Biomedical subjects

Anil K Sood

Publications and source records attributed to Anil K Sood.

At least 19 recordsLinked to original sources

PubMed2026

Hope is linked with more favorable tumor molecular signatures in serous ovarian cancer.

INTRODUCTION: Hope has been associated with improved quality of life and lower mortality in cancer, but the underlying biological mechanisms are poorly characterized. We previously reported that hope was associated with less inflammation and more normalized diurnal cortisol pre-treatment among women with ovarian cancer. We also reported associations of socio-environmental factors with pro-metastatic processes. Here, we used genome-wide transcriptional profiling to quantify associations between hope and tumor molecular signatures reflecting invasiveness, inflammation, and cellular immunity. METHOD: Participants were 74 women with serous ovarian cancer who provided demographic information and completed surveys pre-surgery. Hope was assessed using a face-valid item from the Center for Epidemiological Studies Depression Scale (CES-D). Depression was assessed using the full CES-D without the hope item. Illumina HT12 microarrays were used to assay tumor RNA, and associations between hope and tumor gene expression were quantified, adjusting for depression, age, BMI, grade, and stage. RESULTS: Adjusting for covariates, hope was associated with multiple favorable differences in RNA expression, including lower levels of mesenchymal differentiation (p = 0.008) and pro-inflammatory gene regulation (NF-κB: p < 0.001; IRF1: p = 0.024; STAT: p = 0.018), elevated epithelial differentiation (p = 0.011), and elevated activity of the IRF7 transcription factor which promotes cellular immunity (p = 0.016). CONCLUSIONS: These data suggest that hope is associated with an ovarian tumor gene expression profile characterized by reduced epithelial-mesenchymal transition (EMT) and inflammatory activity, and increased activity of a transcription factor promoting cellular immunity. These findings highlight potential biological implications of a resilience factor such as hope, but need replication with more robust assessments of hope.

Epithelial mesenchymal transition↗

PubMed2007

EphA2 overexpression is associated with angiogenesis in ovarian cancer.

BACKGROUND: EphA2 is overexpressed in the majority of ovarian cancers and predicts poor clinical outcome. Based on EphA2's emerging role in angiogenesis, we hypothesized that tumors overexpressing EphA2 demonstrate greater microvessel density (MVD) and matrix metalloproteinase (MMP) expression. METHODS: After Institutional Review Board (IRB) approval, 77 invasive epithelial ovarian tumors were analyzed for CD31, EphA2, MMP-2, MMP-9, and MT1-MMP expression. RESULTS: The median age of the patients was 59 years (range, 34-83). EphA2 was overexpressed in 76% of tumors and was associated with advanced-stage disease (P < .001) and high-grade histology (P = .04). MVD was stratified into high (>12.7 vessels/high-power field [HPF]) versus low (<or=12.7 vessels/HPF) counts. High MVD was significantly associated with advanced stage (P < .001), presence of ascites (P < .001), and suboptimal surgical cytoreduction (P = .01). MMP expression was scored separately in the stromal (percentage of tumors with high expression: MMP-2 = 43%; MMP-9 = 74%; MT1-MMP = 40%) and epithelial (percentage of tumors with high expression: MMP-2 = 52%; MMP-9 = 61%; MT1-MMP = 44%) compartments. Endothelial cell EphA2 overexpression correlated with epithelial MMP-9 (P = .02), whereas EphA2 overexpression in tumor cells was significantly associated with high MVD (P = .002), as well as strong stromal and epithelial MMP-9 (P = .01 and P = .04, respectively), epithelial MMP-2 (P = .006), and epithelial MT1-MMP (P = .01) expression. CONCLUSIONS: EphA2 overexpression in endothelial and ovarian cancer cells was strongly associated with critical factors involved in angiogenesis and invasion. These findings may explain the poor clinical outcome of patients with EphA2 overexpression.

Adult↗

PubMed2007

Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer.

Metronomic chemotherapy is the frequent administration of low doses of chemotherapeutic agents targeting tumor-associated endothelial cells. We examined the efficacy of metronomic taxanes alone and in combination with AEE788-a dual epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) inhibitor-in an orthotopic mouse model of ovarian cancer. Growth-modulating effects of metronomic and maximum tolerated dose (MTD) regimens on overall survival were tested in vivo using both chemotherapy-sensitive (HeyA8 and SKOV3ip1) and chemotherapy-resistant (HeyA8-MDR) models. Treated tumors were stained for microvessel density (CD31), proliferation index (proliferating cell nuclear antigen), and apoptosis (terminal deoxyribonucleotide transferase-mediated nick-end labeling). The cytotoxic effects of MTD and metronomic dosing were tested with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Effects of metronomic regimens on circulating endothelial precursors (CEP) and tumor-specific cell-free DNA levels were assessed. In vivo, metronomic docetaxel resulted in significant reduction of tumor growth in the taxane-sensitive cell lines, whereas metronomic docetaxel plus AEE788 had an additive effect resulting in significant prolongation in survival. Combination therapy was effective even in the taxane-resistant model. Metronomic chemotherapy alone and combined with AEE788 resulted in a decrease in the proliferative index and microvessel density of treated tumors, whereas combination therapy increased the apoptotic index (P < 0.001). In vitro, metronomic taxanes caused endothelial cell toxicity at 10- to 100-fold lower concentrations compared with MTD dosing. Metronomic regimens inhibited mobilization of CEPs (P < 0.05) and led to a decrease in cell-free DNA levels (P < 0.05). Our results suggest that metronomic taxane chemotherapy with dual EGFR and VEGFR inhibition is highly efficacious and should be considered for future clinical trials.

Angiogenesis Inhibitors↗

PubMed2006

Intraperitoneal delivery of liposomal siRNA for therapy of advanced ovarian cancer.

PURPOSE: Intravenous (IV) delivery of siRNA incorporated into neutral liposomes allows efficient delivery to tumor tissue, and has therapeutic efficacy in preclinical proof-of-concept studies using EphA2-targeting siRNA. We sought to determine whether intraperitoneal (IP) delivery of these siRNA complexes was as effective at delivery and therapy as IV delivery. EXPERIMENTAL DESIGN: SiRNA was incorporated into the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC). Alexa555-siRNA-DOPC was injected IP into nude mice bearing established ovarian tumors, and organs were collected for microscopic fluorescent examination. Subsequently, therapeutic efficacy of the IP versus IV routes was directly compared. RESULTS: Alexa555-siRNA in DOPC liposomes injected IP was diffusely distributed into intraperitoneal ovarian tumors. Delivery was also seen deeply into the liver and kidney parenchyma, suggesting that the predominant means of distribution was through the vasculature, rather than direct diffusion from the peritoneal cavity. In mice with orthotopic ovarian tumors, treatment with combined paclitaxel and IP EphA2-targeting siRNA-DOPC reduced tumor growth by 48-81% compared to paclitaxel/control siRNA-DOPC IP (HeyA8: 0.34 g v 0.66 g; SKOV3ip1: 0.04 v 0.21, p<0.01). This reduction was comparable to concurrently-treated mice with paclitaxel and EphA2 siRNA-DOPC injected IV, which showed a reduction in growth by 45-69% compared to paclitaxel/control siRNA-DOPC injected IV (HeyA8: 0.23g v. 0.42g; SKOV3ip1: 0.04 v. 0.13 g). CONCLUSIONS: IP injection of siRNA incorporated in DOPC allows intra-tumoral delivery and has therapeutic efficacy in orthotopic ovarian tumors. These findings may have therapeutic implications for siRNA-based strategies.

Animals↗

PubMed2006

Efficacy and antivascular effects of EphA2 reduction with an agonistic antibody in ovarian cancer.

BACKGROUND: EphA2 is an oncoprotein and tyrosine kinase receptor that is overexpressed in ovarian and many other cancers. We investigated the effects of reduced EphA2 levels on tumor growth and the tumor microenvironment in an orthotopic ovarian cancer model. METHODS: The effect of the EphA2-agonistic monoclonal antibody EA5, alone or in combination with paclitaxel, on the growth of ovarian cancer cells (SKOV3ip1, HeyA8, and HeyA8MDR [taxane-platinum resistant]) was determined in vitro and in vivo by immunoblotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and immunohistochemical analysis. Expression of EphA2 and markers of angiogenesis (CD31, vascular endothelial growth factor [VEGF], and basic fibroblast growth factor), proliferation (proliferating cell nuclear antigen), and endothelial cell apoptosis (CD31-terminal deoxynucleotidyl transferase biotin-deoxyuridine triphosphate nick-end labeling colocalization) and phosphorylation of Src were analyzed by immunoblotting, immunohistochemistry, immunofluorescence, and in situ hybridization in tumors from treated mice. Statistical tests were two-sided. RESULTS: EA5 antibody treatment led to a more than 90% reduction in EphA2 expression in HeyA8 tumors in vivo. In mice bearing orthotopic SKOV3ip1 or HeyA8 tumors, 4 weeks of EA5 treatment resulted in tumors that weighed 31% and 45% less, respectively, than those in control (IgG-treated) mice (95% confidence interval [CI] = -0.09% to 71% and 20% to 70%, P = .27 and .01, respectively). Combination therapy with EA5 and paclitaxel reduced tumor weight by 77% and 80% (95% CI = 63% to 91% and 68% to 91%), respectively, compared with paclitaxel alone and by 92% and 88% (95% CI = 87% to 97% and 80% to 94%), respectively, compared with IgG alone. Combination therapy also reduced the weight of HeyA8MDR tumors by 47% (95% CI = 24% to 72%) compared with paclitaxel. Mice bearing SKOV3ip1 or HeyA8 tumors that were treated with combination therapy survived longer than those treated with paclitaxel alone (median survival = 144 versus 69 days and 46 versus 37 days, respectively). EA5-treated tumors had reduced microvascular density, proliferation, and VEGF protein and mRNA levels, with increased endothelial cell apoptosis. EphA2 was associated with Src, which was rapidly dephosphorylated after EA5 treatment. CONCLUSIONS: EA5 in combination with paclitaxel decreased tumor growth in an orthotopic ovarian cancer mouse model through antiangiogenic mechanisms associated with reduced levels of VEGF and phosphorylated Src. Humanized antibody constructs against EphA2 are worthy of future study.

Analysis of Variance↗

PubMed2006

Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells.

Recent studies using ovarian cancer cells have shown that the catecholamine hormones norepinephrine (norepi) and epinephrine (epi) may influence cancer progression by modulating the expression of matrix metalloproteinases (MMP) and vascular endothelial growth factor (VEGF). The purpose of this study is to determine if the stress hormone norepi can influence the expression of MMP-2, MMP-9, and VEGF in nasopharyngeal carcinoma (NPC) tumors by using three NPC tumor cell lines. The NPC cell lines HONE-1, HNE-1, and CNE-1 were treated with norepi. The effects of norepi on MMP-2, MMP-9, and VEGF synthesis were measured by ELISA; functional MMP activity was measured by the invasive potential of the cells using a membrane invasion culture system whereas functional activity of VEGF was analyzed using a human umbilical vein endothelial cell tube formation assay. Norepi treatment increased MMP-2, MMP-9, and VEGF levels in culture supernatants of HONE-1 cells, which could be inhibited by the beta-blocker propranolol. Norepi induced the invasiveness of all NPC cell lines in a dose-dependent manner, which was blocked by CMT-3, an MMP inhibitor, and propranolol. Norepi stimulated the release of functional angiogenic VEGF by HONE-1 cells as well. Finally, HONE-1 cells were shown to express beta-adrenergic receptors as did seven of seven NPC biopsies examined. The data suggest that catecholamine hormones produced by the sympathetic-adrenal medullary axis may affect NPC tumor progression, in part, through modulation of key angiogenic cytokines.

Biopsy↗

PubMed2006

Analysis of EphA2 expression and mutant p53 in ovarian carcinoma.

The EphA2 tyrosine kinase receptor is frequently overexpressed in ovarian cancer and this feature is predictive of poor clinical outcome. Preclinical investigation has also linked EphA2 with p53. In our present study, we examined EphA2 and p53 status (both expression and full-length mutation status) in 6 ovarian cell lines and 79 human ovarian cancers to determine potential associations. EphA2 was overexpressed in 80% of ovarian cancer cell lines and in 75% of clinical specimens. In particular, high levels of EphA2 occurred in 91% of tumors with p53 null mutations compared to 68% in tumors with wild-type or missense mutations (p=0.027). EphA2 expression did not relate to critical versus non-critical site missense p53 mutations or the location of mutations on specific p53 exons. We also demonstrated that while EphA2 and p53 can provide independent information regarding clinical status, the combination of EphA2 and p53 status can predict poor clinical outcome. In particular, the combination of EphA2 overexpression and p53 null status was associated with decreased overall patient survival and related to increased incidence of ascites and distant metastasis. Taken together, these data indicate a complex relationship between EphA2 and p53 that appears to regulate EphA2 expression and clinical outcome.

Cell Line, Tumor↗

PubMed2006

Circulating cell-free DNA: a novel biomarker for response to therapy in ovarian carcinoma.

INTRODUCTION: Cell-free DNA (CFDNA) is a reflection of both normal and tumor-derived DNA released into the circulation through cellular necrosis and apoptosis. We sought to determine whether tumor-specific plasma DNA could be used as a biomarker for tumor burden and response to therapy in an orthotopic ovarian cancer model. METHODS: Female nude mice injected intraperitoneally with HeyA8 ovarian cancer cells were treated with either docetaxel alone or in combination with anti-angiogenic agents (AEE788-dual VEGFR and EGFR antagonist or EA5-monoclonal antibody against ephrin A2). Following DNA extraction from plasma, quantification of tumor-specific DNA was performed by real-time PCR using human specific beta-actin primers. The number of genome equivalents (GE/ml) were determined from a standard curve. Apoptosis was assessed by TUNEL staining of treated tumors. RESULTS: The levels of tumor-specific DNA in plasma increased progressively with increasing tumor burden (R2=0.8, p<0.01). Additionally, tumor-specific plasma DNA levels varied following treatment with chemotherapy. In mice with established tumors (19 days following tumor injection), tumor-specific plasma DNA levels increased by 63% at 24 hours following a single dose of docetaxel (15 mg/kg), and then declined to 20% below baseline at 72 hours and were 83% lower than baseline 10 days following therapy. In addition, docetaxel treatment resulted in a significant increase in the apoptotic index at 24 hours (p<0.01). Moreover, in two separate therapy experiments using a combination of cytotoxic chemotherapy with anti-angiogenic agents, tumor-specific plasma DNA levels were significantly higher in mice treated with vehicle compared to the treatment groups. The correlation between tumor weight and tumor-specific DNA in these experiments was 0.71-0.76 (p<0.01). CONCLUSIONS: Our results indicate that tumor-specific CFDNA levels correlate with increasing tumor burden and decline following therapy. Thus, tumor-specific DNA may be a useful surrogate biomarker of therapeutic response and should be evaluated in future clinical trials.

Animals↗

PubMed2006

The BRK tyrosine kinase is expressed in high-grade serous carcinoma of the ovary.

BACKGROUND: We identified the BRK tyrosine kinase in a PCR-based screen of tyrosine kinases expressed by ovarian tumors. BRK expression is restricted to normal differentiating epithelial cells and its overexpression may play a role in processes related to tumor development and growth. Its expression in normal ovary and ovarian tumors has not previously been described, and is the focus of this study. METHODS: BRK expression levels were determined in 14 normal ovaries and 138 high-grade, late stage serous carcinomas of the ovary by immunohistochemical analysis, and in 19 ovarian cancer cell lines and immortalized ovarian surface epithelium by Western blot analysis. Furthermore, BRK/PTK6 gene copy number was determined in seven primary serous carcinomas by fluorescence in situ hybridization. RESULTS: Immunohistochemical studies indicate that BRK is highly expressed in 97/138 (70%) of high-grade, serous carcinomas of the ovary, but is absent in normal ovarian surface epithelia. BRK is also expressed by 9/19 of ovarian cancer cell lines, but is undetectable in immortalized ovarian surface epithelium. Interestingly, the BRK gene has been mapped to chromosome 20q13.3, a site frequently amplified in ovarian cancers, and associated with poor prognosis. We have determined by fluorescence in situ hybridization (FISH) that BRK is specifically amplified at low levels in 6/7 primary ovarian carcinomas. CONCLUSIONS: The amplification of the BRK gene and overexpression of BRK protein in the majority of high-grade serous carcinomas and ovarian cancer cell lines suggest that BRK may play a role in the development and growth of ovarian tumors.

Cell Line, Tumor↗

PubMed2006

Lymphatic mapping and sentinel node biopsy in women with high-risk endometrial cancer.

OBJECTIVE: To evaluate fundal injection of blue dye and radiocolloid for lymphatic mapping and sentinel node identification in women with high-risk endometrial cancer. METHODS: At laparotomy, 18 women with high-risk endometrial cancer had isosulfan blue and technitium-99 radiocolloid injected into the uterine fundus subserosally. Sentinel nodes were then identified either by direct observation of blue dye, by radioactive counts using a handheld gamma counter, or by a combination of both methods. The number and location of sentinel node(s) were recorded and compared with the final lymph node specimens after hysterectomy and selective lymphadenectomy. RESULTS: A sentinel node was identified in only 8 (45%) of the cases. Four patients had sentinel nodes only in the pelvis, 2 had sentinel nodes in the pelvis and above the bifurcation of the aorta, and 2 patients had sentinel nodes above the bifurcation of the aorta only. Seven (88%) patients had unilateral drainage of dye and the radiocolloid; the other patient had bilateral drainage. No patients had metastatic disease to sentinel or nonsentinel lymph nodes. CONCLUSIONS: Subserosal fundal injection of blue dye and the radiocolloid is a poor technique for identifying sentinel lymph nodes in patients with high-risk endometrial cancer.

Adult↗

PubMed2006

Antiangiogenic and antitumor effects of SRC inhibition in ovarian carcinoma.

Src, a nonreceptor tyrosine kinase, is a key mediator for multiple signaling pathways that regulate critical cellular functions and is often aberrantly activated in a number of solid tumors, including ovarian carcinoma. The purpose of this study was to determine the role of activated Src inhibition on tumor growth in an orthotopic murine model of ovarian carcinoma. In vitro studies on HeyA8 and SKOV3ip1 cell lines revealed that Src inhibition by the Src-selective inhibitor, AP23846, occurred within 1 hour and responded in a dose-dependent manner. Furthermore, Src inhibition enhanced the cytotoxicity of docetaxel in both chemosensitive and chemoresistant ovarian cancer cell lines, HeyA8 and HeyA8-MDR, respectively. In vivo, Src inhibition by AP23994, an orally bioavailable analogue of AP23846, significantly decreased tumor burden in HeyA8 (P = 0.02), SKOV3ip1 (P = 0.01), as well as HeyA8-MDR (P < 0.03) relative to the untreated controls. However, the greatest effect on tumor reduction was observed in combination therapy with docetaxel (P < 0.001, P = 0.002, and P = 0.01, for the above models, respectively). Proliferating cell nuclear antigen staining showed that Src inhibition alone (P = 0.02) and in combination with docetaxel (P = 0.007) significantly reduced tumor proliferation. In addition, Src inhibition alone and in combination with docetaxel significantly down-regulated tumoral production of vascular endothelial growth factor and interleukin 8, whereas combination therapy decreased the microvessel density (P = 0.02) and significantly affected vascular permeability (P < 0.05). In summary, Src inhibition with AP23994 has potent antiangiogenic effects and significantly reduces tumor burden in preclinical ovarian cancer models. Thus, Src inhibition may be an attractive therapeutic approach for patients with ovarian carcinoma.

Adenosine Triphosphate↗

PubMed2006

Focal adhesion kinase targeting using in vivo short interfering RNA delivery in neutral liposomes for ovarian carcinoma therapy.

PURPOSE: Focal adhesion kinase (FAK) plays a critical role in ovarian cancer cell survival and in various steps in the metastatic cascade. Based on encouraging in vitro results with FAK silencing, we examined the in vivo therapeutic potential of this approach using short interfering RNA (siRNA) in the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC). EXPERIMENTAL DESIGN: Therapy experiments of FAK siRNA with or without docetaxel were done using human ovarian cancer cell lines SKOV3ip1, HeyA8, and HeyA8MDR in nude mice. Additional experiments with a cisplatin-resistant cell line (A2780-CP20) were also done. Assessments of angiogenesis (CD31), cell proliferation (proliferating cell nuclear antigen), and apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) were done using immunohistochemical analysis. RESULTS: A single dose of FAK siRNA-DOPC was highly effective in reducing in vivo FAK expression for up to 4 days as assayed by Western blot and immunohistochemical analysis. Therapy experiments were started 1 week after injection of the ovarian cancer cells. Treatment with FAK siRNA-DOPC (150 mug/kg twice weekly) reduced mean tumor weight by 44% to 72% in the three cell lines compared with the control group (Ps < 0.05 for HeyA8, A2780-CP20, and SKOV3ip1). When FAK siRNA-DOPC was combined with docetaxel, there was even greater reduction in mean tumor weight in all models (all Ps < 0.05). Similar results were observed in combination with cisplatin. Treatment with FAK siRNA-DOPC plus docetaxel resulted in decreased microvessel density, decreased expression of vascular endothelial growth factor and matrix metalloproteinase-9, and increased apoptosis of tumor-associated endothelial cells and tumor cells. CONCLUSIONS: Taken together, these findings suggest that FAK siRNA-DOPC plus docetaxel or platinum might be a novel therapeutic approach against ovarian cancer.

Animals↗

PubMed2006

Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma.

Stress can alter immunological, neurochemical and endocrinological functions, but its role in cancer progression is not well understood. Here, we show that chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model. These effects are mediated primarily through activation of the tumor cell cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway by the beta(2) adrenergic receptor (encoded by ADRB2). Tumors in stressed animals showed markedly increased vascularization and enhanced expression of VEGF, MMP2 and MMP9, and we found that angiogenic processes mediated the effects of stress on tumor growth in vivo. These data identify beta-adrenergic activation of the cAMP-PKA signaling pathway as a major mechanism by which behavioral stress can enhance tumor angiogenesis in vivo and thereby promote malignant cell growth. These data also suggest that blocking ADRB-mediated angiogenesis could have therapeutic implications for the management of ovarian cancer.

Animals↗

PubMed2006

Preoperative serum vascular endothelial growth factor as a prognostic parameter in ovarian cancer.

OBJECTIVE: Serum vascular endothelial growth factor (VEGF) levels have been shown to be associated with an adverse outcome in patients with ovarian cancer. We studied the clinical value of serum VEGF as an independent prognostic parameter. METHODS: In the present study, we ascertained preoperative serum VEGF in a series of 314 patients with ovarian cancer: 45 new cases and 269 from four previously published studies. Serum VEGF was evaluated prior to primary surgery, results were correlated with clinical data. RESULTS: Median serum VEGF was 407 (238-746) pg/mL. In a univariate Kaplan-Meier analysis, FIGO stage, residual tumor mass, tumor grade, patients' age, serum CA 125, and preoperative serum VEGF were associated with overall survival. In a multivariate Cox regression model, higher FIGO stage, presence of residual tumor mass after primary surgery, and higher serum VEGF were independently associated with a shortened overall survival. Planned subgroup analysis was performed for patients with ovarian cancer FIGO stage I. In a multivariate Cox regression model, higher tumor grade and higher serum VEGF were the only independent prognosticators for overall survival. Patients with FIGO stage I ovarian cancer and a serum VEGF > or = 380 pg/mL had an 8-fold increased risk for experiencing cancer-related death. CONCLUSION: Serum VEGF is an independent prognostic parameter in patients with all stages of ovarian cancer.

CA-125 Antigen↗

PubMed2006

The clinical relevance of stromal matrix metalloproteinase expression in ovarian cancer.

PURPOSE: Matrix metalloproteinases (MMP) are proteolytic enzymes implicated in cancer progression and metastasis. We sought to determine the role of epithelial (tumor cell-derived) and stromal (host-derived) expression of MMPs in predicting the clinical outcome of patients with epithelial ovarian cancer (EOC). EXPERIMENTAL DESIGN: MMP-2, MMP-9, and membrane type 1 (MT1)-MMP expression was evaluated using immunohistochemistry in 90 invasive EOCs, and samples were scored for epithelial and stromal staining. Results were correlated with clinicopathologic characteristics using univariate and multivariate analyses. RESULTS: High expression of MMP-2, MMP-9, and MT1-MMP in tumor epithelium was detected in 54%, 97%, and 100% of cases, and in stromal compartments, in 38%, 70%, and 38% of cases, respectively. High stromal expression of MMP-2, MMP-9, and MT1-MMP was significantly associated with aggressive features such as high stage, high grade ascites, and positive lymph node status. Kaplan-Meier analysis showed that high epithelial and stromal expression of MMP-2, MMP-9, and MT1-MMP were each significantly associated with shorter disease-specific survival (DSS; P < 0.01). On tree-structured survival analysis, patients with strong epithelial MT1-MMP expression had the shortest DSS, whereas patients with moderate epithelial MT1-MMP and low stromal MMP-9 expression had the longest DSS (P < 0.01). On multivariate analysis, high stromal expression of MMP-9 (P = 0.01) and MT1-MMP (P = 0.04), strong epithelial MT1-MMP (P = 0.01) and high stage (P = 0.04) were independent predictors of poor DSS. CONCLUSIONS: Overexpression of stromal MMP-9 and MT1-MMP is independently associated with shorter DSS in EOC. Thus, host-derived MMPs are valuable predictors of clinical outcome in EOC.

Adult↗

PubMed2006

The role of relaxin in endometrial cancer.

Relaxin (RLN) is a naturally occurring hormone that is known to modulate connective tissue remodeling in the uterus and cervix. Our goal was to investigate the role of RLN in endometrial cancer. RLN expression was evaluated using immunohistochemistry in 57 samples of invasive endometrial carcinoma (EC) and ten benign endometrial tissues. 67% of high-stage (III/IV) tumors demonstrated strong RLN expression compared to 37% of low-stage (I/II) cases. Strong RLN expression associated significantly with high-grade and depth of myometrial invasion. Notably, strong RLN expression was associated with a significantly shorter overall survival (p < 0.005) compared to weak or moderate expression. Using RT-PCR, the expression of RLN and its receptor (LGR7) was detected in EC cell lines (HEC-1B and KLE); in addition, LGR7 was expressed in 86% of 15 primary EC tissue samples. Exogenous RLN stimulation caused a significant increase in migration and invasion in both cell lines, but did not stimulate proliferation in vitro. Addition of the MMP inhibitor, FN439 abolished the stimulatory effect of RLN on invasion in both HEC-1B and KLE cells. RLN stimulation caused a significant increase in levels of activated MMP-2 in KLE cells and activated MMP-9 in HEC-1B cells compared to unstimulated cells. Inhibition of endogenous RLN signaling via siRNA targeted to LGR7 caused a significant reduction of EC cell invasiveness. Our results indicate that RLN overexpression is significantly asso- ciated with aggressive features such as high-grade and deep myometrial invasion. We provide the first evidence that overexpression of RLN is associated with poor clinical outcome in women with EC. RLN stimulation enhances the invasive potential of endometrial cancer cells by upregulating MMPs. In turn, downregulation of endogenous RLN signaling decreases invasiveness of endometrial cancer cells. These novel findings may have therapeutic implications in the management of patients with endometrial carcinoma.

Carcinoma, Endometrioid↗

PubMed2006

Stress hormone-mediated invasion of ovarian cancer cells.

PURPOSE: There is growing evidence that stress and other behavioral factors may affect cancer progression and patient survival. The underlying mechanisms for this association are poorly understood. The purpose of this study is to determine the effects of stress-associated hormones norepinephrine, epinephrine, and cortisol on the invasive potential of ovarian cancer cells. EXPERIMENTAL DESIGN: The ovarian cancer cells EG, SKOV3, and 222 were exposed to increasing levels of either norepinephrine, epinephrine, or cortisol, and the in vitro invasive potential was determined using the membrane invasion culture system. Additionally, the effects of these stress hormones on matrix metalloproteinase-2 (MMP-2) and MMP-9 were determined by ELISA. The effects of the beta-adrenergic agonist isoproterenol on in vivo tumor growth were determined using nude mice. RESULTS: Stress levels of norepinephrine increased the in vitro invasiveness of ovarian cancer cells by 89% to 198%. Epinephrine also induced significant increases in invasion in all three cell lines ranging from 64% to 76%. Cortisol did not significantly affect invasiveness of the EG and 222 cell lines but increased invasion in the SKOV3 cell line (P = 0.01). We have previously shown that ovarian cancer cells express beta-adrenergic receptors. The beta-adrenergic antagonist propanolol (1 mumol/L) completely blocked the norepinephrine-induced increase in invasiveness. Norepinephrine also increased tumor cell expression of MMP-2 (P = 0.02 for both SKOV3 and EG cells) and MMP-9 (P = 0.01 and 0.04, respectively), and pharmacologic blockade of MMPs abrogated the effects of norepinephrine on tumor cell invasive potential. Isoproterenol treatment resulted in a significant increase in tumor volume and infiltration in the SKOV3ip1 in vivo model, which was blocked by propranolol. CONCLUSIONS: These findings provide direct experimental evidence that stress hormones can enhance the invasive potential of ovarian cancer cells. These effects are most likely mediated by stimulation of MMPs.

Animals↗

PubMed2006

Historical progress in the initial management of ovarian cancer: intraperitoneal chemotherapy.

Despite measured improvement in survival with the introduction of the platinates and taxanes in treatment of advanced ovarian cancer, little additional progress has been made with conventional cytotoxic agents. Recently, the Gynecologic Oncology Group (GOG) published data from a study evaluating the merits of intraperitoneal chemotherapy in women with advanced, optimally cytoreduced ovarian cancer. They documented a significant advantage in progression-free and overall survival for the experimental regimen, a combination of intravenous paclitaxel and intraperitoneal cisplatin and paclitaxel, compared with standard intravenous cisplatin and paclitaxel chemotherapy. The intraperitoneal regimen was substantially more toxic and was associated with reduced short-term quality of life. The GOG trial joins six other published phase III trials since 1994 comparing intravenous with intraperitoneal chemotherapy in advanced-stage epithelial ovarian cancer. A recent meta-analysis suggests a 21% reduction in the hazard for progression (four studies) and death (seven studies). Reluctance to adopt a new standard of care is rooted in toxicity concerns. Further evaluation is warranted to clarify unanswered questions regarding administration schedule, agents, techniques, number of courses, and patient eligibility for intraperitoneal chemotherapy.

Carcinoma↗