Successful pregnancy with stage IB2 uterine cervical cancer: A case report.

BACKGROUND: Although cervical cancer is one of the most common malignancies in pregnancy, its management mainly follows the guidelines for nonpregnant disease state. Within the limited time, patients, and healthcare workers must make difficult decisions to either delay treatment until documented fetal maturity or start immediate treatment based on the disease stage. CASE: The patient was a 37-year-old woman: gravida 1, para 0. Her cervical cytology revealed a high-grade squamous intraepithelial lesion at 8 weeks' gestation. Moreover, invasive squamous cell carcinoma was suspected based on the findings of uterine cervix biopsy. Cervical conization was performed at 11 weeks' gestation, confirming a histopathological diagnosis of squamous cell carcinoma, pT1b2. Cervical cytology findings continued to be negative for intraepithelial lesion or malignancy from 2 weeks after conization until 2 weeks before a cesarean section. In addition, we performed abdominal pelvic lymphadenectomy at 16 weeks' gestation to determine whether the patient could continue her pregnancy. No lymph node metastasis or local recurrence was observed. Finally, a cesarean section and modified radical hysterectomy were performed at 35 weeks' gestation. There was no carcinoma invasion or metastasis. A baby girl weighing 2056 g was delivered with 1- and 5-min Apgar scores of 8 and 9, respectively. Five years postoperatively, there was no evidence of cancer recurrence. CONCLUSION: Management of cervical cancer during pregnancy by using a combination strategy of deep conization and pelvic lymphadenectomy could be an effective strategy for carefully and safely assessing risks of recurrence and metastasis.

YBX2 and cancer testis antigen 45 contribute to stemness, chemoresistance and a high degree of malignancy in human endometrial cancer.

Y-box binding protein 2 (YBX2) has been associated with the properties of both germ cells and cancer cells. We hypothesized that YBX2 might contribute to the characteristics of cancer stem cells (CSCs). In this study, we clarified the function of YBX2 in endometrial cancer stem cells. We established a human YBX2-expressing Ishikawa (IK) cell line (IK-YBX2 cells). We analyzed gene expression associated with stemness and isolated SP cells from IK-YBX2 cells. The SP population of IK-YBX2 cells, the expression of ALDH1 and serial sphere-forming capacity were associated with levels of YBX2 expression. IK-YBX2 cells were resistant to anti-cancer drugs. In gene expression analysis, a gene for cancer testis antigen, CT45, was generally overexpressed in IK-YBX2 cells. YBX2-mediated CT45 expression was associated with increased levels of self-renewal capacity and paclitaxel resistance. The level of CT45 expression was enhanced in high-grade and/or advanced stages of human endometrial cancer tissues. We conclude that expression of YBX2 is essential for the stem cell-like phenotype. CT45 contributes to stemness associated with YBX2 and might be related to the progression of endometrial cancer.

CT-Guided Pelvic Lymph Nodal Brachytherapy.

PURPOSE: This is a report of our initial experience using computed tomography (CT)-guided interstitial high dose rate (HDR) brachytherapy to treat bulky pelvic nodal metastases as a part of definitive radiotherapy. MATERIAL AND METHODS: Between February 2015 and April 2019, 14 cervical/endometrial cancer patients presenting with bulky pelvic node(s) underwent nodal interstitial brachytherapy boost in our institution. In total, 17 nodes were treated. The median maximum diameters of the positive nodes at the time of diagnosis and at the first nodal implant were 25 mm (range: 10-65 mm) and 16 mm (range: 9-51 mm), respectively. Dosimetry data of the lymph nodal target volume and small bowel were collected and compared using the paired-sample t-test. Treatment-related toxicities were classified using the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: The median follow-up time for all patients was 26 months. Local recurrence in pelvic nodes occurred in one patient (7%) after 16 months. One patient experienced grade 3 bladder bleeding, and one patient experienced grade 2 pubic bone fracture. No patient had grade 2 or greater gastrointestinal toxicity. In the dosimetric analysis, the mean nodal brachytherapy D90% in terms of the total equivalent dose of 2 Gy (EQD2) was 65.6 Gyαß10. The mean small bowel dose (SBD)0.1cc and SBD1cc in terms of the total EQD2 were 60.4 and 56.5 Gyαß3, respectively. Nodal D90% was significantly higher in terms of the total EQD2 than the SBD0.1cc (p = 0.003) and SBD1cc (p < 0.001). The Kaplan-Meier 2-year pelvic control estimate was 90%. CONCLUSIONS: CT-guided interstitial HDR pelvic nodal brachytherapy appears to be well tolerated with excellent local control in cervical or endometrial cancer patients with bulky pelvic nodes. This approach may offer a useful therapeutic option for unresected bulky pelvic nodes.

Case of leiomyosarcoma arising from subserosal leiomyoma.

Uterine leiomyosarcoma (LMS) is a rare tumor. It has not been established if these tumors arise de novo or from pre-existing leiomyomas (LM). We report a case herein of LMS arising from a subserosal LM. A 47-year-old nulliparous woman was diagnosed with a uterine tumor measuring 30 cm in diameter by pelvic magnetic resonance imaging. Serum CA-125 level was 369 U/mL, and the lactate dehydrogenase level was elevated (565 IU/L, respectively). Positron emission tomography-computed tomography revealed abnormal uptake (SUVmax = 25.29) of the abdominal tumor. Upon laparotomy, a large tumor with solid and cystic components was shown to arise from a subserosal LM, with invasion into the greater omentum and small intestine. Abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy and small intestine resection were performed. Macroscopic findings showed that the LMS was adherent to a subserosal LM, without continuity between the tumor and the uterus. Our case supports the hypothesis that LMS can arise from a pre-existing LM.

Isolated Incisional Recurrence in a Patient with Early-Stage Endometrial Cancer: A Case Report and Review of the Literature.

Isolated incisional recurrence in a patient with early-stage endometrioid carcinoma is extremely rare. The mechanism of this recurrence also remains unclear. We describe a case of an isolated incisional recurrence of endometrioid carcinoma from the uterine corpus 4 years after the primary surgery. We review the previous literature and discuss the possible mechanism of isolated incisional recurrence. A 56-year-old woman diagnosed with the International Federation of Gynecology and Obstetrics Stage IA and Grade 2 endometrioid carcinoma in the uterine corpus showed an isolated cystic mass in the abdominal wall 4 years after the primary surgery. She underwent resection of the abdominal tumor, and the pathological findings showed endometrioid carcinoma, which was the same as the primary tumor. She received chemotherapy and remained disease free 8 months after chemotherapy. Long-term follow-up is required to detect recurrence, even in patients with early-stage uterine corpus carcinoma.

Safety and efficacy of neoadjuvant chemotherapy with bevacizumab in advanced-stage peritoneal/ovarian cancer patients.

OBJECTIVE: The aim of this study was to evaluate the outcomes of neoadjuvant chemotherapy (NAC) with bevacizumab (Bev) at our institute. MATERIALS AND METHODS: Eleven patients with stage IIIC or IV peritoneal/ovarian cancer who underwent interval debulking surgery (IDS) after NAC with Bev between December 2014 and December 2016 were enrolled retrospectively (TCB group). As a control group, we enrolled 13 patients evaluated between December 2012 and December 2014 who underwent IDS and received NAC without Bev (TC group). Both the TCB and TC groups received combination chemotherapy consisting of paclitaxel (175 mg/m2) or docetaxel (70 mg/m2) and carboplatin (area under the curve 6 mg/mL/min) administered intravenously every 3 weeks (cycles 3-6). RESULTS: All patients in both groups underwent IDS. There were 7 (63.6%) and 8 (61.5%) cases with stage IIIC disease and 4 (36.3%) and 5 (30.7%) with stage IV disease in the TCB and TC groups, respectively. The complete resection rate was 81.8% in the TCB group and 69.2% in the TC group. The rate of achieving either complete or optimal resection was 100% in the TCB group and 69.2% in the TC group (p = 0.043). Hematoxicity (grade 3 or higher) was observed in 9 patients (81.8%) in the TCB group and 12 (92.3%) patients in the TC group. One patient (9%) in the TCB group experienced abdominal incisional hernia due to a fascial defect. CONCLUSION: IDS after NAC with Bev is safe, with a similar efficacy as that after NAC without Bev.

Drug-induced aortitis in a patient with ovarian cancer treated with bevacizumab combination therapy.

OBJECTIVE: To review and evaluate drug-induced vasculitis, which is an extremely rare complication of chemotherapy. CASE REPORT: A 47-year-old woman with ovarian cancer developed aortitis during bevacizumab combination chemotherapy. Contract-enhanced CT showed concentric thickening of the descending aorta. Antibiotics were administered, but a repeat CE-CT scan showed no resolution of the aortitis. To treat the aortitis, she was started on oral prednisolone. A subsequent CE-CT scan showed no signs of aortitis. She was thus re-started on a modified chemotherapy regimen. CONCLUSION: Aortitis should be considered in patients receiving bevacizumab combination therapy who develop persistent fever and upper-abdominal pain. Contrast-enhanced CT is useful for detecting drug-induced aortitis.

Laparoscopic en bloc resection of a para-cervical cancer with OHVIRA syndrome.

OBJECTIVE: There are some reports of cervical cancer with uterus didelphys but a case of clear cell carcinoma (CCCC) with Obstructed Hemivagina and Ipsilateral Renal Anomaly (OHVIRA) syndrome is extremely rare. The aim of this paper was to report a case of CCCC with OHVIRA syndrome and the difficulty in making a preoperative diagnosis. CASE REPORT: A 65 years old woman presented with postmenopausal bleeding and pelvic examination showed right paracervical mass. Preoperative confirmation of cervical carcinoma was difficult due to the location of the mass, which was inaccessible by cervical punch biopsy. Pelvic examination revealed a large mass in pelvic cavity without parametrial invasion and ultrasound showed approximately 70 mm cervical tumor. Laparoscopic surgery revealed clear cell carcinoma of the para-endocervix with OHVIRA syndrome. CONCLUSION: In the case of cervical carcinoma with OHVIRA syndrome, laparoscopic surgery is preferable for the diagnosis and management.

Surgical and survival outcomes of laparoscopic staging surgery for patients with stage I ovarian cancer.

OBJECTIVE: To assess the feasibility and survival outcomes of laparoscopic staging for patients with stage I ovarian cancer. MATERIALS AND METHODS: Consecutive patients who underwent laparoscopic staging surgery for stage I ovarian cancer from January 2002 to December 2014 were evaluated retrospectively by chart review. RESULTS: Twenty-four patients with mean age 43.9 ± 9.9 years and mean body mass index 24.0 ± 3.8 kg/m2 were included, in which 12 (50%) patients were in stage IA and 12 (50%) in stage IC. The histological types included serous in 6 (25%), mucinous in 7 (29.1%), endometrioid in 6 (25%), clear cell in 5 (20.8%) patients. The mean surgical time was 306.4 ± 98.5 min, and the mean blood loss was 204.2 ± 188.6 mL. None of the patients required conversion to laparotomy. The median numbers of resected pelvic and para-aortic lymph nodes were 20 and 4, respectively. One (4.1%) patient encountered bowel injury intraoperatively, and the other 1 (4.1%) patient hydronephrosis postoperatively. The overall survival rate was 95% in the current series in a median follow-up of 31.5 months. CONCLUSION: Laparoscopic staging surgery performed for early stage ovarian cancer has better long term survival outcomes than the literature report. Laparoscopic treatment by a trained gynecologic oncologist is an ideal alternative for early stage ovarian cancer with the advantage of minimal invasiveness.

The utility and effectiveness of an internal iliac artery balloon occlusion catheter in surgery for large cervical uterine fibroids.

OBJECTIVE: Surgery for uterine cervical fibroids is difficult because of restricted surgical access and risks such as intraoperative bleeding or injury to other organs. The internal iliac artery balloon occlusion catheter (IIABOC) provides effective hemostasis for placenta previa and atonic hemorrhage, and is increasingly used in surgery for uterine fibroids for controlling intraoperative hemorrhage. We investigated the efficacy and safety of the IIABOC for controlling intraoperative bleeding in total abdominal hysterectomies (TAH) and abdominal myomectomies (AM) for large cervical fibroids. MATERIAL AND METHODS: From 2007 to 2014, the IIABOC was used in 22 cases (12 for TAH and 10 for AM) in which cervical fibroids fully occupied the pelvic cavity. Intraoperative blood loss, operating time, sample weight, use of blood transfusion, and injury to other organs were assessed. RESULT: Mean blood loss, operative time, and sample weight in the IIABOC cases were 510 mL, 178 min, and 2550 g for TAH; and 727.5 mL, 157.5 min, and 1850 g for AM. Blood loss divided by sample weight in IIABOC cases was significantly lower than that in non-IIABOC cases during the same time period, for both TAH and AM. Allogeneic blood transfusion was not necessary, and complications of injury to other organs did not occur in any of the 22 cases. CONCLUSIONS: For large cervical fibroids with limited operating space, surgery was performed under bleeding control by occlusion of the internal iliac artery with an IIABOC. This technique enables control of hemorrhage and safe operative management in gynecological surgery.

Efficacy of PET/CT to exclude leiomyoma in patients with lesions suspicious for uterine sarcoma on MRI.

OBJECTIVE: To analyze the efficacy of positron emission tomography/computed tomography (PET/CT) for the diagnosis of uterine sarcoma. MATERIALS AND METHODS: Thirty-four patients evaluated between January 2010 and March 2015 were retrospectively enrolled. All patients in whom uterine sarcoma was suspected based on contrast-enhanced magnetic resonance imaging (MRI) findings (heterogeneous, high signal intensity on T2-weighted images and/or high intensity on T1-weighted images) underwent PET/CT for further assessment. Patients were divided into 2 groups based on postoperative pathological findings: uterine sarcoma (n = 15) and leiomyoma (n = 19). The maximum standardized uptake value (SUVmax) of all lesions was measured using PET/CT; we calculated the optimal cutoff value for diagnosing sarcoma. RESULTS: The median SUVmax for uterine sarcoma and leiomyoma was 12 and 4.1, respectively; these values were significantly different. An SUVmax of greater than 7.5 was able to exclude leiomyoma with 80.8% sensitivity and 100% specificity (area under the curve, 95.3%). A cutoff SUVmax of 7.5 yields 100% specificity, and a cutoff SUVmax of 4.4 yields a 100% negative predictive value (NPV). The combination of PET/CT and lactate dehydrogenase (LDH) levels had a sensitivity of 86.6%, specificity of 100%, positive predictive value of 100%, and an NPV of 90.4%. No relation between histopathology or International Federation of Gynecology and Obstetrics (FIGO) stage and 18-fluoro-2-deoxy-d-glucose uptake value on PET/CT was seen. The surgical outcome trended toward a correlation with the SUVmax, although this was not statistically significant. CONCLUSIONS: In patients with MRI findings consistent with either uterine sarcoma or leiomyoma, PET/CT can decrease the false-positive rate by setting an optimal cutoff SUVmax of 7.5. Using this cutoff can avoid unnecessary surgery.

Polycystic ovary syndrome with asynchronous bilateral adnexal torsion in a natural cycle.

Cases involving polycystic ovaries (PCOs) with adnexal torsion in a natural cycle without ovulation induction are rare, and no reports of such cases have described asynchronous bilateral adnexal torsion. Here, we report a case of PCO syndrome (PCOS) with asynchronous bilateral adnexal torsion in a natural cycle. The patient was a 37-year-old woman with a history of 2 gravidas 1 para. Her primary complaint was left lower abdominal pain. Ultrasonography and MRI identified multiple uterine myomas occupying the pelvis and the left ovary, with oedematous swelling that had moved ventrally to the uterus. She was diagnosed with adnexal torsion and underwent emergency laparoscopic adnexectomy. Nine months after surgery, she experienced right lower abdominal pain. Ultrasonography revealed suspected right adnexal torsion and she underwent emergency surgery. The right ovary was twisted 540° counterclockwise and swollen to 7 cm in size, with partial polycystic changes. She was histopathologically diagnosed with a PCO, and the final diagnosis, which also considered the endocrine test results, was PCOS. In PCOS, adnexal torsion may occur if the swollen ovary moves because of a hysteromyoma or other cause. Accordingly, torsion should be considered during the follow-up of patients with PCOS.

Long-term efficacy and safety of aromatase inhibitor use for leiomyomatosis peritonealis disseminata.

Leiomyomatosis peritonealis disseminata is a rare disease characterized by pelvic smooth-muscle nodules of various sizes. It is sometimes misdiagnosed as ovarian or peritoneal carcinoma metastasis; therefore, surgical excision for pathological diagnosis is required. Treatment options include bilateral salpingo-oophorectomy (BSO), gonadotrophin-releasing hormone agonist therapy, and aromatase inhibitor therapy. All of these suppress estrogen levels, but a standard treatment has not been established. A 40-year-old woman had multiple pelvic tumors, suspicious for ovarian cancer. She underwent laparotomy, where frozen sections of the nodules revealed leiomyomatosis peritonealis disseminata. After she completed gonadotrophin-releasing hormone agonist therapy, we performed a total abdominal hysterectomy and BSO with residual-nodule resection, but the nodules recurred 6 months after surgery. We then started letrozole, and 3 years have now elapsed without nodule enlargement or development of new lesions. The long-term use of aromatase inhibitor therapy is thought to be effective and safe for patients with recurrence after BSO.

Laparoscopic technique of para-aortic lymph node dissection: A comparison of the different approaches to trans- versus extraperitoneal para-aortic lymphadenectomy.

Since Dr Dargent first reported endoscopic surgery using retroperitoneal pelvicoscopy to perform pelvic lymph node sampling in 1987, many literature reviews on the safety and feasibility of laparoscopic staging surgery of gynecologic malignancies have been published. However, the procedure of laparoscopic lymphadenectomy is more difficult to perform due to the limited surgical space and associated technical problems. Especially in the para-aortic lymphadenectomy procedure, there are many barriers to overcome in the surgical field, learning curve, and technique. We present a review of lymphadenectomy, especially para-aortic lymphadenectomy.

Long-term survival outcomes of laparoscopic staging surgery in treating endometrial cancer: 20 years of follow-up.

OBJECTIVE: To assess the long-term outcomes of laparoscopic staging surgery (LSS) in treating patients with endometrial carcinoma. MATERIALS AND METHODS: Patients with endometrial cancer who underwent LSS between June 1995 and June 2014 were prospectively registered. Perioperative data, complications, disease recurrence, and long-term survival were measured. RESULTS: The study included 287 consecutive patients [mean age (± standard deviation), 53±10.4 years; mean body mass index, 27.3±6.7 kg/m(2)] with a median follow-up ranging from 1 to 216 months. No laparotomy conversion was recorded for any patient. The mean operative time was 207±63.5 minutes, and the mean blood loss was 183±166.7 mL. The mean numbers of pelvic nodes and para-aortic nodes removed were 18±4.8 and 8±5, respectively. More than 80% of the patients had an International Federation of Gynecology and Obstetrics (FIGO) Stage 1 disease. The overall complication rate was 3.1%, including two patients of bladder injuries and one with bowel injury intraoperatively, and postoperatively one patient with pelvic abscess, three with urinary tract infection, one with voiding difficulty, and one with bowel perforation. The overall survival rates were 94% in 5 years and 92.7% in 20 years. No port-site metastasis was recorded in this study. CONCLUSIONS: Patients with endometrial carcinoma treated by LSS had compatible or even better long-term survival outcomes and less complication in comparison with the published data, in addition to the benefits of its minimally invasive characteristics. LSS should be the treatment of choice for endometrial cancer.

Analysis of positron emission tomography/computed tomography in patients to differentiate between malignant transformation of endometrioma and endometrioma.

PURPOSE: Of those patients who undergo open surgery for a suspicion of malignant transformation of endometrioma (MTOE) due to solid nodule enhancement identified by contrast-enhanced magnetic resonance imaging (MRI), some benign endometrioma cases are included. The aim of this retrospective study was to determine the value and diagnostic accuracy of positron emission tomography/computed tomography (PET/CT) using 18-fluoro-2-deoxy-D-glucose (FDG) to differentiate between MTOE and endometrioma. PATIENTS AND METHODS: We retrospectively analyzed 1599 consecutive patients who underwent laparoscopic surgery for the diagnosis of endometrioma preoperatively and 31 patients who underwent open surgery for a suspicion of MTOE preoperatively from January 2003 to December 2011. We analyzed the age, serum CA125 levels, and MRI findings of the patients and calculated the optimal cut-off value for PET/CT using receiver operating characteristic curve analysis. RESULTS: Of the 1,599 patients who underwent laparoscopic surgery for a suspicion of endometrioma preoperatively, malignancy was identified in one (0.062 %) patient. Of the 31 patients who underwent open surgery for a suspicion of MTOE preoperatively, 11 were diagnosed with endometrioma (false positive group) and 20 with MTOE stage I (positive group). Age, tumor size, presence of shading on MRI and maximum standardized uptake values (SUVmax) on PET/CT were significantly different between the two groups. A SUVmax cut-off >4.0 is capable of excluding endometrioma cases, with 75 % sensitivity and 100 % specificity (area under the curve 90 %). CONCLUSION: PET/CT is a good diagnostic tool for MTOE using the optimal SUVmax cut-off of 4.0 (75 % sensitivity and 100 % specificity).

Outcome of Neoadjuvant Intra-Arterial Chemotherapy and Radical Hysterectomy for Treatment of Bulky Stage IB to Stage IIB Uterine Cervical Cancer: Can Postoperative Irradiation Be Avoided?

OBJECTIVES: We evaluated whether our neoadjuvant intra-arterial chemotherapy (NAIC) effectively precludes the need for postoperative radiation therapy in patients treated by radical hysterectomy for IB2 to IIB cervical cancer. MATERIALS AND METHODS: Study subjects were 52 patients with a bulky cervical tumor diagnosed and treated at Juntendo University Hospital or Juntendo Nerima Hospital. The NAIC combined cisplatin, epirubicin, mitomycin-C, and 5-fluorouracil; and radical hysterectomy was to be performed after 2 cycles. The main variables analyzed were clinical and histologic response to NAIC, NAIC-related adverse events, adjuvant chemotherapies, relapse-free and overall survival, recurrence, and prognostic factors. RESULTS: Patients were judged eligible for radical hysterectomy, and 51 underwent the surgery. The overall positive response (complete response [CR] + partial response [PR]) to NAIC was 88.5%. Median follow-up time was 84 months (5-136 months). Three-year relapse-free survival and overall survival were 80.5% and 77.8%, respectively. The recurrence rate was 19.2% (10/52 patients). Seven (13.5%) of the 52 patients died from the disease during follow-up. Lymph node status (positive vs negative) and the histologic effect of NAIC (grades 0-1 vs grades 2-3) were shown to be prognostic factors (P = 0.024 and P = 0.021, respectively). CONCLUSIONS: Our NAIC strategy seems to be well tolerated and beneficial for patients with bulky IB2 to IIB cervical cancer. With this strategy, radiation therapy remains an option in cases of recurrence. For cases in which lymph node metastasis is found or the histologic effect of NAIC is low, our adjuvant chemotherapy regimen may need adjustment to improve prognosis.

Up-regulation of lymphocyte antigen 6 complex expression in side-population cells derived from a human trophoblast cell line HTR-8/SVneo.

The continual proliferation and differentiation of trophoblasts are critical for the maintenance of pregnancy. It is well known that the tissue stem cells are associated with the development of tissues and pathologies. It has been demonstrated that side-population (SP) cells identified by fluorescence-activated cell sorting (FACS) are enriched with stem cells. The SP cells in HTR-8/SVneo cells derived from human primary trophoblast cells were isolated by FACS. HTR-8/SVneo-SP cell cultures generated both SP and non-SP (NSP) subpopulations. In contrast, NSP cell cultures produced NSP cells and failed to produce SP cells. These SP cells showed self-renewal capability by serial colony-forming assay. Microarray expression analysis using a set of HTR-8/SVneo-SP and -NSP cells revealed that SP cells overexpressed several stemness genes including caudal type homeobox2 (CDX2) and bone morphogenic proteins (BMPs), and lymphocyte antigen 6 complex locus D (LY6D) gene was the most highly up-regulated in HTR-8/SVneo-SP cells. LY6D gene reduced its expression in the course of a 7-day cultivation in differentiation medium. SP cells tended to reduce its fraction by treatment of LY6D siRNA indicating that LY6D had potential to maintain cell proliferation of HTR-8/SVneo-SP cells. On ontology analysis, epithelial-mesenchymal transition (EMT) pathway was involved in the up-regulated genes on microarray analysis. HTR-SVneo-SP cells showed enhanced migration. This is the first report that LY6D was important for the maintenance of HTR-8/SVneo-SP cells. EMT was associated with the phenotype of these SP cells.

SPARC was overexpressed in human endometrial cancer stem-like cells and promoted migration activity.

OBJECTIVES: We previously demonstrated that side-population (SP) cells found in human endometrial cancer tissue have features of cancer stem cells (CSCs). Endometrial cancer SP cells show enhanced migration, the potential to differentiate into the mesenchymal cell lineage, and they are associated with the epithelial-mesenchymal transition (EMT). In this study, we analyzed the expression and function of a specific protein, SPARC (secreted protein acidic and rich in cysteine) which we found to be up-regulated in endometrial cancer. METHODS: We performed microarray expression analysis to screen for up-regulated genes in CSCs using a set of RK12V-SP cells and -non-SP (NSP) cells. We used the MetaCore package to identify the Gene GO pathway MAPs associated with the up-regulated genes. Here, we investigated the expression and functions of SPARC, one of the genes up-regulated in endometrial CSCs. We established SPARC-overexpressing cells by transfecting endometrial cancer cells (Ishikawa cells [IK-SPARC cells]). We characterized these cells' growth rate, tumorigenicity, migration and invasion activity. The levels and locations of SPARC protein expression in Hec1SP cells-derived tumors and endometrial cancer tissues were examined by immunohistochemistry. RESULTS: SPARC was detected by microarray expression analysis during screens for up-regulated genes in SP and NSP CSC. The level of SPARC expression was enhanced in Hec1 SP cells compared with that in Hec1 non-SP cells. SPARC enhanced fibronectin expression and promoted migration activity in IK cells. SPARC expression suppressed tumor growth but promoted formation of tumor stroma. SPARC was expressed in endometrial cancer tissues, in particular, poorly differentiated endometrioid adenocarcinoma, clear and serous adenocarcinoma,but not in normal endometrial tissue. CONCLUSION: This is the first report of overexpression of SPARC in endometrial cancer stem-like cells. SPARC expression is associated with cell migration and stroma formation.

The inhibitory effect of salinomycin on the proliferation, migration and invasion of human endometrial cancer stem-like cells.

GOALS: We previously demonstrated that side-population (SP) cells in human endometrial cancer cells (Hec1 cells) and in rat endometrial cells expressing oncogenic human K-Ras protein (RK12V cells) have features of cancer stem cells (CSCs). Hec1-SP cells showed enhanced migration and the potential to differentiate into the mesenchymal cell lineage. In this study, we analyzed the association of the epithelial-mesenchymal transition (EMT) with the properties of these endometrial CSCs. We also assessed the effects of salinomycin (a compound with EMT-specific toxicity) on the proliferative capacity, migration and invasiveness of these endometrial CSCs using Hec1-SP cells. METHOD: We performed microarray expression analysis to screen for up-regulated genes in CSCs using a set of RK12V-SP cells and -non-SP(NSP) cells and used the Metacore package to identify the Gene GO pathway MAPs involved in the up-regulated genes. To analyze their association with EMT, the expression of several EMT associated genes in Hec1-SP cells was investigated by real time PCR and compared with that in Hec1-NSP cells. We assessed the expression of BAX, BCL2, LEF1, cyclinD and fibronectin by real time PCR. We also evaluated the viabilities, migration and invasive activities, and tumorigenicities of these SP cells and NSP cells in the presence or absence of salinomycin. RESULTS: We demonstrated that i) EMT processes were observed in both RK12V-SP cells and Hec1-SP cells, ii) the level of fibronectin was enhanced in Hec1-SP cells and salinomycin reduced the level of fibronectin expression, iii) salinomycin induced apoptosis and inhibited Wnt signaling, and iv) salinomycin inhibited the proliferation, migration, invasiveness and tumorigenicity of these SP cells. CONCLUSION: This is the first report of an inhibitory effect of salinomycin on the properties of endometrial CSCs.