A lesson for cancer research : placental microarray gene analysis in preeclampsia

Tumor progression and pregnancy share many common features, such as immune tolerance and invasion. The invasion of trophoblasts in the placenta into the uterine wall is essential for fetal development, and is thus precisely regulated. Its deregulation has been implicated in preeclampsia, a leading cause for maternal and perinatal mortality and morbidity. Pathogenesis of preeclampsia remains to be defined. Microarray-based gene profiling has been widely used for identifying genes responsible for preeclampsia. In this review, we have summarized the recent data from the microarray studies with preeclamptic placentas. Despite the complex of gene signatures, suggestive of the heterogeneity of preeclampsia, these studies identified a number of differentially expressed genes associated with preeclampsia. Interestingly, most of them have been reported to be tightly involved in tumor progression. We have discussed these interesting genes and analyzed their potential molecular functions in preeclampsia, compared with their roles in malignancy development. Further investigations are warranted to explore the involvement in molecular network of each identified gene, which may provide not only novel strategies for prevention and therapy for preeclampsia but also a better understanding of cancer cells. The trophoblastic cells, with their capacity for proliferation and differentiation, apoptosis and survival, migration, angiogenesis and immune modulation by exploiting similar molecular pathways, make them a compelling model for cancer research

The effects of clinical hypnosis versus Neurolinguistic Programming (NLP) before External Cephalic Version (ECV) : a prospective off-centre randomised, double-blind, controlled trial

Objective. To examine the effects of clinical hypnosis versus NLP intervention on the success rate of ECV procedures in comparison to a control group. Methods. A prospective off-centre randomised trial of a clinical hypnosis intervention against NLP of women with a singleton breech fetus at or after 370/7 (259 days) weeks of gestation and normal amniotic fluid index. All 80 participants heard a 20-minute recorded intervention via head phones. Main outcome assessed was success rate of ECV. The intervention groups were compared with a control group with standard medical care alone (n=122). Results. A total of 42 women, who received a hypnosis intervention prior to ECV, had a 40.5% (n=17), successful ECV, whereas 38 women, who received NLP, had a 44.7% (n=17) successful ECV (P > 0.05). The control group had similar patient characteristics compared to the intervention groups (P > 0.05). In the control group (n = 122) 27.3% (n = 33) had a statistically significant lower successful ECV procedure than NLP (P = 0.05) and hypnosis and NLP (P = 0.03). Conclusions. These findings suggest that prior clinical hypnosis and NLP have similar success rates of ECV procedures and are both superior to standard medical care alone

Function of survivin in trophoblastic cells of the placenta

Background: Preeclampsia is one of the leading causes of maternal and perinatal mortality and morbidity worldwide and its pathogenesis is not totally understood. As a member of the chromosomal passenger complex and an inhibitor of apoptosis, survivin is a well-characterized oncoprotein. Its roles in trophoblastic cells remain to be defined. Methods: The placental samples from 16 preeclampsia patients and 16 well-matched controls were included in this study. Real-time PCR, immunohistochemistry and Western blot analysis were carried out with placental tissues. Primary trophoblastic cells from term placentas were isolated for Western blot analysis. Cell proliferation, cell cycle analysis and immunofluorescence staining were performed in trophoblastic cell lines BeWo, JAR and HTR-8/SVneo. Results: The survivin gene is reduced but the protein amount is hardly changed in preeclamptic placentas, compared to control placentas. Upon stress, survivin in trophoblastic cells is phosphorylated on its residue serine 20 by protein kinase A and becomes stabilized, accompanied by increased heat shock protein 90. Depletion of survivin induces chromosome misalignment, abnormal centrosome integrity, and reduced localization and activity of Aurora B at the centromeres/kinetochores in trophoblastic metaphase cells. Conclusions: Our data indicate that survivin plays pivotal roles in cell survival and proliferation of trophoblastic cells. Further investigations are required to define the function of survivin in each cell type of the placenta in the context of proliferation, differentiation, apoptosis, angiogenesis, migration and invasion

Mitotic centromere-associated kinesin (MCAK): a potential cancer drug target

The inability to faithfully segregate chromosomes in mitosis results in chromosome instability, a hallmark of solid tumors. Disruption of microtubule dynamics contributes highly to mitotic chromosome instability. The kinesin-13 family is critical in the regulation of microtubule dynamics and the best characterized member of the family, the mitotic centromere-associated kinesin (MCAK), has recently been attracting enormous attention. MCAK regulates microtubule dynamics as a potent depolymerizer of microtubules by removing tubulin subunits from the polymer end. This depolymerizing activity plays pivotal roles in spindle formation, in correcting erroneous attachments of microtubule-kinetochore and in chromosome movement. Thus, the accurate regulation of MCAK is important for ensuring the faithful segregation of chromosomes in mitosis and for safeguarding chromosome stability. In this review we summarize recent data concerning the regulation of MCAK by mitotic kinases, Aurora A/B, Polo-like kinase 1 and cyclin-dependent kinase 1. We propose a molecular model of the regulation of MCAK by these mitotic kinases and relevant phosphatases throughout mitosis. An ever-increasing quantity of data indicates that MCAK is aberrantly regulated in cancer cells. This deregulation is linked to increased malignance, invasiveness, metastasis and drug resistance, most probably due to increased chromosomal instability and remodeling of the microtubule cytoskeleton in cancer cells. Most interestingly, recent observations suggest that MCAK could be a novel molecular target for cancer therapy, as a new cancer antigen or as a mitotic regulator. This collection of new data indicates that MCAK could be a new star in the cancer research sky due to its critical roles in the control of genome stability and the cytoskeleton. Further investigations are required to dissect the fine details of the regulation of MCAK throughout mitosis and its involvements in oncogenesis

RITA modulates cell migration and invasion by affecting focal adhesion dynamics

RITA, the RBP-J interacting and tubulin-associated protein, has been reported to be related to tumor development, but the underlying mechanisms are not understood. Since RITA interacts with tubulin and coats microtubules of the cytoskeleton, we hypothesized that it is involved in cell motility. We show here that depletion of RITA reduces cell migration and invasion of diverse cancer cell lines and mouse embryonic fibroblasts. Cells depleted of RITA display stable focal adhesions (FA) with elevated active integrin, phosphorylated focal adhesion kinase, and paxillin. This is accompanied by enlarged size and disturbed turnover of FA. These cells also demonstrate increased polymerized tubulin. Interestingly, RITA is precipitated with the lipoma-preferred partner (LPP), which is critical in actin cytoskeleton remodeling and cell migration. Suppression of RITA results in reduced LPP and alpha-actinin at FA leading to compromised focal adhesion turnover and actin dynamics. This study identifies RITA as a novel crucial player in cell migration and invasion by affecting the turnover of FA through its interference with the dynamics of actin filaments and microtubules. Its deregulation may contribute to malignant progression

Targeting cyclin B1 inhibits proliferation and sensitizes breast cancer cells to taxol

Background Cyclin B1, the regulatory subunit of cyclin-dependent kinase 1 (Cdk1), is essential for the transition from G2 phase to mitosis. Cyclin B1 is very often found to be overexpressed in primary breast and cervical cancer cells as well as in cancer cell lines. Its expression is correlated with the malignancy of gynecological cancers. Methods In order to explore cyclin B1 as a potential target for gynecological cancer therapy, we studied the effect of small interfering RNA (siRNA) on different gynecological cancer cell lines by monitoring their proliferation rate, cell cycle profile, protein expression and activity, apoptosis induction and colony formation. Tumor formation in vivo was examined using mouse xenograft models. Results Downregulation of cyclin B1 inhibited proliferation of several breast and cervical cancer cell lines including MCF-7, BT-474, SK-BR-3, MDA-MB-231 and HeLa. After combining cyclin B1 siRNA with taxol, we observed an increased apoptotic rate accompanied by an enhanced antiproliferative effect in breast cancer cells. Furthermore, control HeLa cells were progressively growing, whereas the tumor growth of HeLa cells pre-treated with cyclin B1 siRNA was strongly inhibited in nude mice, indicating that cyclin B1 is indispensable for tumor growth in vivo. Conclusion Our data support the notion of cyclin B1 being essential for survival and proliferation of gynecological cancer cells. Concordantly, knockdown of cyclin B1 inhibits proliferation in vitro as well as in vivo. Moreover, targeting cyclin B1 sensitizes breast cancer cells to taxol, suggesting that specific cyclin B1 targeting is an attractive strategy for the combination with conventionally used agents in gynecological cancer therapy

Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells

High attrition rates of novel anti-cancer drugs highlight the need for improved models to predict toxicity. Although polo-like kinase 1 (Plk1) inhibitors are attractive candidates for drug development, the role of Plk1 in primary cells remains widely unexplored. Therefore, we evaluated the utility of an RNA interference-based model to assess responses to an inducible knockdown (iKD) of Plk1 in adult mice. Here we show that Plk1 silencing can be achieved in several organs, although adverse events are rare. We compared responses in Plk1-iKD mice with those in primary cells kept under controlled culture conditions. In contrast to the addiction of many cancer cell lines to the non-oncogene Plk1, the primary cells' proliferation, spindle assembly and apoptosis exhibit only a low dependency on Plk1. Responses to Plk1-depletion, both in cultured primary cells and in our iKD-mouse model, correspond well and thus provide the basis for using validated iKD mice in predicting responses to therapeutic interventions

Battle of the eternal rivals : restoring functional p53 and inhibiting Polo-like kinase 1 as cancer therapy

Polo-like kinase 1, a pivotal regulator of mitosis and cytokinesis, is highly expressed in a broad spectrum of tumors and its expression correlates often with poor prognosis, suggesting its potential as a therapeutic target. p53, the guardian of the genome, is the most important tumor suppressor. In this review, we address the intertwined relationship of these two key molecules by fighting each other as eternal rivals in many signaling pathways. p53 represses the promoter of Polo-like kinase 1, whereas Polo-like kinase 1 inhibits p53 and its family members p63 and p73 in cancer cells lacking functional p53. Plk1 inhibitors target all rapidly dividing cells irrespective of tumor cells or non-transformed normal but proliferating cells. Upon treatment with Plk1 inhibitors, p53 in tumor cells is activated and induces strong apoptosis, whereas tumor cells with inactive p53 arrest in mitosis with DNA damage. Thus, inactive p53 is not associated with a susceptible cytotoxicity of Polo-like kinase 1 inhibition and could rather foster the induction of polyploidy/aneuploidy in surviving cells. In addition, compared to the mono-treatment, combination of Polo-like kinase 1 inhibition with anti-mitotic or DNA damaging agents boosts more severe mitotic defects, effectually triggers apoptosis and strongly inhibits proliferation of cancer cells with functional p53. In this regard, restoration of p53 in tumor cells with loss or mutation of p53 will reinforce the cytotoxicity of combined Polo-like kinase 1 therapy and provide a proficient strategy for combating relapse and metastasis of cancer

The multifaceted p21 (Cip1/Waf1/CDKN1A) in cell differentiation, migration and cancer therapy

Loss of cell cycle control is characteristic of tumorigenesis. The protein p21 is the founding member of cyclin-dependent kinase inhibitors and an important versatile cell cycle protein. p21 is transcriptionally controlled by p53 and p53-independent pathways. Its expression is increased in response to various intra- and extracellular stimuli to arrest the cell cycle ensuring genomic stability. Apart from its roles in cell cycle regulation including mitosis, p21 is involved in differentiation, cell migration, cytoskeletal dynamics, apoptosis, transcription, DNA repair, reprogramming of induced pluripotent stem cells, autophagy and the onset of senescence. p21 acts either as a tumor suppressor or as an oncogene depending largely on the cellular context, its subcellular localization and posttranslational modifications. In the present review, we briefly mention the general functions of p21 and summarize its roles in differentiation, migration and invasion in detail. Finally, regarding its dual role as tumor suppressor and oncogene, we highlight the potential, difficulties and risks of using p21 as a biomarker as well as a therapeutic target