Acquired Expression of Periostin by Human Breast Cancers Promotes Tumor Angiogenesis through Up-Regulation of Vascular Endothelial Growth Factor Receptor 2 Expression
| Autor: | Carrie Blanchette, Xiao-Fan Wang, Xuefang Bai, Ryan M. Anderson, Rong Shao, Tongyun Dang, Mikhail L. Gishizky, Jeffrey R. Marks, Shideng Bao |
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| Rok vydání: | 2004 |
| Předmět: |
Angiogenesis
Transplantation Heterologous Breast Neoplasms Mice SCID Periostin Biology medicine.disease_cause Gene product Mice chemistry.chemical_compound Cell Line Tumor medicine Animals Humans Serial analysis of gene expression Mammary Glands Human Cell Growth and Development Molecular Biology Oligonucleotide Array Sequence Analysis Neovascularization Pathologic Gene Expression Profiling Endothelial Cells Kinase insert domain receptor Cell Biology Protein-Tyrosine Kinases Integrin alphaVbeta3 Vascular Endothelial Growth Factor Receptor-2 Up-Regulation Gene Expression Regulation Neoplastic Vascular endothelial growth factor Gene expression profiling chemistry Focal Adhesion Kinase 1 Focal Adhesion Protein-Tyrosine Kinases Cancer research Female Carcinogenesis Cell Adhesion Molecules Neoplasm Transplantation Signal Transduction |
| Zdroj: | Molecular and Cellular Biology. 24:3992-4003 |
| ISSN: | 1098-5549 |
| Popis: | The development of human cancers is a multistep complex process by which cancer cells acquire the ability to overcome the restraints imposed by the surrounding normal tissue microenvironment (7). This process is believed to be driven by the intrinsic genomic instability of cancer cells to express genes that confer selective advantages under the adverse growth conditions associated with a rapidly expanding tumor mass, such as hypoxia and a poor supply of nutrients. After reaching a critical mass, cancer cells have to find ways to promote angiogenesis in order to progress and expand during late stages of tumorigenesis (4, 5). To this end, a number of genes, such as the vascular endothelial growth factor (VEGF), have been demonstrated to play critical roles in the development of tumor vasculature (4, 5, 10). However, much more remains to be learned about the molecular nature of still unidentified players and their modes of action in promoting tumor angiogenesis. Recently, large-scale efforts have been made to determine gene expression pattern differences between various types of human cancers and their corresponding normal tissues by using the serial analysis of gene expression (SAGE) and gene array analyses (14, 33-35, 37). Indeed, significant differences in gene expression patterns have been revealed by these studies. In breast cancer, for example, such investigations have led to the application of gene array analysis in the diagnosis, prognosis, and design of rational treatment of patients according to the molecular signatures of the individual tumors (21, 22, 32, 35). In the meantime, although the alterations of oncogenes and tumor suppressor genes have shown a close association with the progression of human cancers based on their defined functions, less is known about the specific contributions of a large number of genes whose expression patterns are also significantly changed during the tumorigenic process. Particularly interesting is the observation that mesenchyme-specific genes, normally associated with osteoblasts, are highly expressed by various types of human cancers (17, 31). However, the expression of mesenchyme-specific genes has not been functionally linked to the development of specific tumor phenotypes. To address this question, we sought to determine the potential contributions of such candidate genes to specific phenotypic changes associated with the progression of late-stage tumorigenesis and identified a mesenchyme-specific gene product, periostin, as a novel angiogenic factor whose overexpression by human breast cancers leads to the significant enhancement of angiogenesis. The angiogenic activity of periostin correlated with the increased expression of the VEGF receptor Flk-1/KDR by endothelial cells through an integrin αvβ3-focal adhesion kinase (FAK)-mediated signaling pathway. These findings indicate that epithelial cell-derived tumors may gain the capabilities to generate more blood vessels, invade, and metastasize during late stages of tumorigenesis by the acquired expression of genes whose functions are normally associated only with mesenchymal cells. |
| Databáze: | OpenAIRE |
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