ABSTRACT
LASP-1 was identified as a protein following mass spectrometric analysis of phosphoproteins consequent to signaling by ErbB2 in SKOV-3 cells. It has been previously identified as an oncogene and is located on chromosomal arm 17q 0.76â Mb centromeric to ErbB2. It is expressed in serous ovarian cancer cell lines as a 40â kDa protein. In SKOV-3 cells, it was phosphorylated and was inhibited by Lapatinib and CP7274714. LASP-1 co-immunoprecipitated with ErbB2 in SKOV-3 cells, suggesting a direct interaction. This interaction and phosphorylation were independent of the kinase activity of ErbB2. Moreover, the binding of LASP-1 to ErbB2 was independent of the tyrosine phosphorylation of LASP-1. LASP-1 was neither expressed on the surface epithelium of the normal ovary nor in the fallopian tube. It was expressed in 28% of ovarian tumours (n = 101) that did not significantly correlate with other clinical factors. In tumours from patients with invasive ductal carcinoma of the breast who had ErbB2 amplification (3+), LASP-1 was expressed in 3/20 (P < 0.001). Analysis of the expression of an independent dataset of ovarian and breast tumours from TCGA showed the significant co-occurrence of ErbB2 and LASP-1 (P < 0.01). These results suggest that LASP-1 and ErbB2 interaction could be important in the pathogenesis of ovarian cancer.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Ovarian Epithelial/metabolism , Cytoskeletal Proteins/metabolism , LIM Domain Proteins/metabolism , Ovarian Neoplasms/metabolism , Receptor, ErbB-2/metabolism , Signal Transduction/genetics , Adaptor Proteins, Signal Transducing/genetics , Adult , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Carcinoma, Ovarian Epithelial/pathology , Cell Line, Tumor , Cohort Studies , Cytoskeletal Proteins/genetics , Female , HEK293 Cells , Humans , LIM Domain Proteins/genetics , Lapatinib/pharmacology , Middle Aged , Ovarian Neoplasms/pathology , Phosphorylation/drug effects , Phosphorylation/genetics , Plasmids , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Receptor, ErbB-2/genetics , Signal Transduction/drug effects , TransfectionABSTRACT
The origin of blood and lymphatic vessels in high-grade serous adenocarcinoma of ovary (HGSOC) is uncertain. We evaluated the potential of cancer stem cells (CSCs) in HGSOC to contribute to their formation. Using spheroids as an in vitro model for CSCs, we have evaluated their role in primary malignant cells (PMCs) in ascites from previously untreated patients with HGSOC and cell lines. Spheroids from PMCs grown under specific conditions showed significantly higher expression of endothelial, pericyte and lymphatic endothelial markers. These endothelial and lymphatic cells formed tube-like structures, showed uptake of Dil-ac-LDL and expressed endothelial nitric oxide synthase confirming their endothelial phenotype. Electron microscopy demonstrated classical Weibel-Palade bodies in differentiated cells. Genetically, CSCs and the differentiated cells had a similar identity. Lineage tracking using green fluorescent protein transfected cancer cells in nude mice confirmed that spheroids grown in stem cell conditions can give rise to all three cells. Bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor inhibited the differentiation of spheroids to endothelial cells in vitro. These results suggest that CSCs contribute to angiogenesis and lymphangiogenesis in serous adenocarcinoma of the ovary, which can be inhibited.
Subject(s)
Adenocarcinoma/pathology , Lymphangiogenesis , Neoplasms, Cystic, Mucinous, and Serous/pathology , Neoplastic Stem Cells/pathology , Neovascularization, Pathologic/pathology , Ovarian Neoplasms/pathology , Adenocarcinoma/blood supply , Adenocarcinoma/ultrastructure , Ascites/metabolism , Ascites/pathology , Bevacizumab/pharmacology , Bevacizumab/therapeutic use , Biomarkers, Tumor/metabolism , Blood Vessels/pathology , Cell Differentiation/drug effects , Cell Line, Tumor , Endothelial Cells/metabolism , Female , Humans , Neoplasm Proteins/metabolism , Neoplasms, Cystic, Mucinous, and Serous/blood supply , Neoplasms, Cystic, Mucinous, and Serous/ultrastructure , Neoplastic Stem Cells/ultrastructure , Ovarian Neoplasms/blood supply , Ovarian Neoplasms/ultrastructure , Pericytes/pathology , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Vascular Endothelial Growth Factor A/metabolismABSTRACT
The focal aim of this study was to assess the frequency of chromosomal aberrations (CA) including chromatid type aberrations (CTA) and chromosomal type aberrations (CSA), micronucleus (MN) and XRCC1 399 Arg/Gln polymorphism in the peripheral blood lymphocytes of 27 petrol pump workers and same number of controls to explore the possible cytogenetic risk on occupational exposure to petrol vapors. The exposed subjects and controls were classified into two groups based on their age (group I < 40 years; group II > 40 years) apart from the classification of the exposed subjects based on their exposure duration (> 8 and < 8 years). CTA and MN frequency were significantly higher in petrol pump workers (p < 0.05) with longer work duration. CTA was found to increase with age in the exposed subjects as well as controls, with exposed subjects showing a statistically higher degree. This effect was not observed in MN. A significantly higher frequency of MN was observed in the smoking petrol pump workers than in control smokers (p < 0.05). No association was found between smoking and CA in both subjects. The study on XRCC1 399 Arg/gln polymorphism in petrol pump workers demonstrated very less difference in allele frequency compared to controls. In conclusion, these datas indicate that petrol pump workers under risk group should be monitored for any long-term adverse effects of the exposure.
