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Multiple roles for the receptor tyrosine kinase axl in tumor formation

Sacha J Holland1, Mark J Powell, Christian Franci

  • 1Rigel, Inc., South San Francisco, California and University of Michigan School of Dentistry, Ann Arbor, MI, USA. sholland@rigel.com

Cancer Research
|October 19, 2005
PubMed

Insights

The receptor tyrosine kinase Axl regulates endothelial cell migration and angiogenesis. Targeting Axl may offer a novel therapeutic strategy for cancer by impacting both tumor cells and their supportive microenvironment.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Cancer therapeutic development increasingly targets the tumor microenvironment.
  • Cell migration is crucial for tumor development and involves complex cellular interactions.
  • Identifying novel regulators of cell migration is key for new cancer therapies.

Purpose of the Study:

  • To discover genes controlling endothelial cell migration using a novel retroviral screening technology.
  • To investigate the role of the receptor tyrosine kinase Axl in cell migration and angiogenesis.
  • To evaluate Axl's necessity in tumor formation and neovascularization.

Main Methods:

  • Developed a retroviral-based screening technology in primary human endothelial cells.
  • Utilized small interfering RNA (siRNA) for gene silencing and protein overexpression.
  • Employed short hairpin RNA (shRNA) for sustained Axl knockdown in vivo.
  • Assessed Axl's role in angiogenesis and tumor formation in mouse models.

Main Results:

  • Identified Axl as a novel regulator of endothelial cell haptotactic migration towards vitronectin.
  • Demonstrated that Axl controls endothelial cell migration, proliferation, and tube formation in vitro.
  • Confirmed Axl's necessity for in vivo angiogenesis.
  • Showed Axl is required for human breast carcinoma cell tumor formation in vivo.

Conclusions:

  • Axl is a critical regulator of both angiogenesis and tumorigenesis.
  • Targeting Axl signaling presents a unique therapeutic approach for cancer.
  • Inhibiting Axl could simultaneously impact tumor and stromal cells, offering a dual-action strategy.

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