, 51 patients were clustered into two subclasses, Clusters AT (n = 43) and BT (n = 8). Clinicopathologically aggressive clear cell RCCs were accumulated in Cluster BT, and the overall survival rate of patients in Cluster BT was significantly lower than that of patients in Cluster AT. Multivariate analysis revealed that belonging to Cluster BT was an independent predictor of recurrence. Cluster BN was completely included in Cluster BT, and the majority of the BAC clones that significantly discriminated Cluster BN from Cluster AN also discriminated Cluster BT from Cluster AT. In individual patients, DNA methylation status in N was basically inherited by the corresponding clear cell RCC. DNA methylation alterations in the precancerous stage may generate more malignant clear cell RCCs and determine patient outcome

Potential role of LMP2 as an anti-oncogenic factor in human uterine leiomyosarcoma: Morphological significance of calponin h1

Uterine leiomyosarcoma (LMS) is a highly metastatic smooth muscle neoplasm for which calponin h1 is suspected to have a biological role as a tumor-suppressor. We earlier reported that LMP2-null mice spontaneously develop uterine LMS through malignant transformation of the myometrium, thus implicating this protein as an anti-tumorigenic candidate as well. In the present study, we show that LMP2 may negatively regulate LMS independently of its role in the proteasome. Moreover, several lines of evidence indicate that although calponin h1 does not directly influence tumorigenesis, it clearly affects LMP2-induced cellular morphological changes. Modulation of LMP2 may lead to new therapeutic approaches in human uterine LMS.ArticleFEBS LETTERS. 586(13):1824-1831 (2012)journal articl

Proteasome LMP2/β1i subunit as biomarker for human uterine leiomyosarcoma

Uterine leiomyosarcoma (Ut-LMS) develops more frequently in the myometrium of the uterine body than in the uterine cervix. Although the development of gynecological tumors is often correlated with the secretion of female hormones that of Ut-LMS does not, and its risk factor(s) remain unknown. Importantly, a diagnostic biomarker that can distinguish malignant tumor Ut-LMS from benign tumor leiomyoma (LMA), has yet to be established. Therefore, the risk factor(s) associated with Ut-LMS need to be examined in order to establish a diagnosis and clinical treatment method. Mice with a homozygous deficiency for the proteasome b-ring subunit, low-molecular mass polypeptide (LMP)2/b1i spontaneously develop Ut-LMS, with a disease prevalence of ~40% by 14 months of age. In recent studies, we showed that LMP2/b1i expression was absent in human Ut-LMS, but present in other human uterine mesenchymal tumors including uterine LMA. Moreover, LMP2/b1i is also known to negatively regulate human Ut-LMS tumorigenesis. Additional experiments furthermore revealed the differential expression of cyclin E and calponin h1 in human uterine mesenchymal tumors. Therefore, LMP2/b1i is a potential diagnostic biomarker when combined with the candidate molecules, cyclin E and calponin h1 for human Ut-LMS, and may be a targeted molecule for a new therapeutic approach.---------------------------------------------Cite this article as: Hayashi T, Horiuchi A Aburatani H, Ishiko O, Yaegashi N, Kanai Y, Zharhary D, Tonegawa S, Konishi I. Proteasome LMP2/ß1i subunit as biomarker for human uterine leiomyosarcoma. Int J Cancer Ther Oncol 2014; 2(1):02018.DOI: http://dx.doi.org/10.14319/ijcto.0201.