Xuan Bich Trinh

The RUNX1 transcription factor is expressed in serous epithelial ovarian carcinoma and contributes to cell proliferation, migration and invasion

Previously, we have identified the RUNX1 gene as hypomethylated and overexpressed in post-chemotherapy (CT) primary cultures derived from epithelial ovarian cancer (EOC) patients, when compared with primary cultures derived from matched primary (prior to CT) tumors. Here we show that RUNX1 displays a trend of hypomethylation, although not significant, in omental metastases compared with primary EOC tumors. Surprisingly, RUNX1 displayed significantly higher expression not only in metastatic tissue, but also in high-grade primary tumors and even in low malignant potential tumors. The RUNX1 expression levels were almost identical in primary tumors and omental metastases, suggesting that RUNX1 hypomethylation might have a limited impact on its overexpression in advanced (metastatic) stage of the disease. Knockdown of the RUNX1 expression in EOC cells led to sharp decrease of cell proliferation and induced G1 cell cycle arrest. Moreover, RUNX1 suppression significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon RUNX1 suppression, while a number of pro-apoptotic genes and some EOC tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the RUNX1 gene in EOC progression and suggest that RUNX1 might be a novel EOC therapeutic target. Further studies are needed to more completely elucidate the functional implications of RUNX1 and other members of the RUNX gene family in ovarian tumorigenesis.

Are Costs of Robot-Assisted Surgery Warranted for Gynecological Procedures?

The exponential use of robotic surgery is not the result of evidence-based benefits but mainly driven by the manufacturers, patients and enthusiastic surgeons. The present review of the literature shows that robot-assisted surgery is consistently more expensive than video-laparoscopy and in many cases open surgery. The average additional variable cost for gynecological procedures was about 1600 USD, rising to more than 3000 USD when the amortized cost of the robot itself was included. Generally most robotic and laparoscopic procedures have less short-term morbidity, blood loss, intensive care unit, and hospital stay than open surgery. Up to now no major consistent differences have been found between robot-assisted and classic video-assisted procedures for these factors. No comparative data are available on long-term morbidity and oncologic outcome after open, robotic, and laparoscopic gynecologic surgery. It seems that currently only for very complex surgical procedures, such as cardiac surgery, the costs of robotics can be competitive to open surgical procedures. In order to stay viable, robotic programs will need to pay for themselves on a per case basis and the costs of robotic surgery will have to be reduced.

Microarray-based oncogenic pathway profiling in advanced serous papillary ovarian carcinoma.

Introduction The identification of specific targets for treatment of ovarian cancer patients remains a challenge. The objective of this study is the analysis of oncogenic pathways in ovarian cancer and their relation with clinical outcome. Methodology A meta-analysis of 6 gene expression datasets was done for oncogenic pathway activation scores: AKT, β-Catenin, BRCA, E2F1, EGFR, ER, HER2, INFα, INFγ, MYC, p53, p63, PI3K, PR, RAS, SRC, STAT3, TNFα, and TGFβ and VEGF-A. Advanced serous papillary tumours from uniformly treated patients were selected (N = 464) to find differences independent from stage-, histology- and treatment biases. Survival and correlations with documented prognostic signatures (wound healing response signature WHR/genomic grade index GGI/invasiveness gene signature IGS) were analysed. Results The GGI, WHR, IGS score were unexpectedly increased in chemosensitive versus chemoresistant patients. PR and RAS activation score were associated with survival outcome (p = 0.002;p = 0.004). Increased activations of β-Catenin (p = 0.0009), E2F1 (p = 0.005), PI3K (p = 0.003) and p63 (p = 0.05) were associated with more favourable clinical outcome and were consistently correlated with three prognostic gene signatures. Conclusions Oncogenic pathway profiling of advanced serous ovarian tumours revealed that increased β-Catenin, E2F1, p63, PI3K, PR and RAS –pathway activation scores were significantly associated with favourable clinical outcome. WHR, GGI and IGS scores were unexpectedly increased in chemosensitive tumours. Earlier studies have shown that WHR, GGI and IGS are strongly associated with proliferation and that high-proliferative ovarian tumours are more chemosensitive. These findings may indicate opposite confounding of prognostic versus predictive factors when studying biomarkers in epithelial ovarian cancer.

Relapse-Free Survival in Breast Cancer Patients Is Associated with a Gene Expression Signature Characteristic for Inflammatory Breast Cancer

Purpose: We hypothesize that a gene expression profile characteristic for inflammatory breast cancer (IBC), an aggressive form of breast cancer associated with rapid cancer dissemination and poor survival, might be related to tumor aggressiveness in non-IBC (nIBC). Experimental Design: RNA from 17 IBC samples and 40 nIBC samples was hybridized onto Affymetrix chips. A gene signature predictive of IBC was identified and applied onto 1,157 nIBC samples with survival data of 881 nIBC samples. Samples were classified as IBC-like or nIBC-like. The IBC signature classification was compared with the classifications according to other prognostically relevant gene signatures and clinicopathologic variables. In addition, relapse-free survival (RFS) was compared by the Kaplan-Meyer method. Results: Classification according to the IBC signature is significantly (P < 0.05) associated with the cell-of-origin subtypes, the wound healing response, the invasive gene signature, the genomic grade index, the fibroblastic neoplasm signature, and the 70-gene prognostic signature. Significant associations (P < 0.01) were found between the IBC signature and tumor grade, estrogen receptor status, ErbB2 status, and patient age at diagnosis. Patients with an IBC-like phenotype show a significantly shorter RFS interval (P < 0.05). Oncomine analysis identified cell motility as an important concept linked with the IBC signature. Conclusions: We show that nIBC carcinomas having an IBC-like phenotype have a reduced RFS interval. This suggests that IBC and nIBC show comparable phenotypic traits, for example augmented cell motility, with respect to aggressive tumor cell behavior. This observation lends credit to the use of IBC to study aggressive tumor cell behavior.

Inhibition of RUNX2 Transcriptional Activity Blocks the Proliferation, Migration and Invasion of Epithelial Ovarian Carcinoma Cells

Previously, we have identified the RUNX2 gene as hypomethylated and overexpressed in post-chemotherapy (CT) primary cultures derived from serous epithelial ovarian cancer (EOC) patients, when compared to primary cultures derived from matched primary (prior to CT) tumors. However, we found no differences in the RUNX2 methylation in primary EOC tumors and EOC omental metastases, suggesting that DNA methylation-based epigenetic mechanisms have no impact on RUNX2 expression in advanced (metastatic) stage of the disease. Moreover, RUNX2 displayed significantly higher expression not only in metastatic tissue, but also in high-grade primary tumors and even in low malignant potential tumors. Knockdown of the RUNX2 expression in EOC cells led to a sharp decrease of cell proliferation and significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as various genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon RUNX2 suppression, while a number of pro-apoptotic genes and some EOC tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the RUNX2 gene in serous EOC progression and suggest that RUNX2 might be a novel EOC therapeutic target. Further studies are needed to more completely elucidate the functional implications of RUNX2 and other members of the RUNX gene family in ovarian tumorigenesis.

The rationale for mTOR inhibition in epithelial ovarian cancer

The AKT/mTOR signaling pathway is frequently overexpressed in human epithelial ovarian cancer and an attractive target for therapy. In vivo mouse models were confirmative for in vitro findings, where the administration of mTOR inhibitors in ovarian cancer xenografts showed antitumoral as well as antiangiogenic effects. Phase I – II trials are now ongoing with mTOR inhibitors in ovarian cancer patients, some in combination with conventional cytotoxic agents. If further development of mTOR inhibition in ovarian cancer is pursued, studying combinations of mTOR inhibitors with other new targeted therapies would be of interest. mTOR inhibitors in the adjuvant setting could have potential, since, for the moment, there is no standard maintenance therapy in ovarian cancer. A crucial challenge will be to identify strong predictive biomarkers. This review highlights the rationale for the use of mTOR inhibitors in ovarian cancer and summarizes the available preclinical findings.

The role of Nuclear Factor-kappa B signaling in human cervical cancer

Background The Nuclear Factor kappaB (NF-kB) family consists of transcription factors that play a complex and essential role in the regulation of immune responses and inflammation. NF-kB has recently generated considerable interest as it has been implicated in human cancer initiation, progression and resistance to treatment. In the present comprehensive review the different aspects of NF-kB signaling in the carcinogenesis of cancer of the uterine cervix are discussed. NF-kB functions as part of a network, which determines the pattern of its effects on the expression of several other genes (such as crosstalks with reactive oxygen species, p53, STAT3 and miRNAS) and thus its function. Activation of NF-kB triggered by a HPV infection is playing an important role in the innate and adaptive immune response of the host. The virus induces down regulation of NF-kB to liquidate the inhibitory activity for its replication triggered by the immune system leading a status of persistant HPV infection. During the progression to high grade intraepithelial neoplasia and cervical cancer NF-KB becomes constitutionally activated again. Mutations in NF-kB genes are rare in solid tumors but mutations of upstream signaling molecules such as RAS, EGFR, PGF, HER2 have been implicated in elevated NF-kB signaling. NF-kB can stimulate transcription of proliferation regulating genes (eg. cyclin D1 and c-myc), genes involved in metastasis, VEGF dependent angiogenesis and cell immortality by telomerase. NF-kB activation can also induce the expression of activation-induced cytodine deaminase (AID) and the APOBEC proteins, providing a mechanistic link between the NF-kB pathway and mutagenic characteristic of cervical cancer. Inhibition of NF-kB has the potential to be used to reverse resistance to radiotherapy and systemic anti-cancer medication, but currently no clinicaly active NF-kB targeting strategies are available.

VEGF-A-independent and angiogenesis-dependent tumour growth in patients with metastatic breast cancer

BackgroundThe mechanisms of tumour progression during anti-VEGF-A treatment are poorly understood.Patients and materialsTwo patients with metastatic breast cancer are described who developed new metastases while receiving anti-VEGF-A treatment. Angiogenic parameters were determined by CD34/Ki67 double staining, Chalkley counts (CC) and endothelial cell proliferation fractions (ECP). RT-PCR Taqman low-density arrays with a gene panel of 94 angiogenesis-related genes were performed on both metastases and compared to 10 unselected primary breast tumours.ResultsBoth lesions showed a high and intermediate CC of, respectively, 7.5±0.62 and 4.8±0.2. Both lesions had elevated ECP values of 14% and 8%. Low-density array screening showed that VEGFR1 mRNA was overexpressed in both samples (z-score=7.85 and 7.81) compared to control samples (out of range [min-max]). Additional analysis confirmed this finding at the protein level by immunohistochemistry.ConclusionThese observations suggest that tumour progression under continuous anti-VEGF-A continues to be angiogenesis dependent. Further exploration is needed to identify the mechanisms of anti-VEGF-A resistance in order to design combination-targeted therapies.

In silico pathway analysis in cervical carcinoma reveals potential new targets for treatment

An in silico pathway analysis was performed in order to improve current knowledge on the molecular drivers of cervical cancer and detect potential targets for treatment. Three publicly available Affymetrix gene expression data-sets (GSE5787, GSE7803, GSE9750) were retrieved, vouching for a total of 9 cervical cancer cell lines (CCCLs), 39 normal cervical samples, 7 CIN3 samples and 111 cervical cancer samples (CCSs). Predication analysis of microarrays was performed in the Affymetrix sets to identify cervical cancer biomarkers. To select cancer cell-specific genes the CCSs were compared to the CCCLs. Validated genes were submitted to a gene set enrichment analysis (GSEA) and Expression2Kinases (E2K). In the CCSs a total of 1,547 probe sets were identified that were overexpressed (FDR < 0.1). Comparing to CCCLs 560 probe sets (481 unique genes) had a cancer cell-specific expression profile, and 315 of these genes (65%) were validated. GSEA identified 5 cancer hallmarks enriched in CCSs (P < 0.01 and FDR < 0.25) showing that deregulation of the cell cycle is a major component of cervical cancer biology. E2K identified a protein-protein interaction (PPI) network of 162 nodes (including 20 drugable kinases) and 1626 edges. This PPI-network consists of 5 signaling modules associated with MYC signaling (Module 1), cell cycle deregulation (Module 2), TGFβ-signaling (Module 3), MAPK signaling (Module 4) and chromatin modeling (Module 5). Potential targets for treatment which could be identified were CDK1, CDK2, ABL1, ATM, AKT1, MAPK1, MAPK3 among others. The present study identified important driver pathways in cervical carcinogenesis which should be assessed for their potential therapeutic drugability.

Neoadjuvant endocrine treatment in early breast cancer: An overlooked alternative?

During the last decade neoadjuvant endocrine therapy (NET) has moved from being reserved for elderly and frail non-chemotherapy candidates to a primary systemic modality in selected patients with hormone sensitive breast cancer. Neoadjuvant hormonal treatment in patients with hormone receptor positive, HER-2 negative early breast cancer is proven to be an effective and safe option; it is associated with a higher rate of breast conserving surgery (BCS), may reduce the need for adjuvant chemotherapy and enables a delay of surgery for medical or practical reasons. Clinical responses range from 13% to 100% with at least 3 months of NET. Methods of assessing response should include MRI of the breast, particularly in lobular tumours. In studies comparing tamoxifen with aromatase inhibitors (AI), AI proved to be superior in terms of tumour response and rates of BCS. Change in Ki67 is accepted as a validated endpoint for comparing endocrine neoadjuvant agents. Levels of Ki67 during treatment are more closely related to long-term prognosis than pretreatment Ki67. Neoadjuvant endocrine therapy provides a unique opportunity for studies of endocrine responsiveness and the development of new experimental drugs combined with systemic hormonal treatment.