Active Estrogen-Succinate Metabolism Promotes Heme Accumulation and Increases the Proliferative and Invasive Potential of Endometrial Cancer Cells.

Uterine endometrial cancer (UEC) is an estrogen-related tumor. Succinate and heme metabolism play important roles in the progression of multiple tumors. However, the relationship between estrogen, succinate, and heme metabolism and related regulatory mechanisms remain largely unknown. In this study, we observed that the expression of aminolevulinate delta synthase 1 (ALAS1) and solute carrier family member 38 (SLC25A38) in UEC tissues is significantly higher than that in normal tissues. Further analysis showed that estrogen and succinate increased the expression of ALAS1 and SLC25A38 in uterine endometrial cancer cells (UECC), and the administration of succinate upregulated the level of the estrogen receptor (ER). Silencing nuclear receptor coactivator 1 (NCOA1) reversed the effects of estrogen and succinate via downregulation of ALAS1 expression. Additionally, exposure of UECC to heme increased cell viability and invasiveness, while silencing the NCOA1 gene weakened this effect. These findings revealed that estrogen and succinate can synergistically increase the expression of ALAS1 and SLC25A38 via the ERß/NCOA1 axis, promoting heme accumulation and increasing the proliferative and invasive potential of UECC.

Salvage image-guided freehand interstitial brachytherapy for pelvic sidewall recurrence after hysterectomy for uterine malignancies.

PURPOSE: Pelvic sidewall recurrence after hysterectomy for uterine malignances has a poor prognosis, and the salvage therapy for this type of recurrence is still challenging. The purpose of this study was to investigate the efficacy of freehand high-dose-rate interstitial brachytherapy (HDR-ISBT) through the perineum using transrectal ultrasonography for this disease. METHODS AND MATERIALS: We retrospectively evaluated 42 patients with pelvic sidewall recurrence after hysterectomy for uterine cervical and endometrial cancers. We investigated patients' characteristics, the 2-year local control and survival rates, and late adverse events of the rectum and bladder. RESULTS: The 2-year overall survival, local control, and progression-free survival rates were 73.7% (95% confidence interval [CI], 60.8-89.3%), 69.4% (95% CI, 55.4-80.1%), and 37.3% (95% CI, 24.6-56.5%), respectively. In Cox multivariate analysis, tumor size at recurrence (<45 mm vs. ≥45 mm) (p = 0.04) and disease-free periods after hysterectomy (<10 months vs. ≥10 months) (p < 0.01) were significant prognostic factors for overall survival. Lymph node metastasis at recurrence (p < 0.01) was also a significant prognostic factor for progression-free survival. Three patients experienced Grade 3-4 late proctitis (7%). CONCLUSIONS: Transperineal freehand salvage HDR-ISBT using transrectal ultrasonography was demonstrated to be a curative treatment option for patients with pelvic sidewall recurrence following hysterectomy. Based on the findings of this study, we emphasize the importance of HDR-ISBT for pelvic sidewall recurrence.

Estrogen inhibits autophagy and promotes growth of endometrial cancer by promoting glutamine metabolism.

BACKGROUND: Excessive estrogen exposure is an important pathogenic factor in uterine endometrial cancer (UEC). Recent studies have reported the metabolic properties can influence the progression of UEC. However, the underlying mechanisms have not been fully elucidated. METHODS: Glutaminase (GLS), MYC and autophagy levels were detected. The biological functions of estrogen-MYC-GLS in UEC cells (UECC) were investigated both in vivo and in vitro. RESULTS: Our study showed that estrogen remarkably increased GLS level through up-regulating c-Myc, and enhanced glutamine (Gln) metabolism in estrogen-sensitive UEC cell (UECC), whereas fulvestrant (an ER inhibitor antagonist) could reverse these effects. Estrogen remarkably promoted cell viability and inhibited autophagy of estrogen sensitive UECC. However, CB-839, a potent selective oral bioavailable inhibitor of both splice variants of GLS, negatively regulated Gln metabolism, and inhibited the effects of Gln and estrogen on UECC's growth and autophagy in vitro and / or in vivo. CONCLUSIONS: CB-839 triggers autophagy and restricts growth of UEC by suppressing ER/Gln metabolism, which provides new insights into the potential value of CB-839 in clinical treatment of estrogen-related UEC.

Antitumor effect of XCT790, an ERRα inverse agonist, on ERα-negative endometrial cancer cells.

PURPOSE: The estrogen-related receptor (ERR) α is structurally similar to classical estrogen receptors (ERs), but is considered to be an orphan nuclear receptor. We previously found that ERRα regulates uterine endometrial cancer progression. Here, we investigated the efficacy of XCT790, a selective inverse agonist of ERRα, on endometrial cancer cells in vitro and in vivo. METHODS: HEC-1A and KLE, ERα-negative endometrial cancer cells exhibiting high ERRα expression levels, and HEC-1A cell-derived xenograft model mice were treated with XCT790. Transcriptional activity and cell proliferation were examined using luciferase, WST-8 and colony formation assays, respectively. Cell cycle progression was evaluated using flow cytometry, immunofluorescence cytochemistry and Western blotting. Apoptosis was evaluated using a caspase-3/7 activity assay. RESULTS: We found that XCT790 significantly inhibited ERRα-induced in vitro transcriptional activity, including that of the vascular endothelial growth factor (VEGF) gene, in a concentration-dependent manner (p < 0.05). We also found that XCT790 suppressed colony formation and cell proliferation in a concentration and time-dependent manner (p < 0.01) without cytotoxicity, and induced apoptosis (p < 0.01). XCT790 was found to cause cell cycle arrest at the mitotic phase. Akt and mTOR phosphorylation was found to be inhibited by XCT790, but PI3K levels were not found to be significantly affected. Combination therapy of XCT790 with paclitaxel elicited a synergistic inhibitory effect. Additionally, we found that XCT790 significantly inhibited in vivo tumor growth and angiogenesis, and induced apoptosis without a reduction in body weight, in xenograft models (p < 0.01). CONCLUSIONS: From our data we conclude that XCT790 has an anti-tumor effect on endometrial cancer cells in vitro and in vivo. As such, it may serve as a novel therapeutic agent for endometrial cancer.

Evaluation of pre-surgical models for uterine surgery by use of three-dimensional printing and mold casting.

We propose an approach to supporting pre-surgical planning for the uterus by integrating medical image analysis and physical model generation based on 3D printing. With our method, we first segment the patient-specific anatomy and lesions of the uterus on MR images; then, we create a 3D physical model, an exact replica of the patient's uterus in terms of size and softness, with transparency for easy observation of the internal structures of the uterus. In our experiments, we created pre-surgical models of hysterectomy for five patients who had been diagnosed to have uterine endometrial cancer. An experienced radiologist, the surgeons, and all of the patients cooperated in our experiment for carrying out subjective evaluations of the usefulness of our model. The accuracy of the physical models was evaluated quantitatively by comparison between the MR images of the patients and the CT images of the models. The results showed that the mean values of the errors in gap ranged from 1.19 to 2.22 mm, which was satisfactory for the surgeons. The feedback from both surgeons and patients demonstrated the usefulness and convenience of the models for efficient patient explanation understanding and pre-surgical planning by surgeons.

The Emerging Role of PET/MR Imaging in Gynecologic Cancers.

This article summarizes recent advances in PET/MR imaging in gynecologic cancers and the emerging clinical value of PET/MR imaging in the management of the 3 most common gynecologic malignancies: cervical, endometrial, and ovarian cancers. PET/MR imaging offers superior soft tissue contrast, improved assessment of primary tumor involvement because of high-resolution multiplanar reformats, and functional MR techniques such as diffusion-weighted MR imaging and dynamic contrast-enhanced MR imaging. This article discusses the challenges, future directions, and technical advances of PET/MR imaging, and the emerging new multimodality, multiparametric imaging techniques for integrating morphologic, functional, and molecular imaging data.

Anti-tumor effect of estrogen-related receptor alpha knockdown on uterine endometrial cancer.

Estrogen-related receptor (ERR)α presents structural similarities with estrogen receptor (ER)α. However, it is an orphan receptor not binding to naturally occurring estrogens. This study was designed to investigate the role of ERRα in endometrial cancer progression. Immunohistochemistry analysis on 50 specimens from patients with endometrial cancer showed that ERRα was expressed in all examined tissues and the elevated expression levels of ERRα were associated with advanced clinical stages and serous histological type (p < 0.01 for each). ERRα knockdown with siRNA suppressed angiogenesis via VEGF and cell proliferation in vitro (p < 0.01). Cell cycle and apoptosis assays using flow cytometry and western blot revealed that ERRα knockdown induced cell cycle arrest during the mitotic phase followed by apoptosis initiated by caspase-3. Additionally, ERRα knockdown sensitized cells to paclitaxel. A significant reduction of tumor growth and angiogenesis was also observed in ERRα knockdown xenografts (p < 0.01). These findings indicate that ERRα may serve as a novel molecular target for the treatment of endometrial cancer.

Clinicopathologic Characteristics and Prognostic Factors of Stage I and II Endometrial cancer of the uterus: A Study of 59 Cases / 대한산부인과학회지

OBJECTIVE: The purpose of this study was to evaluate the clinicopathologic findings, treatment, and prognostic factors of uterine endometrial cancer. METHODS: We retrospectively reviewed 59 patients with histologically proven stage I and II endometrial cancer between January 1994 and December 2004, for clinical profiles and survival. The survival of patients was determined by description of last follow up date in medical records or phone calls. RESULTS: The median age at the time of diagnosis was 51 years (range: 30-71 years) and the most common presenting symptom was vaginal bleeding (83.0%). Endometrioid adenocarcinoma was the most common (96.6%) histologic type of all cases. Forty-nine patients (83.0%) were FIGO stage I and 10 patients were stage II (17.0%), and the histological grades of the tumors were 23 (39.0%) grade 1, 17 (28.8%) grade 2, 7 (11.9%) grade 3, and 12 (20.3%) unknown, respectively. All patients were treated by surgery as primary treatment and given postoperative adjuvant therapy including radiation therapy (32.2%), concurrent chemotherapy and radiation therapy (6.8%), and chemotherapy (3.4%). The 5-year disease free survival rate (DFSR) of stage I and stage II were 92.7% and 66.7%, respectively. The age (> or =60) and menopausal status were significant prognostic factors by univariate anlaysis (p=0.0077; p=0.0149, respectively). However, parity, FIGO surgical stage, histological grade, myometrial invasion, and lymph-vascular space invasion were not significant prognostic factors (p>0.05). CONCLUSION: The age (> or =60) and menopause state were significant prognostic factors of stage I and II uterine endometrial cancer affecting survival of the patients.

Expression of Angiopoietin-1 and -2 and Tie-2 mRNA in Uterine Endometrial Cancer / 대한산부인과학회지

OBJECTIVE: This study was purposed to investigate the expression of angiopoietin (Ang) -1 and -2 and Tie-2 mRNA among uterine endometrial cancer, endometrial hyperplasia, and normal endometrium, and to assess the relationships among their expression and other prognostic factors of uterine endometrial cancer. METHODS: The tissues were obtained from patients with uterine endometrial cancer, patients with endometrial hyperplasia, and patients with normal endometrium undergoing hysterectomy. Total RNA was extracted and reverse transcribed into cDNA. Reverse transcription polymerase chain reaction (RT-PCR) and quantitative competitive-PCR (QC-PCR) were performed to evaluate the mRNA expressions of Ang-1 and -2 and Tie-2. Clinicopathologic factors of uterine endometrial cancer were reviewed with the patient's charts and results were analyzed with Mann-Whitney U test, Spearman correlation test and logistic regression analysis. RESULTS: Ang-1 and -2 mRNA expression in uetrine endometrial cancer were higher than that in endometrial hyperplasia and lower than that in normal endometrium (p<0.05), but there was no significant difference in Tie-2 mRNA expression among uterine endometrial cancer, endometrial hyperplasia, and normal endometrium. A definite correlation was found between Ang-1 mRNA expression and clinical stage and CA-125 levels of uterine endometrial cancer (p<0.05). CONCLUSION: The expression of Ang-1 and -2 mRNA could be associated with the progression of uterine endometrial cancer and might have a role as prognostic parameters in uterine endometrial cancer.

Clinocopathologic analysis of survival of 98 patients with uterine endometrial cancer / 대한산부인과학회지

OBJECTIVE: This study was performed to evaluate the clinicopathologic prognostic factors and overall survival in patients with uterine endometrial cancer. METHODS: From Jan, 1995 to Dec. 2000, medical records of 98 patients with endometrial cancer treated in Kosin University Gospel Hospital were reviewed and the overall survival of patients was determined by support of the death statistics of Korea National Statistical Office. Survival rate was analyzed by Kaplan-Meier method and log-rank test was used for curve comparison, Cox proportional hazards model was used for multivariate analysis. RESULTS: The median age of all patients was 53 years. The most common presenting symptom was abnormal vaginal bleeding (65.3%). The most common histological type was endometrioid adenocarcinoma. (85.1%) The overall 5 years survival rate (5YSR) for all 98 patients was 66.8%. The overall 5YSR for premenopause and postmenopause were 80% and 50%, respectively (p=0.08). The overall 5YSR for preop CA-125 level above 35 U/mL, below 35 U/mL were 40%, 80% (p=0.001). The overall 5YSR of stage I, stage II, stage III, stage IV were 86.8%, 76.9%, 39.4%, 14.4% (p=0.001). The overall 5YSR of grade 1, grade 2, grade 3 were 75%, 70%, 45% (p=0.002). The overall 5YSR of myometrium invasion of none, or=1/2, were 84.3%, 80.3%, 57.2% (p=0.004). The overall 5YSR of peritoneal cytology of negative, posivite were 73.4%, 23.8% (p=0.001). The overall 5YSR of lymphnode metastasis negative, positive were 80.1%, 15% (p=0.001). CONCLUSION: The age (>50), preop CA-125 level, FIGO surgical stage, grade, myometrial invasion, lymph node metastasis and peritoneal cytology were significant prognostic factors of uterine endometrial cancer affecting 5YSR by univariate analysis. The myometrium invasion and grade were significant prognostic factors affecting 5YSR by multivariate analysis.

An Analysis of Clinicopathologic Prognostic Factors Affecting Survival in Patients with Uterine Endometrial Cancer / 대한산부인과학회잡지

OBJECTIVE: This study was performed to evaluate the clinicopathologic characteristics and prognostic factors of uterine endometrial cancer affecting survival of the patients. METHODS: Form Jan. 1995 to Dec. 2001, medical records including operation record and pathologic reports of 111 patients with histologically proven endometrial cancer at Samsung Medical Center were reviewed. The survival of patients was determined by description of last follow up date in medical records or phone calls. RESULTS: The median age of all patients was 52 years and the most common presenting symptom was abnormal vaginal bleeding (74.0%). Histologic type of endometrioid adenocarcinoma was the most common (90%) type of all endometrial cancers. The grades were classified into G1 (65.7%), G2 (17.1%), G3 (12.6%) and unknown (4.5%). The FIGO surgical stage was also classified into stage I(75.7%), stage II (14.4%), stage III (9.0%), and stage IV (0.9%). All patients were treated by primary surgery and postoperative adjuvant therapy including radiation therapy (54.1%), chemotherapy (4.5%) was applied. The overall 5-year disease free survival rate (DFSR) was 86.5% and overall 5-year survival rate was 87.8%. The age (p=0.04), grade (p=0.04), myometrial invasion (p=0.047), FIGO surgical stage (p=0.0067), lymph node metastasis (p=0.0001), lymphovascular space invasion (p=0.01) and C-erb B2 (p=0.04) were significant prognostic factors by univariate analysis. CONCLUSION: The age, grade, myometrial invasion, FIGO surgical stage, lymph node metastasis, lymphovascular space invasion and C-erb B2 were significant prognostic factors of uterine endometrial cancer affecting survival of the patients.

Clinicopathologic Characteristics and Prognosis of Endometrial Cancer: A study of 56 Cases / 대한산부인과학회잡지

OBJECTIVES: This study was performed to evaluate the clinicopathologic characteristics and prognosis of uterine endometrial cancer to identify risk factors of the therapeutic and prognostic values. METHODS: This retrospective study was based on medical records including operation records and pathologic reports of 56 patients who underwent surgical treatment with histologically proven endometrial cancer at Kyung-Hee University Medical Center from Sep. 1979 to Aug. 2001. The survival of patients was determined by description of last follow up date in medical records. If more than 3 months passed from last follow up date, we used mail and phone call to identify the status of patients. Univariate analysis was carried out to compare the importance of prognostic variables. RESULTS: The mean age of these patients was 52.4 years, the most common presenting symptom was abnormal vaginal bleeding (91.1%). All except 2 cases of papillary serous carcinoma (3.6%) and 1 case of clear cell carcinoma (1.8%) were endometrioid adenocarcinoma (94.6%). And there are 6 cases of endometrial carcinoma with squamous differentiation. The grades were classified into grade 1 (53.6%), grade 2 (26.8%), grade 3 (19.6%). The FIGO surgical stages were classified into stage\\'a5\\'b0 (55.4%), stage \\'a5\\'b1 (7.1%), stage \\'a5\\'b2 (30.4%), stage \\'a5\\'b3 (7.1%). Most of the patients (87.5%) were treated by surgery only or surgery followed by adjuvant radiotherapy. The overall 5 years survival rate (5YSR) was 65.6%: The FIGO surgical stage \\'a5\\'b0 83.3%; stage \\'a5\\'b1 66.7%; stage \\'a5\\'b2 37.5%; stage \\'a5\\'b3 33.3%. Recurrent case was only one case. The age, parity, and preoperative Pap test were not significant prognostic factors. The depth of myometrium invasion (p<0.05), FIGO surgical stage (p<0.05), peritoneal cytology (p<0.05) and lymph node metastasis (p<0.05) were significant prognostic factors by univariate analysis. CONCLUSIONS: Although the number of patients was not enough, the depth of myometrial invasion, FIGO surgical stage and lymph node metastasis seemed to be significant prognostic factors of uterine endometrial cancer.