Emerging roles of PDGF-D in EMT progression during tumorigenesis

Platelet-derived growth factor-D (PDGF-D) signaling pathway has been reported to be involved in regulating various cellular processes, such as cell growth, apoptotic cell death, migration, invasion, angiogenesis and metastasis. Recently, multiple studies have shown that PDGF-D plays a critical role in governing epithelial-to-mesenchymal transition (EMT), although the underlying mechanism of PDGF-D-mediated acquisition of EMT is largely unclear. Therefore, this mini review will discuss recent advances in our understanding of the role of PDGF-D in the acquisition of EMT during tumorigenesis. Furthermore, we will summarize the function of chemical inhibitors and natural compounds that are known to inactivate PDGF-D signaling pathway, which leads to the reversal of EMT. In summary, inactivation of PDGF-D could be a novel strategy for achieving better treatment outcome of patients inflicted with cancers.     

HOXA11 hypermethylation is associated with progression of non-small cell lung cancer

This study was aimed at understanding the functional significance of HOXA11 hypermethylation in non-small cell lung cancer (NSCLC). HOXA11 hypermethylation was characterized in six lung cancer cell lines, and its clinical significance was analyzed using formalin-fixed paraffin-embedded tissues from 317 NSCLC patients, and Ki-67 expression was analyzed using immunohistochemistry. The promoter region of HOXA11 was highly methylated in six lung cancer cell lines, but not in normal bronchial epithelial cells. The loss of expression was restored by treatment of the cells with a demethylating agent, 5-aza-2''-deoxycytidine (5-Aza-dC). Transient transfection of HOXA11 into H23 lung cancer cells resulted in the inhibition of cell migration and proliferation. HOXA11 hypermethylation was found in 218 (69%) of 317 primary NSCLCs. HOXA11 hypermethylation was found at a higher prevalence in squamous cell carcinoma than in adenocarcinoma (74% vs. 63%, respectively). HOXA11 hypermethylation was associated with Ki-67 proliferation index (P = 0.03) and pT stage (P = 0.002), but not with patient survival. Patients with pT2 and pT3 stages were 1.85 times (95% confidence interval [CI] = 1.04-3.29; P = 0.04) and 5.47 times (95% CI = 1.18-25.50; P = 0.01), respectively, more likely to show HOXA11 hypermethylation than those with pT1 stage, after adjusting for age, sex, and histology. In conclusion, the present study suggests that HOXA11 hypermethylation may contribute to the progression of NSCLC by promoting cell proliferation or migration.     

Preclinical evaluation of a new liposomal formulation of cisplatin,lipoplatin, to treat cisplatin-resistant cervical cancer

Objective

Cisplatin-based chemotherapy has been shown to improve survival in cervical cancer; however, treatment is associated with tumor resistance and significant toxicity. Lipoplatin is a new liposomal formulation of cisplatin, developed to reduce cisplatin toxicity, to improve drug accumulation at tumor sites and to overcome drug resistance.The aim of this study is to analyze the antitumoral activity of lipoplatin against cisplatin-resistant cervical cancer cells and to investigate its mechanism of action.

Methods

The activity and mechanism of action of lipoplatin were studied in the ME-180 cervical cancer cell line and its cisplatin-resistant clone R-ME-180 and HeLa cells using cell proliferation assays, flow cytometry, ELISA assay, cell migration, spheroids and tumor xenograft.

Results

We demonstrated that lipoplatin exhibited a potent antitumoral activity on HeLa, ME-180 cells and its cisplatin-resistant clone R-ME-180. Lipoplatin inhibited cell proliferation in a dose-dependent manner and was more active than the reference drug cisplatin in R-ME-180 cells and induced apoptosis, as evaluated by Annexin-V staining and DNA fragmentation, caspases 9 and 3 activation, Bcl-2, and Bcl-xL down-regulation, but Bax up-regulation inhibited thioredoxin reductase (TrxR) enzymatic activity and increased reactive oxygen species (ROS) accumulation; reduced EGFR expression and inhibited both migration and invasion. R-ME-180, but not ME-180 cells, generated three-dimensional (3D)-multicellular spheroids expressing the cancer stem cell marker ALDH. The ability of R-ME-180 cells to form spheroids in vitro and tumors in nude mice was also remarkably decreased by lipoplatin.

Conclusions

Overall, our results suggest that lipoplatin has potential for the treatment of cisplatin-resistant cervical cancer.     

The chrondroitin sulfate proteoglycan (CSPG4) regulates human trophoblast function

Introduction

Trophoblast growth and invasion of the uterine endometrium are critical events during placentation and are tightly regulated by locally produced factors. Abnormal placentation can result in early miscarriage or preeclampsia and intrauterine growth restriction, leading to impaired fetal and/or maternal health. Chondroitin sulfate proteoglycan 4 (CSPG4) is involved in cancer cell migration and invasion, processes which are critical during placentation but unlike in cancer, trophoblast invasion is highly regulated. CSPG4 expression and function in trophoblast is unknown. We determined CSPG4 expression in human first trimester placenta and implantation sites, and investigated whether CSPG4 influenced proliferation, migration and invasion of a human extravillous trophoblast (EVT) cell line (HTR8/SVneo cells) as a model for extravillous trophoblast (EVT).

Methods and results

Immunoreactive CSPG4 localized to EVT cells in the trophoblast shell, subpopulations of interstitial EVT cells within the decidua and cytotrophoblast cells in placental villi. In HTR8/SVneo cells, siRNA knockdown of CSPG4 stimulated proliferation and decreased migration/invasion. In primary first trimester placental villi explants two cytokines, interleukin 11 (IL11) and leukemia inhibitory factor (LIF) with known roles in trophoblast function, stimulated CSPG4 mRNA expression and immunoreactive protein in the cyotrophoblast.

Discussion and conclusion

This is the first demonstration of the production and function of CSPG4 in human placentation. These data suggest that locally produced CSPG4 stimulates human EVT migration and invasion and suggests that IL11 and LIF regulate villous cytotrophoblast differentiation towards the invasive phenotype at least in part via CSPG4.     

Professional issues related to obstacles to midwifery practice in the Americas: A pilot survey

Background/Objectives

the WHO (2011) estimates that 350,000 newly trained midwives are needed internationally to meet Goal 5 – Improve Maternal Health – of the 8 Millennium Development Goals established by the United Nations in 2000. Recognizing the challenges in accomplishing this goal, it is also imperative to retain trained midwives in the profession. Little to date has been investigated regarding the factors that lead to experienced midwives leaving the profession prematurely, particularly in low resource countries.

Design

in an effort to initiate identification of barriers that limit midwives' ability to continue in practice, a pilot study was conducted with a convenience sample of 58 midwife attendees, representing 12 countries, at the International Confederation of Midwives – Americas Triennial Regional Meeting in 2010. A survey was distributed to midwife respondents to explore potential influences on work retention, including: encounters of adverse outcomes in practice; empowerment to make change in the work setting; and migration.

Findings

sixty per cent of respondents reported encountering a maternal or newborn death or injury, and 10% had considered leaving the profession. Over 50% of the midwives listed three potential results that could occur after experiencing an adverse outcome in practice. These included: (a) an investigation by a governmental agency; (b) complaints about the midwife via available media; and (c) involvement in a lawsuit. The consequence most frequently cited for not enacting evidence-based changes in the workplace was resistance from obstetrical colleagues.

Conclusions

while there are limitations to gathering data from attendees at a professional meeting, this is the first known international survey of midwives regarding factors that may contribute to their leaving the profession at a time when there is an increasing global awareness of the need for a skilled birth attendant at every birth.     

肉桂抑制人宫颈癌细胞生长增殖的体外研究

目的：研究肉桂对人宫颈癌细胞生长的影响。方法：肉桂水煎液作用于宫颈癌细胞后,CCK-8法检测细胞增殖和贴壁情况,划痕实验分析细胞的迁移能力,流式细胞术分析细胞周期。结果：作用48h后,高、中、低浓度肉桂组宫颈癌细胞生长抑制率分别为97.12%、24.58%、15.40%;贴壁率为48.3%,与对照组相比明显减少（P〈0.05）,且明显降低细胞的迁移（P〈0.05）;FCM显示细胞周期移行被阻滞于G2期。结论：肉桂对体外人宫颈癌细胞增殖有明显抑制作用,并可降低肿瘤细胞贴壁率和迁移能力,阻滞细胞周期于G2期。     

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

Eosinophil extravasation across the endothelium is a key feature of allergic inflammation. Here, we investigated the role of PGE(2) and its receptor, E-type prostanoid receptor (EP)-4, in the regulation of eosinophil interaction with human pulmonary microvascular endothelial cells. PGE(2) and the EP4 receptor agonist ONO AE1-329 significantly reduced eotaxin-induced eosinophil adhesion to fibronectin, and formation of filamentous actin and gelsolin-rich adhesive structures. These inhibitory effects were reversed by a selective EP4 receptor antagonist, ONO AE3-208. PGE(2) and the EP4 agonist prevented the activation and cell-surface clustering of β2 integrins, and L-selectin shedding of eosinophils. Under physiological flow conditions, eosinophils that were treated with the EP4 agonist showed reduced adhesion to endothelial monolayers upon stimulation with eotaxin, as well as after TNF-α-induced activation of the endothelial cells. Selective activation of EP1, EP2, and EP3 receptors did not alter eosinophil adhesion to endothelial cells, whereas the EP4 antagonist prevented PGE(2) from decreasing eosinophil adhesion. Finally, eosinophil transmigration across thrombin- and TNF-α-activated endothelial cells was effectively reduced by the EP4 agonist. These data suggest that PGE(2) -EP4 signaling might be protective against allergic responses by inhibiting the interaction of eosinophils with the endothelium and might hence be a useful therapeutic option for controlling inappropriate eosinophil infiltration.     

肿瘤细胞迁移模式及其转换调控的研究进展

肿瘤细胞在三维培养基质中主要以两种模式迁移,即间充质式迁移(mesenchymal migration)和阿米巴式迁移(amoeboid migration)。本文总结分析了肿瘤细胞在不同迁移模式中的运动特征和不同迁移模式形成的内在动因,以及一定条件下迁移模式间相互转换的诱发因素。了解这些变化及不同迁移模式转换间的内在联系,将会加深对肿瘤细胞在不同条件下迁移特性及其过程机制的认识,进而为控制肿瘤细胞恶性转移找到更为有效的措施。