PLoS ONE: Increased Expression of PITX2 Transcription Factor Contributes to Ovarian Cancer Progression (clear cell ovarian/high grade)

PLoS ONE: Increased Expression of PITX2 Transcription Factor Contributes to Ovarian Cancer Progression

"....According to FIGO grading classification, high-grade ovarian tumor cells are usually poorly histological differentiated [20], grow faster and highly metastatic [7]. In addition, prognosis of high-grade ovarian tumor is poor thereafter it often associates with poor survival rate [21], [22].The clear cell subtype ovarian cancer accounts for approximately 6% of all epithelial ovarian tumors and most cases of this subtype are high-grade tumor exhibiting an aggressive phenotype [3], [22], [23]. Our study showed that both mRNA and protein levels of PITX2 was frequently upregulated in ovarian cancer particularly in the high-grade and clear cell subtypes, indicating that PITX2may play an important role in driving aggressive phenotypes in ovarian cancer.....

paywalled - Gynecologic Oncology - Comparison of ERCC1/XPF genetic variation, mRNA and protein levels in women with advanced stage ovarian cancer treated with intraperitoneal platinum

ScienceDirect.com - Gynecologic Oncology - Comparison of ERCC1/XPF genetic variation, mRNA and protein levels in women with advanced stage ovarian cancer treated with intraperitoneal platinum

Abstract

Objective

Approximately 20% of patients receiving platinum-based chemotherapy for epithelial ovarian cancer (EOC) are refractory or develop early recurrence. Identifying these patients early could reduce treatment-associated morbidity and allow quicker transfer to more effective therapies. Much attention has focused on ERCC1 as a potential predictor of response to therapy because of its essential role in the repair of platinum-induced DNA damage. The purpose of this study was to accurately measure protein levels of ERCC1 and its essential binding partner XPF from patients with EOC treated with platinum-based therapy and determine if protein levels correlate with mRNA levels, patient genotypes or clinical outcomes.

Methods

ERCC1 and XPF mRNA and protein levels were measured in frozen EOC specimens from 41 patients receiving intraperitoneal platinum-based chemotherapy using reverse transcription polymerase chain reaction and western blots. Genotypes of common nucleotide polymorphisms were also analyzed. Patient outcomes included progression free (PFS) and overall survival (OS).

Results

Expression of ERCC1 and XPF were tightly correlated with one another at both the mRNA and protein level. However, the mRNA and protein levels of ERCC1 were not positively correlated. Likewise, none of the SNPs analyzed correlated with ERCC1 or XPF protein levels. There was an inverse correlation between mRNA levels and patient outcomes.

Conclusion

Neither genotype nor mRNA levels are predictive of protein expression. Despite this, low ERCC1 mRNA significantly correlated with improved PFS and OS.

VEGF induces ascites in ovarian cancer patients via increasing peritoneal permeability by downregulation of Claudin 5

VEGF induces ascites in ovarian cancer patients via increasing peritoneal permeability by downregulation of Claudin 5

Objective 
To evaluate the role of VEGF-dependent Claudin 5 production for the development of ascites via influencing endothelial permeability in peritoneal tissue of ovarian cancer patients.

Conclusion 
VEGF induces ascites in ovarian cancer patients. This instance happens due to increased peritoneal permeability, caused by downregulation of the tight junction protein Claudin 5 in the peritoneal endothelium.

press release: Ovarian Cancer: New Tumour Suppressor Gene Identified (protein hVps37A) - Austria

Picture and text available from Monday, 13 February 2012, 9 am CET at:
http://www.fwf.ac.at/en/public_relations/press/pv201202-en.htmlhttp://www.fwf.ac.at/en/public_relations/press/pv201202-en.html

"A recent study published in CLINICAL CANCER RESEARCH suggests that the protein hVps37A suppresses tumour growth in ovarian cancer. The work, which was funded by the Austrian Science Fund FWF, shows, for the first time, that this protein is significantly reduced in ovarian cancer cells. The scientists also found that this reduction affects a cellular signalling pathway that is associated with the membrane receptor EGFR (Epidermal Growth Factor Receptor). The receptor is considered an important biological marker for the course of the disease and therapy, and also serves as a target for modern treatment of different cancer types. In fact, the cells in which hVps37A synthesis was reduced showed resistance to Cetuximab, an approved substance for inhibition of EGFR activity...."

The hVps37A gene as such is not unknown to scientists. In the period 2004 to 2007, a systematic genome search as part of a project funded by the Austrian Science Fund FWF determined that, among others, this gene is down-regulated in ovarian cancer. The then head of studies, Prof. Michael Krainer, has now studied the function of this gene further in this particular type of cancer. The published results of this follow-up project show that hVps37A is a hitherto unknown tumour suppressor gene.

Jan 20th: open access: Journal of Ovarian Research IGFBP-4 tumor and serum levels are increased across all stages of epithelial ovarian cancer - papillary serous tumors; note reference to Hispanic women (Italy/US study)

Background (pdf file)
"Epithelial Ovarian Cancer (EOC) is the most lethal female reproductive tract malignancy with nearly 200,000 new cases and >125,000 deaths attributable to the disease each year worldwide (1).........The search for reliable, specific, and sensitive serum-based biomarkers for EOC
has a long history and its major highlight remains the identification of CA125 nearly 30 years ago (4)."

"Papillary serous tumor samples were collected across all stages (five stage I/II, 11 stage III/IV, two disseminated peritoneal lesions, and two recurrent tumors). For comparison, two borderline tumors were also sequenced."

Research

IGFBP-4 tumor and serum levels are increased across all stages of epithelial ovarian cancer.

Journal of Ovarian Research 2012, 5:3 doi:10.1186/1757-2215-5-3
Published: 20 January 2012

Abstract (provisional)

Background

We sought to identify candidate serum biomarkers for the detection and surveillance of EOC. Based on RNA-Seq transcriptome analysis of patient-derived tumors, highly expressed secreted proteins were identified using a bioinformatic approach.

Methods

RNA-Seq was used to quantify papillary serous ovarian cancer transcriptomes.......... Serum samples from women with benign and malignant pelvic masses and serial samples from women during chemotherapy regimens were measured for IGFBP-4 by ELISA.....

Results

Insulin-like growth factor binding protein (IGFBP-4) was consistently present in the top 7.5% of all expressed genes in all tumor samples. We then screened serum samples to determine if increased tumor expression correlated with serum expression. In an initial discovery set of 21 samples, IGFBP-4 levels were found to be elevated in patients, including those with early stage disease and normal CA125 levels. In a larger and independent validation set (82 controls, 78 cases), IGFBP-4 levels were significantly increased (p<5x10-5). IGFBP-4 levels were ~3x greater in women with malignant pelvic masses compared to women with benign masses. ROC sensitivity was 73% at 93% specificity (AUC 0.816). In women receiving chemotherapy, average IGFBP-4 levels were below the ROC-determined threshold and lower in NED patients compared to AWD patients.

Conclusions

This study, the first to our knowledge to use RNA-Seq for biomarker discovery, identified IGFBP-4 as overexpressed in ovarian cancer patients.  

Beyond this, these studies identified two additional intriguing findings. First, IGFBP-4 can be elevated in early stage disease without elevated CA125. Second, IGFBP-4 levels are significantly elevated with malignant versus benign disease. These findings provide the rationale for future validation studies. 

pdf: 
Future studies are planned primarily to increase sample size and diversity of patients. Unexpectedly, we noted that Hispanic cases have significantly higher serum IGFPB-4 levels compared to other non-Hispanic cases or all controls . We are unaware of previous reports or studies suggesting a biologic basis for this finding. Thus, this intriguing finding will be specifically explored in future studies.

--------------------------------------------------------------

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Jan 2012: Faulty proteins may prove significant in identifying new treatments for ovarian cancer | e! Science News

Link:  PLOS One published study


 Objective
To define the BRCAness profile of sporadic ovarian carcinoma and determine whether BRCA1, PARP, FANCD2, PTEN, H2AX, ATM, and P53 protein expression correlates with response to treatment, disease recurrence, and recurrence-free survival.

"The study -- which was supported by the Sherie Hildreth Ovarian Cancer (SHOC) Foundation -- focused on proteins that are supposed to assist cells in repairing harmful breaks in DNA strands, a process called homologous recombination (HR). The malfunctioning of HR is not well understood in ovarian cancers where there is no family history of the disease. However, there is evidence that these proteins influence a patient's ability to respond to drugs and their survival rates after treatment."

Expert Opinion: The Therapeutic Target Database: an Internet resource for the primary targets of approved, clinical trial and experimental drugs

Note: the full article is pay-per-view ($$$)

".....Increasing numbers of proteins, nucleic acids and other molecular entities have been explored as therapeutic targets.

A challenge in drug discovery is to decide which targets to pursue from an increasing pool of potential targets, given the fact that few innovative targets have made it to the approval list each year.

Knowledge of existing drug targets (both approved and within clinical trials) is highly useful for facilitating target discovery, selection, exploration and tool development. The Therapeutic Target Database (TTD) has been developed and updated to provide information on 358 successful targets, 251 clinical trial targets and 1254 research targets in addition to 1511 approved drugs, 1118 clinical trials drugs and 2331 experimental drugs linked to their primary targets (3257 drugs with available structure data).

This review briefly describes the TTD database and illustrates how its data can be explored for facilitating target and drug searches, the study of the mechanism of multi-target drugs and the development of in silico target discovery tools."

Research uncovers possible new targets for attacking ovarian cancer - Cancerwise | Cancer blog from MD Anderson Cancer Center

Note: in research

Two studies led by scientists at MD Anderson open new areas of research that could potentially improve ovarian cancer treatment.

The discoveries published today in the journal Cancer Cell are preclinical - they employ laboratory experiments to better understand the molecular processes that drive formation and growth of cancer. Both studies found previously unknown roles for two proteins, singling them out for further research and possible drug development. ...cont'd

DNA discovery opens new door to develop tools, therapies for hereditary cancers (in research)

"....Errors in DNA can arise from many types of damage including external harm, such as UV radiation or carcinogens, as well as by intrinsic cellular processes such as DNA replication. Failure to correct these errors leads to mutations, which results in cancer or a number of severe genetic disorders."

“The reason why it can lead to cancer is because if you don’t have mismatch repair proteins that correct these errors, you’re going to accumulate mutations,” said Guarné. “People with defective mismatch repair genes develop cancers at very early ages. You would see a family that in their 30s has colorectal cancer and in their 40s they have it again. There’s no way you can prevent that – you can’t correct your DNA. As you grow older, you’re going to accumulate mutations.”

Proteins linked to ovarian cancer outcomes - (short) news item