title: Multiple roles for the receptor tyrosine kinase axl in tumor formation.
abstract: 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.
authors.affiliation: Rigel, Inc., South San Francisco, California and University of Michigan School of Dentistry, Ann Arbor, MI, USA. sholland@rigel.com
authors.forename: Sacha J
authors.initials: SJ
authors.lastname: Holland
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Powell
authors.forename: Christian
authors.initials: C
authors.lastname: Franci
authors.forename: Emily W
authors.initials: EW
authors.lastname: Chan
authors.forename: Annabelle M
authors.initials: AM
authors.lastname: Friera
authors.forename: Robert E
authors.initials: RE
authors.lastname: Atchison
authors.forename: John
authors.initials: J
authors.lastname: McLaughlin
authors.forename: Susan E
authors.initials: SE
authors.lastname: Swift
authors.forename: Erlina S
authors.initials: ES
authors.lastname: Pali
authors.forename: George
authors.initials: G
authors.lastname: Yam
authors.forename: Stephen
authors.initials: S
authors.lastname: Wong
authors.forename: Joe
authors.initials: J
authors.lastname: Lasaga
authors.forename: Mary R
authors.initials: MR
authors.lastname: Shen
authors.forename: Simon
authors.initials: S
authors.lastname: Yu
authors.forename: Weiduan
authors.initials: W
authors.lastname: Xu
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Hitoshi
authors.forename: Jakob
authors.initials: J
authors.lastname: Bogenberger
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Nör
authors.forename: Donald G
authors.initials: DG
authors.lastname: Payan
authors.forename: James B
authors.initials: JB
authors.lastname: Lorens
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000201:enzymology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D014183:Transplantation, Heterologous; D019096:Vitronectin / Q000494:pharmacology; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D019096:Vitronectin; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase