Multiple roles for the receptor tyrosine kinase axl in tumor formation.
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.
Holland
Sacha J
SJ
Rigel, Inc., South San Francisco, California and University of Michigan School of Dentistry, Ann Arbor, MI, USA. sholland@rigel.com
Powell
Mark J
MJ
Franci
Christian
C
Chan
Emily W
EW
Friera
Annabelle M
AM
Atchison
Robert E
RE
McLaughlin
John
J
Swift
Susan E
SE
Pali
Erlina S
ES
Yam
George
G
Wong
Stephen
S
Lasaga
Joe
J
Shen
Mary R
MR
Yu
Simon
S
Xu
Weiduan
W
Hitoshi
Yasumichi
Y
Bogenberger
Jakob
J
Nör
Jacques E
JE
Payan
Donald G
DG
Lorens
James B
JB
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
D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D019096:Vitronectin; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase