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OBJECTIVE: The association between sarcopenia and prognosis in patients with platinum-resistant recurrent ovarian cancer remains unclear. This study investigated whether sarcopenia is a prognostic factor in patients with platinum-resistant recurrent ovarian cancer. METHODS: A total of 52 patients diagnosed with platinum-resistant recurrent ovarian cancer who had undergone non-platinum chemotherapy at our institution formed our study population. Body composition and clinicopathological data of these patients were collected retrospectively. Abdominal computed tomography (CT) scans obtained at the time of platinum-resistant recurrent ovarian cancer diagnosis were used to measure the cross-sectional area of skeletal muscles at L3 level. These values were corrected for height to calculate the skeletal muscle index, and accordingly sarcopenia was defined. Overall survival was defined as the primary outcome of the study. The impact of sarcopenia on overall survival was assessed using Cox proportional hazards regression models with inverse probability weighting of treatment based on propensity scores and log-rank tests. RESULTS: The median patient age was 63 years (IQR: 53-71). The most common International Federation of Gynecology and Obstetrics (FIGO) 2018 stage was stage III (50%) and the most common histology was serous or adenocarcinoma (67.3%). The optimal cut-off value of skeletal muscle index was 35.6 cm2/m2, which was calculated using the data of 21 patients with sarcopenia and 31 without sarcopenia. Sarcopenia was significantly associated with shorter overall survival (HR 1.93; 95% CI 1.06-3.49; p=0.03). Subgroup analysis based on patient attributes and prognostic factors suggested a consistent prognostic impact of sarcopenia. Sarcopenia was identified as a significant risk factor, particularly in patients who had higher CA125 levels (HR, 2.47; 95% CI, 1.07 to 5.69; p=0.034) and a higher neutrophil-to-lymphocyte ratio (HR, 2.92; 95% CI, 1.02 to 8.31; p=0.045). CONCLUSION: Sarcopenia significantly shortened the overall survival of patients with platinum-resistant recurrent ovarian cancer.
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Introduction: Primary small bowel carcinoma in pregnant women is extremely rare. Small bowel cancer is difficult to diagnose because of its rarity, lack of specific clinical symptoms, and particular anatomical features. We experienced a case of primary small bowel adenocarcinoma with ovarian metastasis during pregnancy. This is the first reported case of a patient with small bowel adenocarcinoma whose pregnancy continued to term and ended in delivery. Case Presentation: A 32-year-old pregnant woman developed abdominal pain, and imaging examination revealed an ovarian tumor at 29 weeks of gestation. We performed laparotomy and resected the ovarian tumor, which was initially suspected to be primary ovarian cancer. The patient continued the pregnancy to term. A detailed examination of the abdominal cavity during cesarean delivery at 37 weeks revealed that the primary lesion was located in the small bowel. Conclusion: It is important to recognize that the small bowel may be the primary site of metastatic ovarian cancer. Detailed and careful examination is necessary to diagnose small bowel cancer during pregnancy.
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INTRODUCTION: Bisphosphonates and denosumab increase bone mineral density (BMD) for osteoporosis treatment in patients with aromatase inhibitor-associated bone loss (AIBL). This study aimed to directly compare bisphosphonates with denosumab in treating patients with AIBL and to determine the effect of denosumab on the trabecular bone score (TBS). MATERIALS AND METHODS: Thirty-nine patients with AIBL receiving osteoporosis treatment (21 in the bisphosphonates group and 18 in the denosumab group) were retrospectively evaluated for changes in lumbar spine and femoral BMD, lumbar spine bone quality (assessed by TBS), and blood bone metabolic markers. The Mann-Whitney and Wilcoxon tests were used for statistical evaluation. RESULTS: After 24 months of treatment, the lumbar spine BMD change rate was 5.82 ± 1.10% with bisphosphonates and 10.49 ± 1.20% with denosumab, with the change rate of denosumab significantly increasing over that of bisphosphonates. The change rate in femoral BMD was 2.69 ± 1.16% with bisphosphonates and 2.95 ± 1.26% with denosumab, with no significant difference between the two groups. The rate of decrease in tartrate-resistant acid phosphatase isoform 5b was significantly higher in the denosumab group. The change rate in TBS at 24 months of treatment was 0.53 ± 1.26% in the bisphosphonates group and 1.08 ± 1.33% in the denosumab group, with no significant difference between the two groups. After 24 months, TBS remained stable. CONCLUSION: Both bisphosphonates and denosumab may increase BMD, improve bone metabolism, and inhibit bone quality loss in patients with AIBL.
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Antenatal cervical screening aims to detect cervical intraepithelial neoplasms as precancerous lesions and invasive cervical cancer. Whether this screening is performed routinely during pregnancy varies depending on each country's screening participation rates, guidelines, and the risks to the pregnant woman. In some countries with the high rate of routinely implemented cervical screening among the target women, women are recommended to defer cervical screening intentionally to post-delivery, though having screening in consultation with physicians may be possible if routine screening overlaps. However, when cervical screening rate in fertile women is low and the incidence of cervical cancer is high, cervical screening during pregnancy may play an important role in the early detection of cervical cancer. Cervical screening using high-risk human papillomavirus (HPV) testing is accepted worldwide as a highly sensitive and objective test method, and it should replace traditional primary cervical cytology in the future. However, the benefits and disadvantages of using HPV testing in pregnant women is unclear because a false positive rate may be increased due to pregnant women being generally under an immunosuppressed condition.
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Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptor to which a spider venom latrotoxin is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the ADGRL3 gene), in association with AR signaling, in urothelial tumorigenesis. In human normal urothelial SVHUC cells, AR overexpression and androgen treatment considerably increased the expression levels of ADGRL3/LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3. In SVHUC or SVHUC-AR cells with exposure to a chemical carcinogen 3-methylcholanthrene, LPHN3 activation via ligand (e.g., α-latrotoxin, FLRT3) treatment during the process of the neoplastic/malignant transformation or LPHN3 knockdown via shRNA virus infection induced or reduced, respectively, the oncogenic activity. In N-butyl-N-(4-hydroxybutyl)nitrosamine-treated female mice, α-latrotoxin or FLRT3 injection accelerated the development of bladder tumors. Immunohistochemistry in surgical specimens further showed the significantly elevated expression of LPHN3 in non-muscle-invasive bladder tumors, compared with adjacent normal urothelial tissues, which was associated with a marginally (p = 0.051) higher risk of disease recurrence after transurethral resection. In addition, positivity of LPHN3 and AR in these tumors was strongly correlated. These findings indicate that LPHN3 functions as a downstream effector of AR and promotes urothelial tumorigenesis.
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OBJECTIVES: The aim of this study was to evaluate whether low skeletal muscle mass before initial treatment is an independent prognostic factor defining overall survival (OS) and progression-free survival (PFS) in patients diagnosed with stage III cervical cancer. METHODS: Body composition and clinicopathologic data were collected retrospectively. Information was extracted and analyzed from the medical records of 92 patients with stage III cervical cancer and undergoing concurrent chemoradiotherapy. Skeletal muscle mass in the L3 region was measured using cross-sectional computed tomography images and corrected for body surface area to calculate the skeletal muscle index (SMI). The primary outcome was OS, and the secondary outcome was PFS. Statistical analyses were performed using the Mann-Whitney U test. The Kaplan-Meier method was used to determine OS and PFS. Univariate and multivariate analyses were performed with Cox proportional hazard ratios. RESULTS: The optimal cutoff value for predicting 5-y survival was 35.6 cm2/m2, defined based on data derived from 24 patients with a low SMI and 68 patients without a low SMI. A low SMI was significantly associated with shorter OS (hazard ratio [HR], 2.470; 95% confidence interval [CI], 1.208-5.053; P = 0.013), with no significant difference in PFS (HR, 1.651; 95% CI, 0.876-3.110; P = 0.121). Multivariate analysis also identified a low SMI as an independent OS-defining prognostic factor (HR, 2.473; 95% CI, 1.151-5.314; P = 0.020). CONCLUSION: A low pretreatment SMI is an independent prognostic factor for OS in patients diagnosed with stage III cervical cancer and treated with concurrent chemoradiotherapy.
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Sarcopenia , Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/terapia , Sarcopenia/diagnóstico , Pronóstico , Estudios Retrospectivos , Estudios Transversales , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , QuimioradioterapiaRESUMEN
In 2013, the Ministry of Health, Labor, and Welfare (MHLW) in Japan announced a suspension of the governmental recommendation for routine HPV vaccinations. In 2020, MHLW started individual notifications of HPV vaccine to the targeted girls. In April 2022, the governmental recommendation was restarted, and catch-up vaccinations started. We evaluated the benefits and limitations of the MHLW's new vaccination strategies by estimating the lifetime risk for cervical cancer for each birth FY under different scenarios to suggest a measure for the vaccine suspension generation. It was revealed that catch-up immunization coverage among the unvaccinated must reach as high as 90% in FY2022, when the program begins, in order to reduce the risk of the females already over the targeted ages to the same level or lower than that of women born in FY1994-1999 who had high HPV vaccination rates. For women whose vaccination coverage waned because of their birth FYs, strong recommendations for cervical cancer screening should be implemented.
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OBJECTIVE: This study was conducted to evaluate the status and role of cervical cytology affected by human papillomavirus infection and other infectious diseases screened during routine prenatal checkups. METHODS: We retrospectively examined medical records containing the screening results for infectious diseases and cervical cancer in women who delivered neonates in our hospital from 2014 to 2017. RESULTS: Among 3393 deliveries, 18.8% of women underwent a regular cervical cancer screening within 1 year of becoming pregnant, and 2641 women underwent a cervical cytology screening during this pregnancy. The cytological diagnostic results showed that 2562 women (97.0%) were negative for intraepithelial lesions or malignancy, whereas 79 (3.0%) had abnormal results. Of those with abnormal cytology results, 70 had abnormal cytology that was newly detected in this pregnancy, and 42 had grade ≥1 cervical intraepithelial neoplasia lesions. Spatulas were the most frequently used cytological sampling instruments, followed by cotton swabs. Cervical cytology revealed no major adverse reactions during these pregnancies. CONCLUSIONS: Our results confirm the importance of screening for infectious diseases during pregnancy. Only 20% of the women underwent a regular pre-pregnancy cervical cytology screening. Cervical cytology screening during pregnancy may currently be playing a crucial role in preventing cervical cancer in Japan.
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Enfermedades Transmisibles , Infecciones por Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Colposcopía , Detección Precoz del Cáncer/métodos , Femenino , Humanos , Recién Nacido , Tamizaje Masivo , Papillomaviridae , Infecciones por Papillomavirus/diagnóstico , Embarazo , Estudios Retrospectivos , Neoplasias del Cuello Uterino/patología , Frotis Vaginal , Displasia del Cuello del Útero/diagnósticoRESUMEN
The underlying molecular mechanisms of resistance to cisplatin-based systemic chemotherapy in bladder cancer patients remain to be elucidated, while the link between androgen receptor (AR) activity and chemosensitivity in urothelial cancer has been implicated. Our DNA microarray analysis in control vs. AR knockdown bladder cancer lines identified GULP1 as a potential target of AR signaling. We herein determined the relationship between AR activity and GULP1 expression in bladder cancer cells and then assessed the functional role of GULP1 in cisplatin sensitivity. Androgen treatment in AR-positive cells or AR overexpression in AR-negative cells considerably reduced the levels of GULP1 expression. Chromatin immunoprecipitation further showed direct interaction of AR with the promoter region of GULP1. Meanwhile, GULP1 knockdown sublines were significantly more resistant to cisplatin treatment compared with respective controls. GULP1 knockdown also resulted in a significant decrease in apoptosis, as well as a significant increase in G2/M phases, when treated with cisplatin. In addition, GULP1 was immunoreactive in 74% of muscle-invasive bladder cancers from patients who had subsequently undergone neoadjuvant chemotherapy, including 53% of responders showing moderate (2+)/strong (3+) expression vs. 23% of non-responders showing 2+/3+ expression (P = 0.044). These findings indicate that GULP1 represents a key downstream effector of AR signaling in enhancing sensitivity to cisplatin treatment.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Receptores Androgénicos/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Cisplatino/uso terapéutico , Biología Computacional , Femenino , Humanos , Inmunohistoquímica , Masculino , Receptores Androgénicos/genéticaRESUMEN
BACKGROUND: The incidence and risk factors of severe anaphylaxis by intravenous anti-cancer drugs are unclear, whereas those of milder reactions have been reported. STUDY DESIGN: Electronic medical charts of cancer patients who have undergone intravenous chemotherapy between January 2013 and October 2020 in a university hospital were retrospectively reviewed. Non-epithelial malignancies were also included in the analysis. "Severe anaphylaxis" was judged using Brown's criteria: typical presentation of anaphylaxis and one or more of hypoxia, shock, and neurologic compromise. (UMIN000042887). RESULTS: Among 5584 patients (2964 males [53.1%], 2620 females [46.9%], median age 66 years), 88,200 person-day anti-cancer drug administrations were performed intravenously, and 27 severe anaphylaxes were observed. The causative drugs included carboplatin (14 cases), paclitaxel (9 cases), and cisplatin, docetaxel, trastuzumab, and cetuximab (1 case each). The person-based lifetime incidence of severe anaphylaxis for patients who received at least one intravenous chemotherapy was 0.48% (27/5584, 95% confidence interval (CI) 0.30%-0.67%) and the administration-based incidence was 0.031% (27/88,200, 95% CI 0.019%-0.043%). Among 124 patients who received at least 10 carboplatin administrations, 10 patients experienced carboplatin-induced severe anaphylaxis (10/124, 8.1%, 95% CI 3.0%-13.1%). Carboplatin caused severe anaphylaxis after at least 9-min interval since the drip started. Thirteen out of 14 patients experienced carboplatin-induced severe anaphylaxis within a 75-day interval from the previous treatment. Paclitaxel infusion caused severe anaphylaxis after a median of 5 min after the first drip of the day at a life-long incidence of 0.93% (9/968, 95% CI 0.27%-1.59%). CONCLUSION: We elucidated the high-risk settings of chemotherapy-induced severe anaphylaxis.
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Anafilaxia/inducido químicamente , Antineoplásicos/efectos adversos , Administración Intravenosa , Anciano , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
AIM: We aimed to conduct a fixed-point observation questionnaire survey of changes in young women's human papillomavirus (HPV) vaccination status over the course of 10 years. We also investigated the influence of suspension of governmental recommendation for HPV vaccination since June 2013. METHODS: During 2011-2020, we conducted a self-completed questionnaire survey among newly enrolled female medical school students in Yokohama, Japan. The questionnaire featured items regarding HPV vaccination status, age, previous sex education, and knowledge about cervical cancer and HPV vaccination. RESULTS: HPV vaccine uptake rates in 2011 (5.4%) and 2012 (13.5%), when vaccination was self-funded, increased after 2013 (48.7%), when vaccination fees were subsidized. The rate dropped drastically in 2019 (14.3%) and 2020 (5.1%), after suspension of recommendation by the government. Comparisons between new students in 2015/2016, who had high vaccination rates (65.2%), and new students in 2019/2020, who had low vaccination rates (9.8%), showed decreased levels of HPV vaccination awareness, with fewer students having covered cervical cancer prevention in sex education and with respondents having less knowledge about the details of HPV vaccination. CONCLUSIONS: After the suspension of proactive HPV vaccine recommendation, markedly fewer students have been vaccinated against HPV, even those at the vaccination target age. This situation has substantially influenced the lower awareness about cervical cancer prevention, even among medical school students. To protect young women from cervical cancer in Japan, it is crucial for the government to resume proactive recommendation of HPV vaccines as soon as possible.
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Alphapapillomavirus , Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Femenino , Estudios de Seguimiento , Conocimientos, Actitudes y Práctica en Salud , Humanos , Infecciones por Papillomavirus/prevención & control , Facultades de Medicina , Estudiantes , Encuestas y Cuestionarios , VacunaciónRESUMEN
Underlying mechanisms for resistance to cisplatin-based chemotherapy in bladder cancer patients are largely unknown, although androgen receptor (AR) activity, as well as extracellular signal-regulated kinase (ERK) signaling, has been indicated to correlate with chemosensitivity. We also previously showed ERK activation by androgen treatment in AR-positive bladder cancer cells. Because our DNA microarray analysis in control vs. AR-knockdown bladder cancer lines identified BXDC2 as a potential downstream target of AR, we herein assessed its functional role in cisplatin sensitivity, using bladder cancer lines and surgical specimens. BXDC2 protein expression was considerably downregulated in AR-positive or cisplatin-resistant cells. BXDC2-knockdown sublines were significantly more resistant to cisplatin, compared with respective controls. Without cisplatin treatment, BXDC2-knockdown resulted in significant increases/decreases in cell proliferation/apoptosis, respectively. An ERK activator was also found to reduce BXDC2 expression. Immunohistochemistry showed downregulation of BXDC2 expression in tumor (vs. non-neoplastic urothelium), higher grade/stage tumor (vs. lower grade/stage), and AR-positive tumor (vs. AR-negative). Patients with BXDC2-positive/AR-negative muscle-invasive bladder cancer had a significantly lower risk of disease-specific mortality, compared to those with a BXDC2-negative/AR-positive tumor. Additionally, in those undergoing cisplatin-based chemotherapy, BXDC2 positivity alone (p = 0.083) or together with AR negativity (p = 0.047) was associated with favorable response. We identified BXDC2 as a key molecule in enhancing cisplatin sensitivity. AR-ERK activation may thus be associated with chemoresistance via downregulating BXDC2 expression in bladder cancer.
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BACKGROUND/AIM: This study aimed to evaluate the outcome of radiation therapy for patients with distant lymph node (LN) metastases, without organ metastases from uterine cervical cancer (UCC). PATIENTS AND METHODS: Twenty-six patients with UCC with distant LN metastases received radiotherapy and were retrospectively analyzed. The sites of distant LN metastasis were as follows; Supraclavicular in 19, inguinal in nine, axillary in four, and others in three. The mean dose prescribed for these was 50 (range=40-60) Gy. RESULTS: The 2-year overall, cause-specific, and progression-free survival, and local control of primary tumor rates were 51.3%, 51.3%, 46.9%, and 67.9%. In multivariate analysis, performance status ≥1 (p=0.007), para-aortic LN metastases (p=0.001), and lack of high-dose-rate intracavitary brachytherapy (p=0.033) were significantly associated with poor overall survival. Performance status ≥1 (p=0.004), and para-aortic LN metastases (p=0.014) were significantly associated with poor cause-specific survival. CONCLUSION: This study demonstrated favorable local control in patients with UCC with distant LN metastases.
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Neoplasias del Cuello Uterino , Femenino , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática , Estadificación de Neoplasias , Estudios Retrospectivos , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/radioterapiaRESUMEN
Although intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been the gold standard for nonsurgical management of non-muscle-invasive bladder cancer, a considerable number of patients exhibit resistance to the adjuvant treatment with unexplained mechanisms. This study aimed to investigate whether and how androgen receptor (AR) signals modulate BCG cytotoxicity in bladder cancer. AR knockdown or overexpression in bladder cancer lines resulted in induction or reduction, respectively, in intracellular BCG quantity and its cytotoxic activity. Microarray screening identified Rab27b, a small GTPase known to mediate bacterial exocytosis, which was upregulated in BCG-resistant cells and downregulated in AR-shRNA cells. Knockdown of Rab27b, or its effector SYTL3, or overexpression of Rab27b also induced or reduced, respectively, BCG quantity and cytotoxicity. In addition, treatment with GW4869, which was previously shown to inhibit Rab27b-dependent secretion, induced them and reduced Rab27b expression in bladder cancer cells. Meanwhile, AR expression was upregulated in BCG-resistant lines, compared with respective controls. In a mouse orthotopic xenograft model, Rab27b/SYTL3 knockdown or GW4869 treatment enhanced the amount of BCG within tumors and its suppressive effect on tumor growth. Moreover, in non-muscle-invasive bladder cancer specimens from patients subsequently undergoing BCG therapy, positivity of AR/Rab27b expression was associated with significantly higher risks of tumor recurrence. AR activation thus correlates with resistance to BCG treatment, presumably via upregulating Rab27b expression. Mechanistically, it is suggested that BCG elimination from urothelial cells is induced by Rab27b/SYTL3-mediated exocytosis. Accordingly, Rab27b inactivation, potentially via antiandrogenic drugs and/or exocytosis inhibition are anticipated to sensitize the efficacy of BCG therapy, especially in patients with BCG-refractory AR/Rab27b-positive bladder cancer.
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Vacuna BCG/uso terapéutico , Exocitosis/efectos de los fármacos , Inmunoterapia/métodos , Receptores Androgénicos/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Proteínas de Unión al GTP rab/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Vacuna BCG/farmacología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Transducción de SeñalRESUMEN
We found that FOXO1-shRNA sublines or FOXO1-positive cells co-treated with a FOXO1 inhibitor were significantly more resistant to cisplatin treatment at pharmacological concentrations, compared with respective control sublines or those with mock treatment. Western blot demonstrated considerable increases in the expression levels of a phosphorylated inactive form of FOXO1 (p-FOXO1) in cisplatin-resistant sublines established by long-term culture with low/increasing doses of cisplatin, compared with respective controls. Immunohistochemistry in surgical specimens from patients with muscle-invasive bladder cancer undergoing cisplatin-based neoadjuvant therapy further showed a strong trend to associate between p-FOXO1 positivity and unfavorable response to chemotherapy.
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Antineoplásicos/farmacología , Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , Proteína Forkhead Box O1/genética , Silenciador del Gen , Neoplasias de la Vejiga Urinaria/genética , Proteína Forkhead Box O1/metabolismo , Expresión Génica , Humanos , Inmunohistoquímica , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
Recent preclinical evidence has indicated that both androgen receptor (AR) inactivation and glucocorticoid receptor (GR) transrepression are associated with suppression of urothelial carcinogenesis. We therefore assessed the effect of a unique compound, 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride (Compound A; CpdA), which could function as an AR antagonist as well as a GR ligand, on urothelial tumorigenesis. Using the in vitro system with GR-positive non-neoplastic urothelial SVHUC cells stably expressing AR (SVHUC-AR), neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene (MCA) was inhibited similarly by an anti-androgen hydroxyflutamide and a glucocorticoid prednisone, and more strongly by CpdA. CpdA also prevented the neoplastic transformation of AR-negative MCA-SVHUC cells, which was diminished by a GR antagonist RU486, but failed to prevent that of GR knockdown MCA-SVHUC cells. In MCA-SVHUC-AR cells, CpdA significantly reduced the expression levels of oncogenes (c-Fos/c-Jun/c-Myc) and induced those of tumor suppressors (UGT1A/p21/p27/p53/PTEN). Additionally, a potent carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine induced bladder cancer in all of 8 mock-treated mice versus 4 (50%) of flutamide-treated (P = 0.021), 4 (50%) of prednisone-treated (P = 0.021), or 2 (25%) of CpdA-treated (P = 0.002) animals. Finally, CpdA was found to reduce AR transactivation and selectively induce GR transrepression (i.e. suppression of NF-κB transactivation and expression of its regulated genes), but not GR transactivation (i.e. activation of glucocorticoid-response element-mediated transcription and expression of its targets) in SVHUC cells. These findings suggest that CpdA suppresses urothelial tumorigenesis via both the AR and GR pathways, which may consequently provide an effective option of chemoprevention for bladder cancer, especially in patients with superficial disease following transurethral surgery.
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Androgen receptor (AR) and estrogen receptor-ß (ERß) have been implicated in urothelial tumor outgrowth as promoters, while underlying mechanisms remain poorly understood. Our transcription factor profiling previously performed identified FOXO1 as a potential downstream target of AR in bladder cancer cells. We here investigated the functional role of FOXO1 in the development and progression of urothelial cancer in relation to AR and ERß signals. In non-neoplastic urothelial SVHUC cells or bladder cancer lines, AR/ERß expression or dihydrotestosterone/estradiol treatment reduced the expression levels of FOXO1 gene and induced those of a phosphorylated inactive form of FOXO1 (p-FOXO1). In chemical carcinogen-induced models, FOXO1 knockdown via shRNA or inhibitor treatment resulted in considerable induction of the neoplastic transformation of urothelial cells or bladder cancer development in mice. Similarly, FOXO1 inhibition considerably induced the viability, migration, and invasion of bladder cancer cells. Importantly, in FOXO1 knockdown sublines, an anti-androgen hydroxyflutamide or an anti-estrogen tamoxifen did not significantly inhibit the neoplastic transformation of urothelial cells, while dihydrotestosterone or estradiol did not significantly promote the proliferation or migration of urothelial cancer cells. In addition, immunohistochemistry in surgical specimens showed that FOXO1 and p-FOXO1 expression was down-regulated and up-regulated, respectively, in bladder tumor tissues, which was further associated with worse patient outcomes. AR or ERß activation is thus found to correlate with inactivation of FOXO1 which appears to be their key downstream effector. Moreover, FOXO1, as a tumor suppressor, is likely inactivated in bladder cancer, which contributes in turn to inducing urothelial carcinogenesis and cancer growth.
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Receptor beta de Estrógeno/genética , Proteína Forkhead Box O1/metabolismo , Receptores Androgénicos/metabolismo , Urotelio/metabolismo , Línea Celular Tumoral , Proliferación Celular , HumanosRESUMEN
Glucocorticoids, including dexamethasone (DEX) and prednisone (PRED), have been prescribed in patients with neoplastic disease as cytotoxic agents or comedications. Nonetheless, it remains uncertain whether they have an impact on the development of bladder cancer. We, therefore, assessed the functional role of the glucocorticoid-mediated glucocorticoid receptor (GR) signaling in urothelial tumorigenesis. Tumor formation was significantly delayed in xenograft-bearing mice with implantation of control bladder cancer UMUC3 cells or nonneoplastic urothelial SVHUC cells undergoing malignant transformation induced by a chemical carcinogen 3-methylcholanthrene (MCA), compared with respective GR knockdown xenografts. Using the in vitro system with MCA-SVHUC cells, we screened 11 GR ligands, including DEX, and found significant inhibitory effects of PRED on their neoplastic transformation. The effects of PRED were restored by a GR antagonist RU486 in GR-positive MCA-SVHUC cells, while PRED failed to inhibit the neoplastic transformation of GR knockdown cells. Significant decreases in the expression levels of oncogenes (c-Fos/c-Jun) and significant increases in those of a tumor suppressor UGT1A were seen in MCA-SVHUC-control cells (vs GR-short hairpin RNA) or PRED-treated MCA-SVHUC-control cells (vs mock). In addition, N-butyl-N-(4-hydroxybutyl) nitrosamine induced bladder cancer in all of eight mock-treated mice vs seven (87.5%) of DEX-treated (P = .302) or four (50%) of PRED-treated (P = .021) animals. Finally, DEX was found to considerably induce both transactivation (activation of glucocorticoid-response element mediated transcription and expression of its targets) and transrepression (suppression of nuclear factor-kappa B transactivation and expression of its regulated genes) of GR in SVHUC cells, while PRED more selectively induced GR transrepression. These findings suggest that PRED could prevent urothelial tumorigenesis presumably via inducing GR transrepression.
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Transformación Celular Neoplásica/efectos de los fármacos , Glucocorticoides/farmacología , Receptores de Glucocorticoides/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Urotelio/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Línea Celular , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Humanos , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Interferencia de ARN , Receptores de Glucocorticoides/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Urotelio/citología , Urotelio/metabolismoRESUMEN
Emerging evidence has suggested that androgen receptor signaling plays an important role in ovarian cancer outgrowth. Specifically, androgen receptor activation appears to be associated with increased risks of developing ovarian cancer and inducing tumor progression. However, conflicting findings have also been reported. This review summarizes and discusses the available data indicating the involvement of androgens as well as androgen receptor and related signals in ovarian carcinogenesis and cancer growth. Although the underlying molecular mechanisms for androgen receptor functions in ovarian cancer remain far from being fully understood, current observations may offer effective chemopreventive and therapeutic approaches, via modulation of androgen receptor activity, against ovarian cancer. Indeed, several clinical trials have been conducted to determine the efficacy of androgen deprivation therapy in patients with ovarian cancer.
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Neoplasias Ováricas/metabolismo , Receptores Androgénicos/metabolismo , Transducción de Señal , Carcinogénesis/metabolismo , Resistencia a Antineoplásicos , Femenino , Humanos , Factores de RiesgoRESUMEN
The transcription factor forkhead box O1 (FOXO1) can be inactivated via its phosphorylation, resulting in suppression of apoptosis. Using immunohistochemistry, the expression of a phosphorylated form of FOXO1 was assessed in upper urinary tract urothelial carcinoma (UUTUC) specimens. Overall, phospho-FOXO1 (p-FOXO1) was immunoreactive in all 99 UUTUC specimens [12 (12.1%) weak (1+), 46 (46.5%) moderate (2+) and 41 (41.4%) strong (3+)], which was significantly (P=0.018) increased, compared with benign urothelium specimens [77/82 (93.9%): 18 (22.0%) 1+, 41 (50.0%) 2+ and 18 (22.0%) 3+]. Muscle invasion (P=0.031) and lymphovascular invasion (P=0.025) were observed more frequently in p-FOXO1(2+/3+) tumor samples compared with p-FOXO1(1+) tumor samples. No statistically significant associations between p-FOXO1 expression and tumor grade or presence of concurrent carcinoma in situ, hydronephrosis or lymph node metastasis were observed. Furthermore, the levels of p-FOXO1 and estrogen receptor-ß expression were significantly (P<0.05) correlated in UUTUC samples [correlation coefficient (CC)=0.244], particularly in tumor samples from male patients (CC=0.330). Additionally, patients with p-FOXO1(3+) tumors had a significantly increased risk of cancer-specific mortality (P=0.043), compared with those with p-FOXO1(1+/2+) tumors. Multivariate analysis further demonstrated a notable, albeit not significant, association between p-FOXO1 expression and cancer-specific survival (hazard ratio=2.204; P=0.053). These findings indicate that FOXO1 is inactivated in UUTUC specimens and p-FOXO1 overexpression may serve as a predictor of poor patient outcomes.