Cancer research (Chicago, Ill.), 2005-10, Vol.65 (20), p.9294-9303
2005
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- Autor(en) / Beteiligte
- Titel
- Multiple roles for the receptor tyrosine kinase axl in tumor formation
- Ist Teil von
- Cancer research (Chicago, Ill.), 2005-10, Vol.65 (20), p.9294-9303
- Ort / Verlag
- Philadelphia, PA: American Association for Cancer Research
- Erscheinungsjahr
- 2005
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- A focus of contemporary cancer therapeutic development is the targeting of both the transformed cell and the supporting cellular microenvironment. Cell migration is a fundamental cellular behavior required for the complex interplay between multiple cell types necessary for tumor development. We therefore developed a novel retroviral-based screening technology in primary human endothelial cells to discover genes that control cell migration. We identified the receptor tyrosine kinase Axl as a novel regulator of endothelial cell haptotactic migration towards the matrix factor vitronectin. Using small interfering RNA-mediated silencing and overexpression of wild-type or mutated receptor proteins, we show that Axl is a key regulator of multiple angiogenic behaviors including endothelial cell migration, proliferation, and tube formation in vitro. Moreover, using sustained, retrovirally delivered short hairpin RNA (shRNA) Axl knockdown, we show that Axl is necessary for in vivo angiogenesis in a mouse model. Furthermore, we show that Axl is also required for human breast carcinoma cells to form a tumor in vivo. These findings indicate that Axl regulates processes vital for both neovascularization and tumorigenesis. Disruption of Axl signaling using a small-molecule inhibitor will hence simultaneously affect both the tumor and stromal cell compartments and thus represents a unique approach for cancer therapeutic development.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0008-5472eISSN: 1538-7445DOI: 10.1158/0008-5472.CAN-05-0993Titel-ID: cdi_proquest_miscellaneous_68697555
- Format
- –
- Schlagworte
- Animals, Biological and medical sciences, Breast Neoplasms - blood supply, Breast Neoplasms - enzymology, Carcinogenesis, carcinogens and anticarcinogens, Cell Growth Processes - physiology, Cell Line, Tumor, Cell Movement - genetics, Cell physiology, Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes, Cell Transformation, Neoplastic - metabolism, Cells, Cultured, Chemotaxis - drug effects, Chemotaxis - physiology, Coculture Techniques, Endothelial Cells - cytology, Endothelial Cells - enzymology, Fundamental and applied biological sciences. Psychology, General aspects, Humans, Medical sciences, Mice, Mice, SCID, Molecular and cellular biology, Neovascularization, Pathologic - enzymology, Neovascularization, Pathologic - genetics, Neovascularization, Physiologic - genetics, Neovascularization, Physiologic - physiology, Oncogene Proteins - antagonists & inhibitors, Oncogene Proteins - biosynthesis, Oncogene Proteins - genetics, Oncogene Proteins - physiology, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases - antagonists & inhibitors, Receptor Protein-Tyrosine Kinases - biosynthesis, Receptor Protein-Tyrosine Kinases - genetics, Receptor Protein-Tyrosine Kinases - physiology, RNA, Small Interfering - genetics, Signal Transduction, Transfection, Transplantation, Heterologous, Tumors, Vitronectin - pharmacology