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. (Cancer Res 2005; 65(20): 9294-303)

AXL regulates mesothelioma proliferation and invasiveness

“…AXL is characterized by a unique extracellular composition consisting of immunoglobulin-like and fibronectin-type III-like domains, which are also found in adhesion molecules of the cadherin and immunoglobulin superfamily, therefore suggesting that AXL might regulate cell adhesion (Burchert et al, 1998). Other evidence is consistent with roles of AXL in tumor cell invasion, metastasis and survival (Jacob et al, 1999;Holland et al, 2005;Mahadevan et al, 2007).…”

An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies

“…Axl is expressed on endothelial cells and enhances vascular endothelial growth factor (VEGF)-induced endothelial tubule formation (Holland et al, 2005;Li et al, 2009); we tested whether anti-Axl mAb could enhance the antitumor growth property of anti-VEGF (Liang et al, 2006). Anti-VEGF antibody alone and YW327.6S2 alone had similar effects on A549 tumor growth (Figure 2a).…”

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

“…MP470 had an IC 50 of 2 mM in the GIST-R cell line ( Figure 3a) indicating that MP470 acts as an AXL kinase inhibitor. We utilized the MDA-MB-231 breast cancer cell line (as an independent positive control) that overexpresses an active tyrosine phosphorylated AXL (Holland et al, 2005) to evaluate the efficacy of MP470 to inhibit its phosphorylation. Western blotting analysis shows inhibition of tyrosine phosphorylation of AXL by MP470 at 1.0 mM ( Figure 3b) and is in the range observed for the GIST-R cells ( Figure 2a).…”