Boron uptake of boronophenylalanine and the effect of boron neutron capture therapy in cervical cancer cells.

There are few studies about boron neutron capture therapy (BNCT) for cervical cancer. The present study evaluated the biodistribution of boronophenylalanine (BPA) and the effect of BNCT on cervical cancer cell lines. BPA exposure and neutron irradiation of cervical cancer cell lines resulted in decreased survival fraction compared to irradiation only. In vivo cervical cancer tumor boron concentration was highest at 2.5 h after BPA intraperitoneal administration, and higher than in the other organs. BNCT may be effective against cervical carcinoma.

Postsurgical urodynamic study of total laparoscopic nerve-sparing radical hysterectomy for uterine cervical cancer.

AIM: To evaluate the impact on urodynamic results between the laparoscopic nerve-sparing radical hysterectomy (LRH) following a step-by-step procedure and abdominal nerve-sparing radical hysterectomy (ARH) for patients with uterine cervical cancer. METHODS: This retrospective study enrolled 76 patients with cervical cancer: 35 in the LRH group and 41 in the ARH group. We analyzed their postoperative bladder function in a urodynamics study and examined the volume of resected pelvic nerves contained in parametrial sections using S-100 antibody staining. RESULTS: Estimated blood loss and hospital stay after operation for the LRH group were significantly better than those in the ARH group (p < 0.0001). As well, the number of harvested lymph nodes was significantly higher in the LRH group (p = 0.044). There was no difference in perioperative complications between the two groups in this study. The 5-year disease-free survival rates and overall survival rates were 91.2% and 94.0% in the LRH group and 87.8% and 95.1% in the ARH group, both respectively. Although the median residual urine volume were no statistical differences between the LRH group and the ARH group, the recovery of postoperative bladder function (uroflowmetry) in the LRH group rapidly reached presurgery levels at 1 month, and the LRH group had a smaller number of s-100 antibody stained nerves contained the parametrial sections. CONCLUSION: We demonstrated that LRH following a step-by-step procedure could achieve a higher level of prevention of damage to the bladder branch of the pelvic splanchnic nerve plexus and thus restore bladder function more rapidly.

The efficacy of human papillomavirus vaccination in young Japanese girls: the interim results of the OCEAN study.

Human papillomavirus (HPV) vaccine has been used to prevent chronic HPV infection, which accounts for cervical cancer. Japanese Ministry of Health, Labor and Welfare (MHLW) conducted an HPV vaccination campaign in 2010 and the Obstetrical Gynecological Society of Osaka initiated a multicenter, prospective cohort study in Osaka, Japan - OCEAN (Osaka Clinical resEArch of HPV vacciNe) study - to investigate the oncogenic HPV prevalence and the long-term protection rate of HPV vaccine. A total of 2814 participants were enrolled on their visit for HPV vaccination between 12 and 18 years old. Among them, 102 participants received HPV/Pap co-test as primary cancer screening at the age of 20-21. We compared the prevalence in two groups (the vaccinated and the unvaccinated group). HPV infection ratio was significantly lower in the vaccinated group compared to the unvaccinated (12.9% vs. 19.7%; p = .04). In particular, HPV 16 and 18 were not detected in the vaccinated group, while 4.9% of participants in the unvaccinated group were infected (p = .001), suggesting that vaccination provided effective protection against high-risk types of HPV. The cross-protection effect of HPV vaccines was also observed against HPV 31, 45, and 52. Although HPV vaccines were not contributed to the reduction of cervical intraepithelial neoplasia 1 (CIN) (p = .28), CIN2 or worse was not observed in vaccinated group. Our research showed that at the age of 20-21, HPV vaccine inhibited the infection of high-risk HPV and had impacted on the development to CIN2 or worse in Japan.

Hemoperitoneum associated with uterine fibroids: A case report.

INTRODUCTION: Uterine fibroids, which are common benign tumors, rarely cause acute complications. We herein report a case of hemoperitoneum associated with uterine fibroid that could be diagnosed preoperatively with contrast-enhanced computerized tomography (CT). PATIENT CONCERNS: A 48-year-old woman with uterine fibroid developed extremely severe lower abdominal pain on the first day of her menstrual period. DIAGNOSIS: Ultrasonography and contrast-enhanced CT revealed a uterine fibroid and extravasation from the dilated vessels of the uterine fibroid. INTERVENTION: Emergent abdominal hysterectomy was performed. OUTCOMES: The total amount of bleeding was 4,600 mL. Intraoperative blood salvage (1,357 mL), 6 units of red blood cells, 4 units of fresh frozen plasma, and 20 units of platelet concentrates were transfused. The postoperative course was uneventful. Pathological examination confirmed a benign uterine fibroid. CONCLUSION: CT could be useful to determine a diagnosis for bleeding from ruptured subserosal uterine fibroid.

Prognostic significance of peritoneal cytology in low-risk endometrial cancer: comparison of laparoscopic surgery and laparotomy.

BACKGROUND: There is uncertainty surrounding the prognostic value of peritoneal cytology in low-risk endometrial cancer, especially in laparoscopic surgery. The objective of this retrospective study is to determine the prognostic significance of positive peritoneal cytology among patients with low-risk endometrial cancer and to compare it between laparoscopic surgery and conventional laparotomy. METHODS: From August 2008 to December 2019, all cases of pathologically confirmed stage IA grade 1 or 2 endometrial cancer were reviewed at Osaka Medical College. Statistical analyses used the Chi-square test and the Kaplan-Meier log rank. RESULTS: A total of 478 patients were identified: 438 with negative peritoneal cytology (232 who underwent laparotomy and 206 who undertook laparoscopic surgery) and 40 with positive peritoneal cytology (20 who underwent laparotomy and 20 who received laparoscopic surgery). Survival was significantly worse among patients with positive peritoneal cytology compared to patients with negative peritoneal cytology. However, there was no significant difference among patients with negative or positive peritoneal cytology between laparoscopic surgery and laparotomy. CONCLUSION: This retrospective study suggests that, while peritoneal cytology is an independent risk factor in patients with low-risk endometrial cancer, laparoscopic surgery does not influence the survival outcome when compared to laparotomy.

Oncologic outcomes for patients with endometrial cancer who received minimally invasive surgery: a retrospective observational study.

BACKGROUND: Laparoscopic hysterectomy has been performed for patients with endometrial cancer as minimally invasive surgery; however, the long-term outcomes of high-risk disease compared to open surgery remain unclear. METHODS: Eight hundred and eighty-three patients with endometrial cancer who underwent laparoscopic or abdominal hysterectomy were categorized into three groups. Low-risk disease was defined as stage IA disease with endometrioid carcinoma of grade 1 or 2. Uterine-confined disease was defined as stage IA disease with high-grade tumors or stage IB and II disease. Advanced disease was defined as stage III or IV disease. The progression-free survival (PFS) and overall survival (OS) rates were compared between laparoscopic and laparotomic hysterectomy. RESULTS: Among 478 patients with low-risk disease, including 226 with laparoscopy and 252 with laparotomy, the prognosis was not significantly different between the groups (3-year PFS rate, 97.4% vs. 97.1%, p = 0.8; 3-year OS rate, 98.6% vs. 98.3%, p = 0.9). Among the 229 patients with uterine-confined disease, including 51 with laparoscopy and 178 with laparotomy, the prognosis was not significantly different between the groups (3-year PFS rate, 90.5% vs. 85.5%, p = 0.7; 3-year OS rate, 91.3% vs. 92.5%, p = 0.8). Among the 176 patients with advanced disease, including 24 with laparoscopy and 152 with laparotomy, laparoscopic hysterectomy had a higher PFS rate and OS rate than laparotomic hysterectomy (3-year PFS rate, 74.5% vs. 51.5%, p = 0.01; 3-year OS rate, 92.3% vs. 75.1%, p = 0.03). CONCLUSIONS: Laparoscopic procedures are not associated with a poorer outcome than laparotomy in patients with advanced endometrial cancer or uterine-confined endometrial cancer.

The Diagnostic Accuracy of an Intraoperative Frozen Section Analysis and Imprint Cytology of Sentinel Node Biopsy Specimens from Patients with Uterine Cervical and Endometrial Cancer: a Retrospective Observational Study.

Sentinel node biopsy (SNB) may be a decision-making tool for function preservation surgery, including radical trachelectomy and ovary preservation in the treatment of cervical and endometrial cancer. The intraoperative diagnosis is important for guiding treatment decisions for patients with these conditions. Three hundred seventy-one patients with cervical and endometrial cancer received SNB with an intraoperative frozen section analysis and imprint cytology. The sentinel node was cut in half, parallel to the longest axis, to obtain the maximum section area. After performing imprint cytology, one half was used to create a frozen section. The specimen was cut at 2-mm intervals into 5-µm-thick sections, which were subjected to hematoxylin and eosin staining. The diagnostic accuracy of intraoperative frozen section analyses and imprint cytology was compared to the final pathological diagnosis. Among 951 detected sentinel nodes, 51 nodes were found to be positive in the final pathological diagnosis. The sensitivity of a frozen section analysis, imprint cytology and the combination of the two modalities was 76.5%, 72.6%, and 92.2%, respectively. The specificity of a frozen section analysis and imprint cytology was 100%. The negative predictive value of a frozen section analysis and imprint cytology was 98.7% and 98.5%, respectively. In these settings, the accuracy of the frozen section analysis and imprint cytology in the evaluation of SNB specimens was considered acceptable; however, the sensitivity of the combined approach was higher in comparison to when a frozen section analysis or imprint cytology was performed alone.

Serum exosomal microRNA-34a as a potential biomarker in epithelial ovarian cancer.

BACKGROUND: Ovarian cancer (OC) is a leading cause of cancer-related death in women, and thus an accurate diagnosis of the predisposition and its early detection is necessary. The aims of this study were to determine whether serum exosomal microRNA-34a (miR-34a) in ovarian cancer could be used as a potential biomarker. METHODS: Exosomes from OC patients' serum were collected, and exosomal miRNAs were extracted. The relative expression of miR-34a was calculated from 58 OC samples by quantitative real-time polymerase chain reaction. RESULTS: Serum exosomal miR-34a levels were significantly increased in early-stage OC patients compared with advanced-stage patients. Its levels were significantly lower in patients with lymph node metastasis than in those with no lymph node metastasis. Furthermore, its levels in the recurrence group were significantly lower than those in the recurrence-free group. CONCLUSIONS: Serum exosomal miR-34a could be a potential biomarker for improving the diagnostic efficiency of OC.

A survey of Japanese mothers on the effectiveness of the Ministry of Health, Labor and Welfare's revised HPV vaccine leaflet.

Introduction: In June of 2013, Japan's Ministry of Health, Labor and Welfare (MHLW) suspended its position of strong recommendation for the routine immunization of young girls against the Human Papilloma Virus (HPV) because of reports of adverse reactions after the vaccination. For the next four years, the MHLW's website warned about the significance of these adverse events. In January of 2018, MHLW's website was modified to reflect a less negative stance. We have studied public awareness of MHLW's revised leaflet in Japanese women whose daughters were of the targeted age for receiving the HPV vaccine and how this awareness influenced their intentions to get their daughters vaccinated. Materials and Methods: From June to December of 2018, a survey was conducted through the Departments of Obstetrics and Gynecology at 14 different medical facilities. The questionnaire was distributed to women whose daughters were of the HPV-vaccine-targeted age. The survey measured their responses before and after being presented with the 2018-revised MHLW leaflet. Responses from 384 mothers were analyzed. Results: Before being presented with the leaflet, the survey found that the percentage of responder's daughters already vaccinated was 6.5% (24/372). After reading the MHLW leaflet, an additional 6.9% (24/346) responded "I want to get my daughter vaccinated immediately", and 37.6% (130/346) responded "I have positive feelings about HPV vaccination". Discussion: By presenting the new MHLW leaflet at obstetrics and gynecology facilities, we expect to be able to effectively increase the HPV vaccination rate in Japan.

Pharmacokinetic evaluation and antitumor potency of liposomal nanoparticle encapsulated cisplatin targeted to CD24-positive cells in ovarian cancer.

CD24, which is upregulated in several human malignancies, is related to Epithelial-mesenchymal-transition (EMT) and has characteristics of cancer stem-like cells, especially in cisplatin-resistant ovarian carcinoma cells. Drug delivery systems represent a promising therapeutic approach for diseases with treatment resistance, and the present study investigated a novel CD24-targeted drug delivery system for advanced ovarian carcinoma. We produced liposomal cisplatin with a red fluorescent substance - cyanine 5.5 (GL-CDDP-Cy5.5). In order to target CD24-positive cells, an anti-CD24 monoclonal antibody was modified to the above drug (CD24-GL-CDDP-Cy5.5). Specific uptake of CD24-GL-CDDP-Cy5.5 was confirmed using a therapeutically resistant ovarian cancer cell line, Caov-3 cells. Antitumor effects of CD24-GL-CDDP-Cy5.5 were then evaluated in Caov-3 ×enograft mice. CD24-GL-CDDP-Cy5.5 showed more specific uptake by flow cytometry than GL-CDDP-Cy5.5. In xenograft mice, GL-CDDP-Cy5.5 and CD24-GL-CDDP-Cy5.5 treatment had significantly higher platinum concentration in disseminated tumor cells than cisplatin (P<0.05). Moreover, CD24-GL-CDDP-Cy5.5 suppressed tumor growth and prolonged survival time compared with other treatments. Median survival times of the control, cisplatin, GL-CDDP-Cy5.5 and CD24-GL-CDDP-Cy5.5 groups were 37, 36, 46 and 54 days after inoculation, respectively. Immunohistochemical analysis showed that CD24-GL-CDDP-Cy5.5 treatment, compared with GL-CDDP-Cy5.5, decreased the number of CD24-positive cells and suppressed the EMT phenomenon significantly (P<0.05). The present study demonstrated that CD24-GL-CDDP-Cy5.5, compared with other treatments, improved therapeutic efficacy. The present results suggested the potential for targeting anticancer therapeutics for CD24-positive cells to prevent disease progression.

Urodynamic outcomes after pelvic nerve-sparing radical hysterectomy with or without neoadjuvant chemotherapy.

OBJECTIVE: Our purposes of this study were to characterize a group of bulky cervical cancer patients who underwent a nerve sparing radical hysterectomy (NSRH) with or without neoadjuvant chemotherapy (NAC), to compare surgical outcomes and the preservation of bladder function, and to compare prognoses. RESULTS: Fifty-three patients had NSRH without NAC (Group A), and 33 patients had NSRH after NAC (Group B). With regard to prognostic factors, there was only a significant difference between both groups with regard to lymph node metastasis (15% vs 42%, P = 0.01). Moreover, bladder function in Group B patients improved to the same extent as the preoperative rate three months postoperatively. These data were similar to the results in Group A. With regard to overall survival, the 5-year survival rate was 98.1% (95% confidence interval (CI) 87.8-99.7) in Group A and 86.7% (95% CI 71.7-96.7) in Group B (P > 0.1). METHODS: We retrospectively identified 86 patients with cervical cancer who underwent NSRH at Osaka Medical College from May 2009 to November 2016. NAC was performed via balloon occluded arterial infusion. We extracted data on the patient's stage of progress, tumor volume, histological subtype, bleeding volume, urodynamic study results, and postoperative complications. The data were divided into two groups - those patients who received NAC and those who did not - and then compared. CONCLUSIONS: According to our analysis, NSRH surgery after NAC via balloon occluded arterial infusion brings beneficial results to patients with bulky IB2 to IIB cervical cancers.

A rare case of ovarian carcinosarcoma with squamous cell carcinoma.

BACKGROUND: Ovarian carcinosarcoma, which contains sarcomatous and carcinomatous components, is a very rare tumor. The carcinomatous component is often adenocarcinoma, and squamous cell carcinoma is extremely rare. We herein report a case of ovarian carcinosarcoma in which the carcinomatous component was squamous cell carcinoma. CASE PRESENTATION: A 68-year-old woman presented with a huge ovarian tumor with a clinical diagnosis of malignant tumor of the ovary. She underwent hysterectomy, bilateral adnexectomy, omentectomy and lymphadenectomy. Histologically, the tumor cells showed undifferentiated pleomorphic sarcoma as the sarcomatous component and squamous cell carcinoma as the carcinomatous component. The final diagnosis was ovarian carcinosarcoma with squamous cell carcinoma in the carcinomatous component, stage IIIA1. Postoperatively, the patient was treated with six cycles of combination chemotherapy with paclitaxel and carboplatin as adjuvant therapy. The patient was free of disease at 45 months' follow-up consultation. CONCLUSION: This is a rare report of ovarian carcinosarcoma with an epithelial component composed of squamous cell carcinoma. Combination chemotherapy with paclitaxel and carboplatin may be an effective choice as adjuvant chemotherapy in cases of ovarian carcinosarcoma including squamous cell carcinoma.

Preoperative diffusion-weighted magnetic resonance imaging and intraoperative frozen sections for predicting the tumor grade in endometrioid endometrial cancer.

OBJECTIVE: The histological tumor grade is a strong predictor of nodal metastasis in endometrial cancer; as such, an accurate pre- or intraoperative diagnosis is important for performing lymphadenectomy. METHODS: Ninety-one patients with endometrioid endometrial cancer were imaged on DW-MRI with the apparent diffusion coefficient (ADC) calculated and a frozen section (FS) diagnosis made before and at hysterectomy. The diagnostic accuracy for predicting the tumor grade for diffusion weighted magnetic resonance inaging (DW-MRI) and the FS diagnosis compared to the ultimate histologic status was analyzed. RESULTS: Among 91 patients with endometrioid endometrial cancer, high-grade (endometrioid G3) tumors had lower ADC values than low-grade (endometrioid G1/2) tumors. The cut-off of the mean ADCmean values for predicting high-grade tumors resulted in 743×10-6 mm2/sec according to the receiver operating characteristic curve. The true positive rates of ADC values and FSs for the prediction of high-grade tumors did not differ to a statistically significant extent (73.3% vs. 66.7%, p=0.7), however, the true negative rate of ADC values for the prediction of low-grade tumors was significantly lower than that of the FSs (64.5% vs. 98.7%, p=0.01). The kappa statistics of ADC values and FSs were 0.23 and 0.73, respectively. Of note, all five patients with high-grade tumors for whom intraoperative FSs indicated low-grade tumors were predicted to have high-grade tumors on preoperative DW-MRI. CONCLUSION: A FS diagnosis is more suitable for predicting high-grade tumors than DW-MRI; however, physicians should pay close attention to tumors with low ADC values on preoperative DW-MRI.

A case of ovarian clear cell carcinoma arising from ovarian mature cystic teratoma.

BACKGROUND: It is well known that ovarian mature cystic teratomas (MCTs) occasionally go through malignant transformations. Among these, approximately 75% of histological types are squamous cell carcinoma, with the other types being exceptionally rare. We report an extremely rare case of ovarian clear cell carcinoma arising from ovarian mature cystic teratoma. CASE PRESENTATION: The case was a 71-year-old woman with abdominal distention. Ultrasonography and magnetic resonance imaging showed a huge mass in her abdominal cavity. Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed FDG uptake not only in the pelvic tumor but also in the hepatic nodule, thus suggesting metastases. We performed a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and an omentectomy. The pathological diagnosis showed clear cell carcinoma of the right ovary which arose from the MCT with malignant transformation pT2aNXM1. Although the patient underwent chemotherapy, she died after 17 months. CONCLUSION: This case is histologically characteristic of the proof of transition from simple squamous epithelium via simple glandular epithelium to papillary change with atypia. This is the first case report of unaccompanied clear cell carcinoma arising from MCT reported in English literatures.

Neoadjuvant intra-arterial chemotherapy using an original four-lumen double-balloon catheter for locally advanced uterine cervical cancer.

OBJECTIVE: We report a balloon-occluded arterial infusion therapy with an original four-lumen double-balloon catheter (4L-DB) which allows for the efficient injection of an anticancer agent at a high concentration to the target spot for patients with locally advanced uterine cervical cancer. METHODS: One hundred and forty-three patients with locally advanced cervical cancer treated with neoadjuvant intra-arterial chemotherapy (NAIAC) or a primary radical hysterectomy (PRH) were retrospectively assessed. The patients in the NAIAC group received irinotecan 70 mg/m2 intravenously on day 1 and 8 and cisplatin 70 mg/m2 intra-arterially using the 4L-DB on day 2 of a 21-day course, and two courses were performed in principle. The radical hysterectomy was performed within 6 weeks after NAIAC. RESULTS: Ninety-four patients were treated with NAIAC, and 49 patients undertook a PRH. The response rate of NAIAC on MRI was 92.6%. Fourteen patients (14.6%) had no evidence of cancer cells on pathologic diagnoses. The NAIAC group had a longer disease-free survival than the PRH group (p=0.02); however, the overall survival was not significantly different. The relative risk (RR) for recurrence was higher in patients with lymph node metastasis (RR, 4.31; 95% CI, 2.23-8.43) and lower in those who underwent NAIAC (RR, 0.30; 95% CI, 0.14-0.68). CONCLUSION: Our results with NAIAC using the 4L-DB catheter in locally advanced cervical cancer indicates beneficial effects on primary lesions and improves disease-free survival.

The detection of sentinel lymph nodes in laparoscopic surgery can eliminate systemic lymphadenectomy for patients with early stage endometrial cancer.

BACKGROUND: The examination of a sentinel lymph node (SLN), where lymph node metastasis first occurs, may be advocated as an alternative staging technique. The aim of this study was to evaluate the feasibility and detection rates of an SLN biopsy in patients with endometrial cancer. STUDY DESIGN: Two hundred and eleven patients with endometrial cancer underwent an SLN biopsy at hysterectomy using three kinds of tracers including 99m-technetium-labeled tin colloid (99mTc), indigo carmine and indocyanine green. Factors related to the side-specific detection rate, sensitivity and false negative rate were analyzed. RESULTS: The detection rates of the SLN biopsy using 99mTc, indigo carmine and indocyanine green were 77.9, 17.0 and 73.4%, respectively. The detection rate was lower in elderly patients (≥60 years) (67.9 vs 89.2%, p < 0.01), patients with >50% myometrial invasion (68.3 vs 85.2%, p < 0.01), patients with high-grade tumors (69.5 vs 84.9%, p < 0.01) and patients who underwent laparotomy (71.2 vs 84.9%, p < 0.01). There were no significant differences in body mass index. The sensitivity was not significantly different in any factor. However, the false negative rate was higher in patients with > 50% myometrial invasion (11.5 vs 1.2%, p < 0.01), high-grade tumors (13.3 vs 0.8%, p < 0.01) and who underwent laparotomy (12.2 vs 0.4%, p < 0.01). CONCLUSION: Patients who underwent laparoscopy with < 50% myometrial invasion and low-grade tumors not only have higher detection rates, but also have lower false negative rates. These patients may avoid systemic lymphadenectomy according to the status of the SLN biopsy.

The efficacy of the cyclin-dependent kinase 4/6 inhibitor in endometrial cancer.

BACKGROUND: PD-0332991, the selective cyclin-dependent kinase 4/6 inhibitor palbociclib, causes cell cycle arrest by inhibiting phosphorylation of retinoblastoma (Rb) protein. The aim of this study was to evaluate the therapeutic potential of PD-0332991 in endometrial cancer. METHODS AND FINDINGS: Four human endometrial cancer cell lines, ECC, HEC1A, HEC108 and TEN, were treated with PD-0332991 and their function was evaluated. In vivo, the therapeutic efficacy was evaluated in a model of subcutaneous endometrial cancer. An immunohistochemical analysis was performed in 337 endometrial cancer specimens. A proliferation assay revealed that 2 of the 4 cell lines that expressed Rb were sensitive to PD-0332991 with an IC50 of 0.65 µM (HEC1A) and 0.58 µM (HEC108), respectively. Both cell lines had G0/G1 cell cycle arrest after treatment with PD-0332991 according to flow cytometry. In vivo, PD-0332991 had antitumoral efficacy with a reduction in the activity of Ki67 and phosphorylation of Rb. Immunohistochemical analyses revealed that the positive rate of Rb was 67.7%, however, there was no significant relationship between the expression levels of Rb and the tumor grade. CONCLUSIONS: PD-0332991 had therapeutic potential against endometrial cancer cell lines expressing Rb protein. Our immunohistochemical analysis revealed that approximately 70% of patients with endometrial cancer might have therapeutic indications for PD-0332991. Of note, the tumor grade had no impact on the indications for treatment.

CD24 expression is a marker for predicting clinical outcome and regulates the epithelial-mesenchymal transition in ovarian cancer via both the Akt and ERK pathways.

The degree of peritoneal dissemination and chemotherapy-resistant tumors is related to the prognosis in patients with advanced-stage ovarian cancer. The epithelial-mesenchymal-transition (EMT) is a multifaceted pathological program that endows cancer cells with the ability to invade and disseminate. CD24 is frequently overexpressed in various human cancers and is correlated with a poor prognosis. We herein examined the functions of CD24 in human ovarian cancer cell lines and evaluated how it contributes to the molecular mechanism underlying the regeneration of cancer stem-like cells (CSCs) through the EMT mechanism in ovarian carcinoma. We demonstrated that CD24 was expressed in 70.1% of primary ovarian carcinoma tissues, which were obtained from 174 patients, and that the expression of CD24 was an independent predictor of survival in patients with ovarian cancer. The expression of CD24 has been found to be correlated with the FIGO stage, presence of peritoneal and lymph node metastasis. CD24 induces the EMT phenomenon, which is involved in cell invasion, the highly proliferative phenotype, colony formation and which is associated with cisplatin resistance and the properties of CSCs, via the activation of PI3K/Akt, NF-κB and ERK in Caov-3 cisplatin-resistant cell lines. CD24-positive ovarian carcinomas have been shown to have a greater potential for intra-abdominal tumor cell dissemination in in vivo models. Our findings suggest that CD24 induced the EMT phenomenon in ovarian cancer, and that CD24 amplified cell growth-related intracellular signaling via the PI3K/Akt and MAPK pathways by affecting the EMT signal pathways. We believe that CD24 is a key molecule of metastatic progression in the EMT phenomenon and a promising therapeutic target for advanced ovarian cancer.

CD24 expression as a marker for predicting clinical outcome and invasive activity in uterine cervical cancer.

CD24, a small heavily glycosylated mucin-like glycosyl-phosphatidylinositol-anchored cell surface protein, plays an important role in the carcinogenesis of various human malignancies. However, its function in cervical cancer remains unclear. The aim of the present study was to evaluate the expression of CD24 clinicopathologically and to analyze its functional behavior biologically in cervical cancer. A total of 117 uterine cervical cancer tumors were immunohistochemically analyzed using a CD24 monoclonal antibody on paraffin blocks. We also examined whether CD24 enhanced the invasive activity or the Akt, ERK, NF-κB and MMP activity in a uterine cervical cancer cell line (CaSki) by a western blot analysis. The patients with enhanced CD24 expression had a higher rate of advanced clinical stage (50 vs. 16.5%, p<0.01), lymph node metastasis (34.6 vs. 14.3%) and lymphovascular involvement (65.4 vs. 20.4%, p=0.01), and a poor overall and disease-free survival (5-year survival rate: 62 vs. 86%, p=0.03). CD24 overexpression in CaSki cells resulted in activation of Cell Signaling proteins, including Akt, ERK, NF-κB and MMP-9. An invasion assay showed that CD24 overexpression in CaSki cells led to increased invasion ability. The CD24 overexpression also increased mRNA expression of Slug but not Snail. Moreover, the CD24 overexpression also decreased expression of E-cadherin and increased N-cadherin protein levels. Increased expression of CD24 may be associated with tumor progression and prognosis in patients with uterine cervical cancer. CD24 expression may therefore be used not only as a prognostic marker in uterine cervical cancer, but also as a target for the development of new therapeutic approaches.

Met Signaling Cascade Is Amplified by the Recruitment of Phosphorylated Met to Lipid Rafts via CD24 and Leads to Drug Resistance in Endometrial Cancer Cell Lines.

Endometrial cancer is the most prevalent gynecologic cancer in the Western world, and the number of advanced chemotherapy-resistant cancers is increasing with the absolute increase in patients. The development of resistance to chemotherapeutic drugs by cancer cells represents a major challenge in the clinical cure of advanced and metastatic cancers. CD24 has been reported to be a marker for a poor prognosis in several tumors, and we herein examined the functions of CD24 in human endometrioid adenocarcinoma cell lines and evaluated how it contributes to cancer drug resistance. We demonstrated that CD24 was responsible for the recruitment of phosphorylated Met to the lipid raft domain of the cell membrane, resulting in amplification of the Met signaling cascade, ultimately leading endometrial cancer cells to express higher levels of ATP-binding cassette (ABC) transporters. Our findings suggest that CD24-mediated amplification of the Met cascade may contribute to the drug resistance of endometrial cancer.