RESUMO
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.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Epitelial do Ovário/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas com Domínio LIM/metabolismo , Neoplasias Ovarianas/metabolismo , Receptor ErbB-2/metabolismo , Transdução de Sinais/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Estudos de Coortes , Proteínas do Citoesqueleto/genética , Feminino , Células HEK293 , Humanos , Proteínas com Domínio LIM/genética , Lapatinib/farmacologia , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Plasmídeos , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptor ErbB-2/genética , Transdução de Sinais/efeitos dos fármacos , TransfecçãoRESUMO
High grade serous ovarian cancer is characterized by relatively few mutations occurring at low frequency, except in TP53. However other genetic aberrations such as copy number variation alter numerous oncogenes and tumor suppressor genes. Oncogenes are positive regulators of tumorigenesis and play a critical role in cancer cell growth, proliferation, and survival. Accumulating evidence suggests that they are crucial for the development and the progression of high grade serous ovarian carcinoma (HGSOC). Though many oncogenes have been identified, no successful inhibitors targeting these molecules and their associated pathways are available. This review discusses oncogenes that have been identified recently in HGSOC using different screening strategies. All the genes discussed in this review have been functionally characterized both in vitro and in vivo and some of them are able to transform immortalized ovarian surface epithelial and fallopian tube cells upon overexpression. However, it is necessary to delineate the molecular pathways affected by these oncogenes for the development of therapeutic strategies.
RESUMO
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.