[Show abstract][Hide abstract] ABSTRACT: The notion that menopausal estrogen replacement therapy increases ovarian cancer risk, but only for the two more common types (i.e. serous and endometrioid), while possibly decreasing risk for clear cell tumors, is strongly suggestive of causality. However, whether estradiol (E2) is tumorigenic or promotes development of occult preexisting disease is unknown. The present study investigated molecular and cellular mechanisms by which E2 modulates the growth of high grade serous ovarian cancer (HGSOC). Results showed that ERα expression was necessary and sufficient to induce the growth of HGSOC cells in in vitro models. Conversely, in vivo experimental studies demonstrated that increasing the levels of circulating estrogens resulted in a significant growth acceleration of ERα-negative HGSOC xenografts, as well. Tumors from E2-treated mice had significantly higher proliferation rate, angiogenesis, and density of tumor-associated macrophage (TAM) compared to ovariectomized females. Accordingly, immunohistochemical analysis of ERα-negative tissue specimens from HGSOC patients showed a significantly greater TAM infiltration in premenopausal compared to postmenopausal women. This study describes novel insights into the impact of E2 on tumor microenvironment, independently of its direct effect on tumor cell growth, thus supporting the idea that multiple direct and indirect mechanisms drive estrogen-induced tumor growth in HGSOC.
[Show abstract][Hide abstract] ABSTRACT: Male gender is a risk factor for medulloblastoma (MB), being also a negative predictor for clinical outcome. This study sought to assess sex differences in tumor biological features and hormone receptor profiles in a cohort of MB patients.
Sixty-four MBs and 5 normal cerebella were included in the study. Cell proliferation (Ki67), apoptosis (cleaved caspase-3) and microvessel density (CD31) were evaluated in tumors by immunohistochemistry. Tissues were analyzed for Estrogen Receptor α (ERα), ERβ1, ERβ2, ERβ5 and Androgen Receptor (AR) expression. Results demonstrated sex-specific features in MBs, with tumors from females exhibiting a higher apoptosis/proliferation ratio along with a decreased tumor vascularization compared to males. MBs were negative for ERα and AR, while expressing ERβ isoforms at similar levels between sexes. Altogether these findings indicate that signaling mechanisms that control cell turnover and angiogenesis are more efficiently operating in females compared to males. The lack of sex differences in the hormone receptor profiles suggests that circulating estrogens could be the major determinants of the sexual dimorphism observed in MB features.
Here we give molecular support to epidemiological data showing gender differences in MB incidence and outcome, completely defining the hormone receptor profile of the tumors. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Background
The male-to-female sex ratio for medulloblastoma (MB) is approximately 1.5∶1, female gender being also a favorable prognostic factor. This study aimed at evaluating the impact of gender on MB tumorigenesis.
In vitro activity of 17β-estradiol (E2), DPN [2,3-bis(4-hydroxyphenyl)-propionitrile, a selective estrogen receptor β (ERβ)-agonist], PPT [4,4′,4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol, a selective ERα-agonist] or DHT (5 alpha-dihydrotestosterone) was evaluated in three human MB cell lines. D283 Med cells were transplanted into athymic mice.
A significant expression of ERβ, with little or no ERα, and low AR (androgen receptor) was found in MB cell lines. The compounds tested did not affect cell proliferation. In vivo, we observed a significantly lower growth of D283 Med in nude female mice compared to males. At microscopic examination, tumors from females showed a shift towards differentiation, as evaluated by lower nestin, and higher NSE (neuron-specific enolase) and GFAP (glial fibrillary acidic protein) expression compared to males. Tumors from females also showed lower Ki67 and p53 expression. The wild-type ERβ protein (ERβ1) was lost in male tumors, while it was a permanent feature in females, and a strong negative correlation was found between Ki67 and ERβ1 expression. Conversely, tumor levels of ERβ2 and ERβ5 did not significantly differ between genders. Increased levels of cyclin-dependent kinase inhibitor p21 were observed in females, suggesting that estrogen may decrease tumor growth through blocking cell cycle progression. An inhibition of the insulin-like growth factor I (IGF-I) signaling was also evident in females.
We provides mechanistic evidence supporting the idea that ERβ1 signaling may have pro-differentiation and tumor suppressive function in medulloblastomas.
[Show abstract][Hide abstract] ABSTRACT: In the present study we have examined the pattern of expression of the full length Estrogen Receptor β (ERβ1) and two ERβ splice variant isoforms (ERβ2, ERβ5) in well-characterised serous advanced ovarian cancers.
Immunohistochemistry was performed with ERβ1, ERβ2, and ERβ5 antibodies and results were correlated with pathological and clinical follow-up data. Expression of ERβ isoforms in a panel of ovarian cancer cell lines and human tumor xenografts was also assessed.
Immunohistochemical staining revealed cellular compartment-specific distribution for each isoform in malignant ovarian tissues exhibiting both nuclear and cytoplasmic staining. Patients with cytoplasmic ERβ2 expression had significantly worse outcome (p=0.006 at the Multivariate analysis), the 5-year survival rate being nearly 28% for patients who did express cytoplasmic ERβ2, and 60% in negative patients. Cytoplasmic ERβ2 expression was also found to be significantly associated with chemoresistance. In concordance with clinical results both nuclear and cytoplasmic expression was observed for the three isoforms in the cancer cell lines and human tumor xenograts tested.
This is the first study to uncover an unfavorable prognostic role of ERβ2 in advanced serous ovarian cancer. If anomalies of ERβ2 cytoplasmic expression could be demonstrated to represent an independent unfavorable prognostic marker and/or a marker predicting chemoresistance in advanced serous ovarian cancer, its immunohistochemical assessment at the time of surgery, could help to recognize candidates for clinical trials of new interventions.
No preview · Article · Dec 2013 · Gynecologic Oncology
[Show abstract][Hide abstract] ABSTRACT: The prognostic relevance of estrogen (ER) and progesterone receptor (PR) expression in endometrioid endometrial cancer is still controversially discussed. The present study has focused on the evaluation of the prognostic value of ERα, ERβ1, ERβ2, and PR in this histotype. Specifically, we were interested in evaluating whether the relative level of ER subtype-specific expression (in terms of a ratio ERα/ERβ1 and ERα/ERβ2) would predict clinical outcome better than their absolute levels in patients with endometrioid endometrial cancer. To this end, protein content was assessed by immunohistochemistry in a group of 121 cases and staining was analyzed in relation to clinicopathologic variables, disease-free survival and overall survival. Results obtained have demonstrated that none of the biological markers analyzed possess an independent prognostic role with regard to disease-free survival. Multivariate analysis of overall survival has shown that ERα alone is not an independent prognostic indicator in patients with endometrioid endometrial cancer (hazard ratio [HR]; 0.5; 95% confidence interval [CI], 0.09-3.0; P = .5). On the other hand, an ERα/ERβ1 ratio of 1 or less or an ERα/ERβ2 ratio of 1 or less has proved to be independently associated with a higher risk of death (HR, 6.4 [95% CI, 1.0-40.6; P = .04] and 9.7 [95% CI, 1.1-85.3; P = .04], respectively) along with age, tumor stage, and Ki-67. In conclusion, we report here that the ERα/ERβ1 and ERα/ERβ2 expression ratios are independent prognostic markers of survival in endometrioid endometrial cancer; these findings suggest that phenotyping these interacting markers conjointly may better predict patient survival than each individual marker alone.
[Show abstract][Hide abstract] ABSTRACT: Hyaluronan (HA)-receptors (mainly CD44 and RHAMM) are overexpressed in a wide variety of cancers including ovarian tumors, and HA-bioconjugates have been developed to enhance selective entry of cytotoxic drugs into HA receptor-expressing cancerous cells. Here, we evaluated the potential application of a new HA-paclitaxel bioconjugate, ONCOFID-P, for intraperitoneal (IP) treatment of ovarian cancer.
In vitro cytotoxic effect of ONCOFID-P was first assessed on CD44(+) OVCAR-3 and SKOV-3 human ovarian cancer cell lines. Studies were performed in female Balb/c athymic mice IP implanted with OVCAR-3 or SKOV-3 and treated with IP ONCOFID-P, and IP and intravenous (IV) free paclitaxel, at their maximum tolerated dose (MTD 168, 80 and 80 mg/kg, total dose, respectively). The potential detrimental effect of the IP ONCOFID-P and IP free paclitaxel on hematopoiesis was also assessed on peripheral blood, bone marrow and spleen.
Results show that ONCOFID-P cytotoxicity against both OVCAR-3 and SKOV-3 cell lines was somewhat less effective than free paclitaxel. Conversely, in in vivo experiments, IP treatment with ONCOFID-P was overall more effective than IV and IP free paclitaxel in inhibiting intra-abdominal tumor dissemination, abrogating ascites, prolonging survival and curing mice. ONCOFID-P and IP free paclitaxel were equivalent in terms of myelotoxicity, although the former was administered at a two-fold higher dose.
Present data strongly support the development of ONCOFID-P for locoregional treatment of ovarian cancer.
Full-text · Article · Jul 2011 · Cancer Chemotherapy and Pharmacology
[Show abstract][Hide abstract] ABSTRACT: The aim of study was to highlight parameters that in association with Model for End-stage Liver Disease (MELD) provide predictive criteria for long-term survival after treatment with the Molecular Adsorbent Recirculating System (MARS). Two homogenous groups were studied: one treated with standard medical therapy (SMT) and the other, with MARS.
Twenty acute-on-chronic liver failure patients on the waiting list for liver transplantation and affected by alcoholic cirrhosis with similar MELD scores (20-29) were evaluated for 7 days from inclusion and for 6-month survival. Ten patients (seven males and three females) were treated with MARS. Their mean age was 48.5 years (range = 35-61). The number of MARS applications was six for 6 consecutive days, and the length of the applications was 8 hours. Ten other patients (seven males and three females) were treated with SMT, including prophylaxis against bacterial infections and judicious use of diuretics. The precipitating factors were also treated appropriately. The mean age of the patients was 51 years (range = 37-64). All the variables that were significant upon univariate analysis were enrolled in a receiver operating characteristic analysis, with the intention to detect predictive parameters for patient death at 6 months. We considered a significant area under curve (AUC) value to be greater than 0.5.
Among 11 patients who died within 6 months there were in the MARS group and eight in the SMT group: the 3- and 6-month patient survival rates were 90% and 70% versus 30% and 20% in the two groups, respectively. Nine measures resulted in an AUC > 0.5: DeltaMELD; interleukin (IL)-8; IL-6; tumor necrosis factor- alpha, MELD score; creatinine, bilirubin international normalized ratio (INR) and cardiac index. DeltaMELD and postoperative IL-8 concentrations showed better results (AUC = 0.899), followed by postoperative creatinine (AUC = 0.879), postoperative cardiac index (AUC = 0.833), and postoperative INR (AUC = 0.818). Postoperative creatinine showed the best sensitivity (100%), while IL-8, the best specificity (88.9%).
A combination of biochemical and clinical variables probably represent the best way to predict the survival of patients, allowing physicians to select the best therapies for each patient.
Full-text · Article · May 2010 · Transplantation Proceedings
[Show abstract][Hide abstract] ABSTRACT: This study was aimed at evaluating the potential application of benzophenanthridine alkaloids, sanguinarine and cheleritrine, in the therapy of melanoma cancer. In vitro antiproliferative activity of sanguinarine was higher than that of cheleritrine against the B16 melanoma 4A5 cells. Both agents were able to produce DNA breaks, and the DNA unwinding assay showed that they act as DNA intercalating agents. Sanguinarine was selected for determination of its in vivo preclinical efficacy. Oral treatment with sanguinarine reduced the tumor burden in a transplantable murine tumor grown in a syngeneic host (B16 melanoma 4A5 in C57BL/6 mice), and in a human tumor xenograft grown in immunodeficient mice (A375 human melanoma in athymic nude mice). In A375 tumors a significant decrease in the proliferation marker Ki67, and a reduction in the activated mitogen-activated protein kinases (p-p44/42 MAPK), and in protein kinase B (pAKT) were also observed. Three out of eleven A375-bearing treated mice were tumor-free at the end of treatment, and did not develop any tumor after a further, treatment-free, observation period of 60 days. Sanguinarine also showed a striking antiangiogenic activity in mice. Data from the present study support the concept that sanguinarine can be effective in melanoma skin cancer.
Full-text · Article · Aug 2009 · Biochemical pharmacology
[Show abstract][Hide abstract] ABSTRACT: Delayed graft function (DGF) represents one of the most common complications after kidney transplantation. The increased use of expanded criteria donors (ECD) is related to a greater risk for DGF. The objective of our study was to analyze the incidence of DGF among ECD versus standard criteria donors (SCD). Among 121 cases we obtained 2 groups: group A (SCD; n = 75) and group B (ECD; n = 46). Group B was composed of older donors (P < .0001), with an increased incidence of diabetes mellitus (DM; P < .0001), arterial hypertension (AH; P < .0001), cerebrovascular accidents (P = .013), and lower creatinine clearances (CrCl; P = .008). Recipient age was significantly lower among group A (P < .0001), with an increased incidence of donor hypotensive episodes (P = .016). The global incidence of DGF was 40 patients (33%), who were mainly in group B (P = .004). Analyzing the entire population, donor age >or= 60 years (P = .005), CrCl < 40 mL/min (P = .025), donor history of DM (P = .026) and AH (P = .017), and cold ischemia time > 15 hours (P < .0001) were parameters related to increased incidences of DGF. A biopsy score of 3 was not significantly associated with DGF. The results of our study underlined the increased risk for DGF related to the use of ECD. Donor age >or= 60 years and cold ischemia time > 15 hours showed strong associations with this complication.
Full-text · Article · May 2009 · Transplantation Proceedings
[Show abstract][Hide abstract] ABSTRACT: This study was designed to compare the effects of 17beta-estradiol (17beta-E2) and a phytoestrogen-containing soy extract on the immune system in an ovariectomized rat model of menopause. Specifically, T- and B-lymphocyte subsets, the balance of type 1 and 2 immune responses in the mesenteric lymph nodes, and serum levels of different classes of immunoglobulin were examined as study endpoints.
Ovariectomized rats were treated with either the phytoestrogen-containing soy extract (50 or 100 mg/kg/day PO), 17beta-E2 (0.5 mg/kg/day PO), or vehicle; a sham control was included in the study. After the rats were killed, mesenteric lymph nodes and blood samples were collected. B- and T (CD4 and CD8)-lymphocyte subsets in mesenteric lymph nodes were evaluated by flow cytometry analysis. Cytokine-producing T lymphocytes were identified within each T-lymphocyte subset as TH1 (interferon-gamma CD4), TH2 (interleukin-4 CD4), TC1 (interferon-gamma CD8), and TC2 (interferon-4 CD8) lymphocytes. Serum levels of immunoglobulin classes were determined by enzyme-linked immunosorbent assay.
There were no differences in the proportions of B lymphocytes and CD4 and CD8 T lymphocytes among groups. Treatment with 17beta-E2 and phytoestrogen-containing soy extract induced a reduction in TH1 and TC1 lymphocytes paralleled by a slight, nonsignificant, increase in the frequency of TH2. Data expressed as TH1/TH2 and TC1/TC2 ratios depicted a significant polarization of local immunity toward a humoral response. Evaluation of immunoglobulin serum levels did not show any significant difference among groups.
Here we show that estrogens and soy phytochemicals similarly polarize the immune system toward a type 2 immune response in a preclinical model of menopause; our data draw attention to the crucial need to evaluate in clinical studies the potential side effects on the immune system of the complex soy products that are actually consumed in the postmenopausal setting.
[Show abstract][Hide abstract] ABSTRACT: Polycystic disease causes a progressive decrease in renal function and liver degeneration. The progression of the disease evolves separately between organs and transplantation options vary: simultaneous or sequential liver-kidney transplantation or single-organ transplantation. From September 2006 to June 2007 3 combined liver kidney transplantations (CLKT) were performed for polycystic disease with end-stage renal disease: 2 with polycystic liver disease, and 1 with hepatic failure due to congenital hepatic fibrosis. The widest dimensions of the polycystic liver of 50 and 60 cm diameter were due to extensive cystic degeneration. We performed 1 simultaneous CLKT and 2 sequential transplantations: 1 liver after kidney, and 1 kidney after liver. At present all patients are alive with 100% graft function. Median creatinine level at discharge was 0.9 mg/dL (ranges, +/-0.2). Good liver graft function was reported in all 3 cases. Transplant benefit in polycystic liver-kidney disease has been already demonstrated; conservative surgical options may result in a high incidence of complications in highly involved polycystic livers. Delaying transplantation results in a more difficult surgical technique, a higher rate of postoperative complications, and a disturbance of optimal graft retrieval because of the worse preoperative condition of the patients.