1. ¹Department of Molecular Oncology, Genentech Inc., South San Francisco, CA, USA
2. ²Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, USA
3. ³Department of Pathology, Genentech Inc., South San Francisco, CA, USA
4. ⁴Department of Bioinformatics, Genentech Inc., South San Francisco, CA, USA
5. ⁵Department of Tumor Biology and Angiogenesis, Genentech Inc., South San Francisco, CA, USA
6. ⁶Department of Cell Regulation, Genentech Inc., South San Francisco, CA, USA

Correspondence: Dr L Pei, Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. E-mail: lpei@gene.com

⁷These authors contributed equally.

Received 4 February 2009; Revised 3 June 2009; Accepted 19 June 2009; Published online 27 July 2009.

Abstract

Dysregulation of Axl and its ligand growth arrest-specific 6 is implicated in the pathogenesis of several human cancers. In this study, we have used RNAi and monoclonal antibodies to assess further the oncogenic potential of Axl. Here we show that Axl knockdown reduces growth of lung and breast cancer xenograft tumors. Inhibition of Axl expression attenuates breast cancer cell migration and inhibits metastasis to the lung in an orthotopic model, providing the first in vivo evidence that links Axl directly to cancer metastasis. Axl knockdown in endothelial cells impaired tube formation and this effect was additive with anti-vascular endothelial growth factor (VEGF). Further analysis demonstrated that Axl regulates endothelial cell functions by modulation of signaling through angiopoietin/Tie2 and Dickkopf (DKK3) pathways. We have developed and characterized Axl monoclonal antibodies that attenuate non-small cell lung carcinoma xenograft growth by downregulation of receptor expression, reducing tumor cell proliferation and inducing apoptosis. Our data demonstrate that Axl plays multiple roles in tumorigenesis and that therapeutic antibodies against Axl may block Axl functions not only in malignant tumor cells but also in the tumor stroma. The additive effect of Axl inhibition with anti-VEGF suggests that blocking Axl function could be an effective approach for enhancing antiangiogenic therapy.