[Requirement for the tyrosine kinase Axl in angiogenesis and tumor growth]
>>Abstract Number: 2019
Presentation Title: Requirement for the tyrosine kinase Axl in angiogenesis and tumor growth
Presentation Start/End Time: Monday, Apr 18, 2005, 8:00 AM -12:00 PM
Board Number: Board #1
Author Block: Weiduan Xu, Mark J. Powell, Annabelle M. Friera, Christian Franchi, Emily Chan, Yasumichi Hitoshi, Jacques E. Nor, Donald G. Payan, James B. Lorens, Sacha J. Holland. Rigel, Inc., S. San Francisco, CA, University of Michigan School of Dentistry, Ann Arbor, MI
Cell migration is a basic physiological process that is central to both embryonic development and adult homeostatic function. This process also plays an important role in pathological conditions such as angiogenesis, metastasis and inflammation.
In present study, we have used a retroviral-based functional genetic screen to identify genes that control the haptotactic migration of primary human endothelial cells ( EC ) towards vitronectin. We have identified the oncogenic receptor tyrosine kinase Axl as a regulator of multiple EC functions required for angiogenesis.
We demonstrate that both Axl knockdown using RNAi-mediated gene silencing and interference with Axl signaling by the overexpression of a kinase-inactive receptor, blocks EC migration, proliferation and in vitro tube formation. Furthermore, the physiological importance of these observations has been substantiated by an in vivo study. Using stable, retrovirally-delivered shRNAi-mediated gene knockdown, we were able to show that Axl silencing impaired formation of functional human blood vessels in the SCID mouse model of human angiogenesis. Moreover, we tested the hypothesis that Axl expression may drive tumor proliferation and/or progression independent of its function in angiogenesis. We present the evidence showing that loss of Axl expression in tumor cells blocks the growth of solid human neoplasms in an in vivo MDA-MB-231 breast carcinoma xenograft model.
In conclusion, Axl, revealed here as a modulator of EC migration, regulates multiple process required for the activated, proliferative and invasive angiogenic phenotype and correspondingly controls angiogenesis in vivo. Our data provide the first evidence linking Axl expression to the growth of solid human tumors in vivo. Axl inhibition is, therefore, a potential target for cancer therapy, that could act independently upon both EC and neoplastic cell compartment s within the tumor and complement existing therapeutic strategies. Compounds identified in an HTS screen for Axl inhibitors are currently being profiled. <<
Cheers, Tuck |
