Update on rare epithelial ovarian cancers: based on the Rare Ovarian Tumors Young Investigator Conference

There has been significant progress in the understanding of the pathology and molecular biology of rare ovarian cancers, which has helped both diagnosis and treatment. This paper provides an update on recent advances in the knowledge and treatment of rare ovarian cancers and identifies gaps that need to be addressed by further clinical research. The topics covered include: low-grade serous, mucinous, and clear cell carcinomas of the ovary. Given the molecular heterogeneity and the histopathological rarity of these ovarian cancers, the importance of designing adequately powered trials or finding statistically innovative ways to approach the treatment of these rare tumors has been emphasized. This paper is based on the Rare Ovarian Tumors Conference for Young Investigators which was presented in Tokyo 2015 prior to the 5th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG)

EWS/ETS Regulates the Expression of the Dickkopf Family in Ewing Family Tumor Cells

BACKGROUND: The Dickkopf (DKK) family comprises a set of proteins that function as regulators of Wnt/beta-catenin signaling and has a crucial role in development. Recent studies have revealed the involvement of this family in tumorigenesis, however their role in tumorigenesis is still remained unclear. METHODOLOGY/PRINCIPAL FINDINGS: We found increased expression of DKK2 but decreased expression of DKK1 in Ewing family tumor (EFT) cells. We showed that EFT-specific EWS/ETS fusion proteins enhance the DKK2 promoter activity, but not DKK1 promoter activity, via ets binding sites (EBSs) in the 5' upstream region. EWS/ETS-mediated transactivation of the promoter was suppressed by the deletion and mutation of EBSs located upstream of the DKK2 gene. Interestingly, the inducible expression of EWS/ETS resulted in the strong induction of DKK2 expression and inhibition of DKK1 expression in human primary mesenchymal progenitor cells that are thought to be a candidate of cell origin of EFT. In addition, using an EFT cell line SK-ES1 cells, we also demonstrated that the expression of DKK1 and DKK2 is mutually exclusive, and the ectopic expression of DKK1, but not DKK2, resulted in the suppression of tumor growth in immuno-deficient mice. CONCLUSIONS/SIGNIFICANCE: Our results suggested that DKK2 could not functionally substitute for DKK1 tumor-suppressive effect in EFT. Given the mutually exclusive expression of DKK1 and DKK2, EWS/ETS regulates the transcription of the DKK family, and the EWS/ETS-mediated DKK2 up-regulation could affect the tumorigenicity of EFT in an indirect manner

Phosphorylated tyrosine-containing proteins in primary lung cancer correlates with proliferation and prognosis

To determine the usefulness of tyrosine phosphorylation in evaluating biological characteristics, we attempted to evaluate the relationship between the amount of phosphorylated tyrosine-containing proteins and clinicopathological factors, cell proliferation and outcome in non-small cell lung cancer. To evaluate phosphorylated tyrosine-containing proteins we used 96 surgically resected materials of non-small cell lung cancer and normal peripheral lung, while immunohistochemical evaluation was performed. Cell proliferating ability was evaluated using the labelling index of proliferating cell nuclear antigen-positive nuclear staining cells. There were statistically significant differences between the expression levels of phosphorylated tyrosine-containing proteins of normal and cancerous tissues (P<0.0001). Evaluations based on clinicopathological factors apart from histopathological differentiation, showed no statistically significant differences of phosphorylated tyrosine-containing proteins expression. However, phosphorylated tyrosine-containing proteins correlated with cell proliferation activity evaluated (P(Low, High)<0.0001; P(Low, Int) <0.0001; P(Int, High)<0.0001). Furthermore, non-small cell lung cancer cases with high expression and intermediate expression of phosphorylated tyrosine-containing proteins had a significantly shorter disease-free postoperative survival than those with low expression of phosphorylated tyrosine-containing proteins using log-rank analysis (P(Low, Int) <0.0028; P(Low, High)=0.0002). Furthermore, phosphorylated tyrosine-containing proteins expression level statistically contributed to disease-free survival in Cox's proportional hazard model. Therefore, phosphorylated tyrosine-containing proteins in non-small cell lung cancer tissues seem to reflect its biological malignancy, and this evaluation may be valuable for constructing the most appropriate therapeutic strategy

Sphingomyelin Functions as a Novel Receptor for Helicobacter pylori VacA

The vacuolating cytotoxin (VacA) of the gastric pathogen Helicobacter pylori binds and enters epithelial cells, ultimately resulting in cellular vacuolation. Several host factors have been reported to be important for VacA function, but none of these have been demonstrated to be essential for toxin binding to the plasma membrane. Thus, the identity of cell surface receptors critical for both toxin binding and function has remained elusive. Here, we identify VacA as the first bacterial virulence factor that exploits the important plasma membrane sphingolipid, sphingomyelin (SM), as a cellular receptor. Depletion of plasma membrane SM with sphingomyelinase inhibited VacA-mediated vacuolation and significantly reduced the sensitivity of HeLa cells, as well as several other cell lines, to VacA. Further analysis revealed that SM is critical for VacA interactions with the plasma membrane. Restoring plasma membrane SM in cells previously depleted of SM was sufficient to rescue both toxin vacuolation activity and plasma membrane binding. VacA association with detergent-resistant membranes was inhibited in cells pretreated with SMase C, indicating the importance of SM for VacA association with lipid raft microdomains. Finally, VacA bound to SM in an in vitro ELISA assay in a manner competitively inhibited by lysenin, a known SM-binding protein. Our results suggest a model where VacA may exploit the capacity of SM to preferentially partition into lipid rafts in order to access the raft-associated cellular machinery previously shown to be required for toxin entry into host cells