Survival After Minimally Invasive Surgery in Older Women With Endometrial Carcinoma.

BACKGROUND/AIM: To analyze the impact of minimally invasive surgery for endometrial cancer on overall survival among age >65. PATIENTS AND METHODS: We examined women who underwent hysterectomy from 2010 to 2015 from the U.S. National Cancer Data Base (NCDB). We evaluated the impact of surgical approach on survival. RESULTS: Of 243,601 endometrial cancer cases, 42,458 met the inclusion criteria. Laparoscopic approach was associated with improved survival by 14% (HR=0.86; 95%CI=0.80-0.92; p<0.001) and robotic approach was associated with improved survival by 12% (HR=0.88; 95%CI=0.83-0.93; p<0.0001), compared to the open approach. Similarly, the weighted adjusted 5-year overall survival was 73.1% (95%CI=72%-74.2%), 76.4% (95%CI=75.1-77.7%), and 75.5% (95%CI=74.7-76.4%) for open, laparoscopic, and robotic approaches, respectively (p<0.001). CONCLUSION: Minimally invasive surgery improved overall survival in women over 65 years with endometrial cancer.

Gynecologic oncology care during the COVID-19 pandemic at three affiliated New York City hospitals.

BACKGROUND: New York City was among the epicenters during the COVID-19 pandemic. Oncologists must balance plausible risks of COVID-19 infection with the recognized consequences of delaying cancer treatment, keeping in mind the capacity of the health care system. We sought to investigate treatment patterns in gynecologic cancer care during the first two months of the COVID-19 pandemic at three affiliated New York City hospitals located in Brooklyn, Manhattan and Queens. METHODS: A prospective registry of patients with active or presumed gynecologic cancers receiving inpatient and/or outpatient care at three affiliated New York City hospitals was maintained between March 1 and April 30, 2020. Clinical and demographic data were abstracted from the electronic medical record with a focus on oncologic treatment. Multivariable logistic regression analysis was explored to evaluate the independent effect of hospital location, race, age, medical comorbidities, cancer status and COVID-19 status on treatment modifications. RESULTS: Among 302 patients with gynecologic cancer, 117 (38.7%) experienced a COVID-19-related treatment modification (delay, change or cancellation) during the first two months of the pandemic in New York. Sixty-four patients (67.4% of those scheduled for surgery) had a COVID-19-related modification in their surgical plan, 45 (21.5% of those scheduled for systemic treatment) a modification in systemic treatment and 12 (18.8% of those scheduled for radiation) a modification in radiation. Nineteen patients (6.3%) had positive COVID-19 testing. On univariate analysis, hospital location in Queens or Brooklyn, age ≤65 years, treatment for a new cancer diagnosis versus recurrence and COVID-19 positivity were associated with treatment modifications. On multivariable logistic regression analysis, hospital location in Queens and COVID-19 positive testing were independently associated with treatment modifications. CONCLUSIONS: More than one third of patients with gynecologic cancer at three affiliated New York City hospitals experienced a treatment delay, change or cancellation during the first two months of the COVID-19 pandemic. Among the three New York City boroughs represented in this study, likelihood of gynecologic oncology treatment modifications correlated with the case burden of COVID-19.

Ruptured clear cell carcinoma of the ovary presenting as acute abdomen.

BACKGROUND: Ovarian cancer remains one of the leading causes of cancer-related deaths among women. Clear cell ovarian carcinoma is a rare histologic subtype accounting for 5-10% of all epithelial ovarian cancers and is often associated with endometriosis. Patients generally present with vague abdominal and pelvic complaints. However, patients can present in the acute setting with pleural effusions, ascites, bowel obstructions, and deep vein thrombosis. CASE: A 54 year old woman presenting with an acute abdomen secondary to rupture of ovarian clear cell carcinoma. CONCLUSION: Ovarian clear cell carcinoma should remain in the differential diagnosis in a patient presenting with an acute abdomen and imaging suspicious for a gynecologic malignancy originating from the ovary.

Complementary and alternative medicine therapies for the anesthesiologist and pain practitioner: a narrative review.

PURPOSE: This narrative review provides an overview of the complementary and alternative medicine (CAM) therapies that anesthesiologists and pain management practitioners commonly encounter along with recommendations for evaluation and implementation. SOURCE: A literature search of PubMed was performed using the comprehensive MeSH term, "Complementary Therapies OR Dietary Supplements", and a search was conducted of the various licensing organizations and books published on the topics of CAM and integrative medicine. PRINCIPAL FINDINGS: In North America, the most commonly encountered CAM therapies include 1) manipulation and procedural therapies; 2) herbs, nutritional supplements (nutraceuticals), and dietary therapies; and 3) mind-body and energy therapies. Controversy exists regarding many of these therapies, particularly those with a higher risk of harm, such as chiropractic manipulation, acupuncture, and nutraceutical use. Several well-conducted studies were analyzed to show how research in CAM can control for placebo responses. Practical considerations are provided for patients and practitioners interested in pursuing or already employing CAM in perioperative and chronic pain management settings. CONCLUSIONS: Complementary and alternative medicine therapies in general may provide a useful adjunct in the management of chronic pain. Nevertheless, many patients are not aware of the risks and benefits of individual therapies. In the perioperative setting, the most concerning CAM therapy is the use of herbs and other supplements that may produce physiologic and metabolic derangements and may interact with prescription medications. Resources exist to aid pain specialists, anesthesiologists, and patients in the evidence-based utilization of CAM therapies.

NDN is an imprinted tumor suppressor gene that is downregulated in ovarian cancers through genetic and epigenetic mechanisms.

NDN is a maternally imprinted gene consistently expressed in normal ovarian epithelium, is dramatically downregulated in the majority of ovarian cancers. Little or no NDN expression could be detected in 73% of 351 epithelial ovarian cancers. NDN was also downregulated in 10 ovarian cancer cell lines with total loss in 6 of 10. Re-expression of NDN decreased Bcl-2 levels and induced apoptosis, which significantly inhibited ovarian cancer cell growth in cell culture and in xenografts. In addition, re-expression of NDN inhibited cell migration by decreasing actin stress fiber and focal adhesion complex formation through deactivation of Src, FAK and RhoA. Loss of NDN expression in ovarian cancers could be attributed to LOH in 28% of 18 informative cases and to hypermethylation of CpG sites 1 and 2 of NDN promoter in 23% and 30% of 43 ovarian cancers, respectively. Promoter hypermethylation was also found in 5 of 10 ovarian cancer cell lines. Treatment with the demethylating agent 5-aza-2'-deoxycytidine restored NDN expression in 4 of 7 cell lines with enhanced promoter methylation levels. These observations support the conclusion that NDN is an imprinted tumor suppressor gene which affects cancer cell motility, invasion and growth and that its loss of function in ovarian cancer can be caused by both genetic and epigenetic mechanisms.

Postanesthesia Care for the Elderly Patient.

PURPOSE: As the general population lives longer, the perioperative physician is more likely to encounter disease states that increase in incidence in an aging population. This review focuses on anesthetic considerations for rational drug choices during the perioperative care of elderly patients. The primary aim of the review was to identify intraoperative and postanesthetic considerations for diseases associated with advancing age; it includes highlights of the commonly impaired major organs (eg, cardiovascular, pulmonary, neurologic, renal, hepatic systems). We also outline an approach to frequent issues that arise in the immediate postsurgical period while caring for these patients. METHODS: A systematic review was performed on aspects of the perioperative and postoperative periods that relate to the elderly. A list of pertinent key words was derived from the authors, and a PubMed database search was performed. FINDINGS: The anesthesiologist must account for changes in various organ systems that affect perioperative care, including the cardiovascular, pulmonary, renal, hepatic, and central nervous systems. The pharmacokinetic principles frequently differ and are often unpredictable because of anatomic changes and decreased renal and hepatic function. The most important pharmacodynamic consideration is that elderly patients tend to exhibit an exaggerated hypoactivity after anesthesia. IMPLICATIONS: Before surgery, it is essential to identify those patients at risk for delirium and other commonly encountered postanesthesia scenarios. Failure to manage these conditions appropriately can lead to an escalation of care and prolonged hospitalization.

Brain metastasis from uterine serous carcinoma: A case report and review of literature.

•Brain metastasis from UPSC is rare, with 9 cases in the literature.•UPSC may resemble other endometrial cancers in regard to brain metastatic behavior.•When appropriate, it seems that multimodal therapy offers the best outcomes.

Risk assessment for epithelial ovarian cancer: proposing a new approach to a deadly problem.

Presently the majority of women diagnosed with epithelial ovarian cancer (EOC) have advanced stage disease (III-IV) with a poor 5-year survival rate (12-30 %). This significantly contrasts when early stage disease is detected, which has a 5-year survival rate approximating 90 %. Therefore, detection of early stage disease is critical to making an impact on outcome. By using genetic algorithms, modifications of transvaginal ultrasonography and use of novel biomarkers, we propose a risk assessment profile to identify at-risk women and enable ovarian cancer screening to become a reality. Such a novel algorithm starts by applying classic genetic pedigree assessment and uses a panel of multiple biomarkers that identify both phenotypic and genotypic expression of high-risk markers followed with conventional ultrasound and advanced ultrasound techniques such as microvascular contrast-enhancement as a secondary test. We presently employ a multidisciplinary program incorporating genetics, molecular biology, tumor immunology, gynecologic oncology and diagnostic imaging to identify asymptomatic high risk women.

Expression of H1.5 and PLZF in granulosa cell tumors and normal ovarian tissues: a short report.

PURPOSE: Ovarian granulosa cell tumors (GCTs) typically exhibit an excellent prognosis, but their recurrences are associated with high mortality rates. In the past, immunohistochemistry (IHC)-based approaches have been used to facilitate the distinction between GCTs and other, more frequently occurring, primary or metastatic tumors. The purpose of this study was to assess the added value of H1.5 and PLZF protein expression in the correct delineation of GCTs. METHODS: Consecutive 5-µm thick sections from routinely fixed and paraffin embedded tissues from 30 GCTs and 33 benign ovaries were processed for IHC using anti-PLZF and anti-H1.5 monoclonal antibodies. The respective protein staining intensities and distributions were quantified into reported scores for all tissue samples. Student's t-test and Fisher's exact test were used to compare the mean scores for each group. A p-value of <0.05 was considered statistically significant. Also, both the sensitivity and the specificity of the two antibodies were evaluated. RESULTS: A statistically significant difference in the expression of H1.5 between the GCT and normal ovary groups was observed (p < 0.0001). Normal ovarian tissues were found to strongly express H1.5, whereas GCTs were found to weakly express this protein. In contrast, PLZ expression was not found to be significantly different between both study groups. CONCLUSIONS: From our results we conclude that H1.5 is down-regulated in GCTs compared to normal ovarian tissues. Additional investigations on larger and more heterogeneous study populations, and on the molecular mechanism (s) underlying down-regulation of the H1.5 protein, may further substantiate the use of H1.5 as a diagnostic/prognostic marker and, in addition, provide insight into the pathogenesis of GCTs.

Immunohistochemical detection of promyelocytic leukemia zinc finger and histone 1.5 in uterine leiomyosarcoma and leiomyoma.

OBJECTIVES: The accurate distinction of leiomyoma from leiomyosarcoma is essential for patient management. However, the distinction can be difficult to make, particularly in tissue biopsy samples. Immunohistochemistry has been established as a useful technique to aid in the diagnosis of malignancies. The advantages of immunohistochemical studies are their ease of use and interpretation. This study is the first to evaluate the utility of the promyelocytic leukemia zinc finger (PLZF) protein and the histone 1.5 (H1.5) protein as potential diagnostic immunohistochemical markers for distinguishing leiomyosarcoma from leiomyoma. METHODS: Tissue samples from 21 leiomyosarcomas and 26 leiomyomas were studied. The student t-test and the Fisher exact test were used to calculate the differences in staining between the 2 groups. RESULTS: Statistically significant differences were found in the staining indices of anti-PLZF and anti-H1.5 when comparing benign and malignant tumors (P < .0001 and P < .0001, respectively). The mean H1.5 staining score in leiomyosarcomas was 158.3, compared to 28.3 in leiomyomas. The mean PLZF score in leiomyosarcomas was 1.5 in contrast to 71.5 in leiomyomas. For H1.5 at a score ≥60, the sensitivity and specificity were 90.5% and 84.6%, respectively. For PLZF, a score ≤15 had a test sensitivity and specificity of 100% and 80.8%, respectively. This suggests that staining for H1.5 or PLZF can serve as a good screening test. Additionally, combining the 2 immunostains results in a sensitivity and specificity of 90.5% and 97.5%, respectively, in differentiating between leiomyoma and leiomyosarcoma. CONCLUSIONS: We describe immunostaining for PLZF and H1.5 in benign and malignant uterine smooth muscle tumors. Statistically significant differences in staining patterns were found, suggesting utility in distinguishing leiomyosarcomas from leiomyomas.

microRNA-181a has a critical role in ovarian cancer progression through the regulation of the epithelial-mesenchymal transition.

Ovarian cancer is a leading cause of cancer deaths among women. Effective targets to treat advanced epithelial ovarian cancer (EOC) and biomarkers to predict treatment response are still lacking because of the complexity of pathways involved in ovarian cancer progression. Here we show that miR-181a promotes TGF-ß-mediated epithelial-to-mesenchymal transition via repression of its functional target, Smad7. miR-181a and phosphorylated Smad2 are enriched in recurrent compared with matched-primary ovarian tumours and their expression is associated with shorter time to recurrence and poor outcome in patients with EOC. Furthermore, ectopic expression of miR-181a results in increased cellular survival, migration, invasion, drug resistance and in vivo tumour burden and dissemination. In contrast, miR-181a inhibition via decoy vector suppression and Smad7 re-expression results in significant reversion of these phenotypes. Combined, our findings highlight an unappreciated role for miR-181a, Smad7, and the TGF-ß signalling pathway in high-grade serous ovarian cancer.

Survival analysis of robotic versus traditional laparoscopic surgical staging for endometrial cancer.

OBJECTIVE: The purpose of this study was to compare the survival of women with endometrial cancer managed by robotic- and laparoscopic-assisted surgery. STUDY DESIGN: This was a retrospective study conducted at 2 academic centers. Primary outcomes were overall survival, disease-free survival (DFS), and disease recurrence. RESULTS: From 2003 through 2010, 415 women met the study criteria. A total of 183 women had robotic and 232 women had laparoscopic-assisted surgery. Both groups were comparable in age, body mass index, comorbid conditions, histology, surgical stage, tumor grade, total nodes retrieved, and adjuvant therapy. With a median follow-up of 38 months (range, 4-61 months) for the robotic and 58 months (range, 4-118 months) for the traditional laparoscopic group, there were no significant differences in survival (3-year survival 93.3% and 93.6%), DFS (3-year DFS 83.3% and 88.4%), and tumor recurrence (14.8% and 12.1%) for robotic and laparoscopic groups, respectively. Univariate and multivariate analysis showed that surgery is not an independent prognostic factor of survival. CONCLUSION: Robotic-assisted surgery yields equivalent oncologic outcomes when compared to traditional laparoscopic surgery for endometrial adenocarcinoma.

Epithelial-mesenchymal transition enhances nanoscale actin filament dynamics of ovarian cancer cells.

Epithelial ovarian cancer cells enhance their ability to migrate and invade through the epithelial-mesenchymal transition (EMT), resulting in cell seeding and metastasis in the peritoneal cavity and onto adjacent organ surfaces. It has been speculated that cytoskeletal dynamics, such as those of the actin filament, play a role in enhanced cell motility; however, direct evidence has not been provided. Herein, we have directly measured pico- to nanonewton-scale mechanical forces generated by actin dynamics of ovarian cancer SKOV-3 cells upon binding of integrin α5ß1 to fibronectin (FN), i.e., formation of a focal adhesion, using real-time atomic force microscopy (AFM) in a force spectroscopy mode. The dendrimer surface chemistry through which FN was immobilized on the AFM probe surfaces further enhanced the sensitivity of the force measurement by 1.5-fold. Post-EMT SKOV-3 cells, induced by transforming growth factor-ß, generated larger focal adhesion mechanical forces (17 and 41 nN before and after EMT, respectively) with migration faster than that of pre-EMT cells. Importantly, 22% of the forces transmitted through a single FN-integrin α5ß1 pair from post-EMT cells were shown to be sufficient to rupture the binding between FN and integrin α5ß1 on the cells, a result which is not observed on pre-EMT cells. This implies that post-EMT cells, by generating forces strong enough to break the FN-integrin binding, migrate and metastasize beyond the ovary, whereas pre-EMT cancer cells are confined in the ovary without such force generation. These results demonstrate quantitative and direct evidence for the role of actin dynamics in the enhanced motility of post-EMT ovarian cancer cells, providing a fundamental insight into the mechanism of ovarian cancer metastasis.

Biomarkers for early detection of ovarian cancer.

Ovarian cancer is the most lethal gynecological malignancy. However, effective screening strategies have not been established and continue to be elusive. A good screening test must adequately address validity, reliability, yield, cost, acceptance and follow-up services. An ideal screening test for ovarian cancer must have a high sensitivity in order to correctly diagnose all women with the disease and a high specificity to avoid false-positive results. The current screening modalities of bimanual examination, CA-125 and transvaginal ultrasonography together allow us to detect only 30-45% of women with early-stage disease. Recent developments in proteomic and genomic research have identified a number of potential biomarkers. Although panels of tumor markers and proteomic-based technologies may improve the positive predictive value, all markers require validation and interfacing with newly developed diagnostic imaging technologies. While a large amount of information on miRNAs has been promising, much remains to be elucidated. This review will examine the current status of biomarkers and technologies of interest in the effort of early detection of ovarian cancer.

Does the type of surgery for early-stage endometrial cancer affect the rate of reported lymphovascular space invasion in final pathology specimens?

OBJECTIVE: Laparoscopically assisted vaginal hysterectomy (LAVH), which usually involves the use of an intrauterine manipulator for optimal surgical control, has been shown to be as effective and safe as conventional total abdominal hysterectomy (TAH) for the staging of endometrial carcinoma. The purpose of this study was to determine whether the use of an intrauterine manipulator was associated with an increase in the pathologic reporting of lymphovascular space invasion (LVSI), which is an important determinant in choosing adjuvant therapy. We hypothesized that intracavitary manipulation and an increase of the intrauterine pressure could cause pseudolymphovascular invasion. STUDY DESIGN: We performed a retrospective chart review of endometrial cancer patients treated at our institution from January 1996 through January 2006. Records were reviewed for patient's age, preoperative diagnosis, procedure type, final surgical staging, and final pathology report. Using the 2009 International Federation of Gynecology and Obstetrics staging, we included all patients having stage IA or IB endometrioid-type endometrial cancer who had undergone either a TAH or LAVH with or without pelvic and paraaortic lymph node dissection. The χ2 and Fisher exact tests were used to measure the association between risk of positive lymphovascular invasion and surgical groups. RESULTS: Of 568 women identified as having endometrioid-type endometrial cancer, 486 (85.6%) met criteria for stage IA-IB endometrioid histology, grade 1, 2, or 3. LVSI was reported in 553/568 cases, with LVSI positivity in 16.9% (n = 96/568). The mean ages of the LAVH and TAH groups were significantly different (59.4 vs 62.4 years, respectively, P = .0050). Also, mean estimated blood loss and uterine weight significantly varied between TAH and LAVH groups (P = .0001 and .008, respectively). For stage IA, 17/220 (7.7%) who had been treated with LAVH had positive LVSI compared with 20/199 (10.1%) of patients receiving TAH (P = .73). For stage IB, 11/25 (44.0%) of patients treated with LAVH had positive LVSI compared with 10/31 (32.3%) of patients receiving TAH (P = .53). The stage I cancer patients were further subdivided into histological grades 1, 2, and 3, and LVSI was not significantly different between TAH and LAVH groups per grade of cancer. We found no differences between TAH and LAVH in early-stage endometrial cancer (stage IA and IB), with respect to the presence of positive peritoneal washings. CONCLUSION: In early-stage endometrial cancer (stage IA and IB), there were no differences between TAH and LAVH in the final pathologic report of LVSI. The use of an intrauterine manipulator for LAVH was not associated with an increased detection of LVSI.

Early detection of ovarian cancer with conventional and contrast-enhanced transvaginal sonography: recent advances and potential improvements.

Recently, there have been several major technical advances in the sonographic diagnosis of ovarian cancer in its early stages. These include improved assessment of tumor morphology with transvaginal sonography (TVS), and detection and characterization of tumor neovascularity with transvaginal color Doppler sonography (TV-CDS) and contrast-enhanced transvaginal sonography (CE-TVS). This paper will discuss and illustrate these improvements and describe how they enhance detection of early-stage ovarian cancer. Our initial experience with parametric mapping of CE-TVS will also be mentioned.

Recognition of linear stress fibers based on Hough transform.

OBJECTIVE: To present an algorithm based on Hough transform for recognition and extraction of linear stress fibers formed on exposure to lysophosphatidic acid (LPA). STUDY DESIGN: A ridge set of head points with lower shoulders is calculated, followed by a thinning process shrinking long, narrow regions to regions of single pixel thickness, then converted into a rectangular map whose value is the number of regional points in the path of a straight line at the angle and intercept determined by two coordinates. The location of the maximum in the map is sought, and the corresponding line with an unlimited length is constructed from the paired coordinates. We removed the line before repeating the process for the next longest straight line, continuing until all lines with reasonable lengths are extracted. RESULTS: Application of the algorithm to the stress fiber images of DOV13 cells stained with Texas red-phalloidin on LPA and AG1478 demonstrates close matches between stress fibers in the original images and linear lines. CONCLUSION: An algorithm for recognition of linear stress fibers formed on exposure to LPA is described and applications to stress fiber images using DOV13 cells with Texas red-phalloidin staining are demonstrated.

The NF-κB pathway mediates lysophosphatidic acid (LPA)-induced VEGF signaling and cell invasion in epithelial ovarian cancer (EOC).

OBJECTIVES: Our previous report has implicated the involvement of VEGF-VEGFR-2 h signaling in LPA-induced EOC invasion. However, the mechanism by which LPA regulates VEGF and VEGFR-2 expression remains to be elucidated. In the present study, we systematically examined the signal transduction pathways activated by LPA and further evaluated whether LPA's effect on VEGF-VEGFR-2 signaling and EOC invasion was mediated by the activation of NF-κB pathway. METHODS: Using a signal transduction PathwayFinder PCR array, we examined the expression change of 86 key genes representing 18 signal transduction pathways in DOV13 and SKOV3 cells upon LPA (20 µM) treatment. We also used quantitative PCR, Western blotting and ELISA to evaluate the effect of NF-κB pathway inhibition on VEGF(121), VEGF(165) and VEGFR-2 mRNA and protein expression/secretion with or without the presence of LPA (20 µM) in SKOV3. Cell invasion under various treatment conditions was assessed by Matrigel invasion assay and MMP-2 secretion was detected by gelatin zymography. RESULTS: Our results showed that in both DOV13 and SKOV3, several of the NF-κB pathway components, such as TNF, are consistently activated by LPA stimulation. In addition, treatment with an NF-κB pathway activation inhibitor, at 10 µM, significantly decreased LPA-induced VEGF(121), VEGF(165) and VEGFR-2 mRNA expression and VEGF secretion, as well as LPA-induced SKOV3 invasion (p<0.05). When combined with an EGFR inhibitor, NF-κB pathway inhibition exhibited a significantly stronger effect than used alone (p<0.05) on reducing LPA-induced VEGF secretion and cell invasion. Additionally, NF-κB inhibition also decreased LPA-induced MMP-2 secretion and MMP-1 expression (p<0.05). CONCLUSIONS: These results suggest that the NF-κB pathway plays an important role in LPA-induced VEGF signaling and EOC invasion and targeting this pathway may reveal potential therapeutic options for metastatic EOC.

Spatial-genetic structuring in a red-breasted merganser (Mergus serrator) colony in the Canadian Maritimes.

The clustering of kin is widespread across the animal kingdom and two of the primary mechanisms underlying the formation of these patterns in adult kin are (1) philopatric tendencies and (2) actively maintained kin associations. Using polymorphic microsatellites, we had set out to characterize the level of genetic-spatial organization within a colony of female red-breasted mergansers (Mergus serrator) breeding on a series of small barrier islands in Kouchibouguac National Park, NB, Canada. Additionally, using nesting data from this colony, we explored possibilities for the existence of kin associations and/or cooperative interactions between these individuals; specifically in the form of the synchronization of breeding activities (i.e., incubation initiation). Our results include: (1) the detection of broad-scale genetic structuring over the entire colony, as females nesting on separate islands were to some extent genetically distinct; (2) the detection of weak, yet significant, positive spatial autocorrelation of kin at the fine scale, but only in the more densely-populated areas of this colony; and (3) the synchrony of breeding activities among proximally nesting females, apart from any factors of relatedness. While these results confirm the existence of genetic-spatial organization within this colony, the underlying mechanisms producing such a signal are inconclusive.

MMP-1-PAR1 axis mediates LPA-induced epithelial ovarian cancer (EOC) invasion.

OBJECTIVES: MMP-1 is over-expressed in many cancers, with high expression often associated with poor survival. In the present study, we examined the expression of MMP-1 in EOC and its role in EOC invasion. Moreover, we evaluated the role of a newly identified MMP-1-protease activated receptor (PAR)-1 axis in LPA-induced EOC invasion. METHODS: MMP-1 and PAR1 mRNA expression in EOC cell lines was determined by real time PCR. MMP-1 mRNA expression in 96 normal and carcinoma ovarian tissue specimens was analyzed using a TissueScan real time PCR array. MMP-1 concentration in conditioned medium was measured by MMP-1 ELISA. PAR1 protein expression was detected by Western blotting. Cell invasion was evaluated by in vitro Matrigel invasion assay. RESULTS: In ovarian tumor tissues more MMP-1 expression was observed than in normal ovarian tissues (p<0.05), and its expression correlated with tumor grade (grade 3>grade 2>grade 1). Human recombinant MMP-1 as well as serum free conditioned medium containing high levels of MMP-1 from DOV13 and R182 cells significantly promoted DOV13 cell invasion (p<0.05), implicating a direct role of MMP-1 in EOC invasion. Moreover, MMP-1 induced DOV13 invasion was significantly blocked by PAR1 siRNA silencing. Furthermore, MMP-1 and PAR1 were both significantly induced by LPA (20 µM), and siRNA silencing of MMP-1 and PAR1 both significantly reduced LPA's invasion-promoting effect in DOV13 cells (p<0.05). CONCLUSIONS: Our results suggest that the MMP-1-PAR1 axis is involved in EOC invasion and at least partially mediates LPA-induced EOC invasion. Therefore, blocking MMP-1 or PAR1 may represent a new therapeutic option for metastatic EOC.