AXL Is an Essential Factor and Therapeutic Target for Metastatic Ovarian Cancer

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University, Stanford, California 94305-5152, USA.
Cancer Research (Impact Factor: 9.33). 10/2010; 70(19):7570-9. DOI: 10.1158/0008-5472.CAN-10-1267
Source: PubMed


The receptor tyrosine kinase AXL is thought to play a role in metastasis; however, the therapeutic efficacy of an AXL-targeting agent remains largely untested in metastatic disease. In this study, we defined AXL as a therapeutic target for metastatic ovarian cancer. AXL is primarily expressed in metastases and advanced-stage human ovarian tumors but not in normal ovarian epithelium. Genetic inhibition of AXL in human metastatic ovarian tumor cells is sufficient to prevent the initiation of metastatic disease in vivo. Mechanistically, inhibition of AXL signaling in animals with metastatic disease results in decreased invasion and matrix metalloproteinase activity. Most importantly, soluble human AXL receptors that imposed a specific blockade of the GAS6/AXL pathway had a profound inhibitory effect on progression of established metastatic ovarian cancer without normal tissue toxicity. These results offer the first genetic validation of GAS6/AXL targeting as an effective strategy for inhibition of metastatic tumor progression in vivo. Furthermore, this study defines the soluble AXL receptor as a therapeutic candidate agent for treatment of metastatic ovarian cancer, for which current therapies are ineffective.

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    • "The PI3K signaling pathway has been shown to be a downstream effector of Axl in cancer cells, and its activation was described as correlating with higher levels of Axl expression (Lee et al., 2002; Ruan and Kazlauskas, 2012; Paccez et al., 2013). Activation of Akt by Axl leads to phosphorylation of IKKα and consequent phosphorylation, ubiquitination, and degradation of IκBα, triggering the activation of NF-κB (Gjerdrum et al., 2010; Rankin et al., 2010; Paccez et al., 2013). "
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    ABSTRACT: The receptor tyrosine kinase Axl has been described as an oncogene and its deregulation has been implicated in the progression of several human cancers. While the role of Axl in oesophageal adenocarcinoma has been addressed, there is no information about its role in oesophageal squamous cell carcinoma. In the current report, we identified, for the first time, deregulation of Axl expression in oesophageal squamous cell carcinoma (OSCC). Axl is consistently overexpressed in OSCC cell lines and human tumor samples, mainly in advanced stages of the disease. Blockage of Axl gene expression by small interfering RNA inhibits cell survival, proliferation, migration, and invasion in vitro and oesophageal tumor growth in vivo. Additionally, repression of Axl expression results in Akt-dependent inhibition of pivotal genes involved in the NF-κB pathway and in the induction of GSK3β activity, resulting in loss of mesenchymal and induction of epithelial markers. Furthermore, treatment of oesophageal cancer cells with the Akt inhibitor wortmannin inhibits NF-κB signaling, induces GSK3β activity and blocks OSCC cell proliferation in an Axl-dependent manner. Taken together, our results establish a clear role for Axl in OSCC tumorigenesis with potential therapeutic implications. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 01/2015; DOI:10.1091/mbc.E14-04-0868 · 4.47 Impact Factor
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    • "Likewise, AXL is overexpressed in colon [21], thyroid [22], breast [23], renal cell [24], and ovarian [25] cancers. The latter study suggests that the GAS6/AXL axis may be involved in driving tumorigenesis of this cancer [25]. AXL protein expression was found to be significantly higher in ovarian carcinomas than in ovarian epithelium, and knockdown of AXL in SKOV3 cells also reduced the expression of MMP-1 and MMP-9, which contribute to tumour cell invasion. "
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    ABSTRACT: Seeking new biomarkers for epithelial ovarian cancer, the fifth most common cause of death from all cancers in women and the leading cause of death from gynaecological malignancies, we performed a meta-analysis of three independent studies and compared the results in regard to clinicopathological parameters. This analysis revealed that GAS6 was highly expressed in ovarian cancer and therefore was selected as our candidate of choice. GAS6 encodes a secreted protein involved in physiological processes including cell proliferation, chemotaxis, and cell survival. We performed immunohistochemistry on various ovarian cancer tissues and found that GAS6 expression was elevated in tumour tissue samples compared to healthy control samples (P < 0.0001). In addition, GAS6 expression was also higher in tumours from patients with residual disease compared to those without. Our data propose GAS6 as an independent predictor of poor survival, suggesting GAS6, both on the mRNA and on the protein level, as a potential biomarker for ovarian cancer. In clinical practice, the staining of a tumour biopsy for GAS6 may be useful to assess cancer prognosis and/or to monitor disease progression.
    BioMed Research International 06/2013; 2013:238284. DOI:10.1155/2013/238284 · 1.58 Impact Factor
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    • "In this article, we demonstrate the novel mechanism by which GO-LDL mediates Axl upregulation and its crosstalk with Gas6, which could be relevant to the pathogenesis of diseases such as DN. Recently, studies demonstrated that Axl plays a role in metastasis as a novel therapeutic target in solid tumours such as metastatic ovarian cancer and breast cancer tumours [7]–[8]. In addition, reports suggest that Axl plays a role in the pathogenesis of vascular and diabetic diseases. "
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    ABSTRACT: Low-density lipoprotein (LDL) is subjected to glycoxidation in diabetes, and a novel signalling mechanism by which glycoxidised LDL functions in glomerular mesangial cells remains to be ascertained. We performed gene expression analysis in mouse glomerular mesangial cells treated with LDL modified by glycation and oxidation (GO-LDL, 100 µg/ml) for 48 h by using DNA microarray analysis and quantitative real-time PCR. We examined the GO-LDL-specific changes in gene and protein expression in mesangial cells and glomeruli of type 2 diabetic Zucker diabetic fatty (ZDF) rats. By microarray profiling, we noted that GO-LDL treatment increased Axl receptor tyrosine kinase (Axl) mRNA expression (∼2.5-fold, p<0.05) compared with normal LDL (N-LDL) treatment in mesangial cells. Treatment with GO-LDL also increased the protein levels of Axl and its ligand Gas6 as measured by Western blotting. These increases were inhibited by neutralising Axl receptor-specific antibody. Silencing Gas6 by siRNA inhibited GO-LDL-induced Axl expression in mesangial cells. Axl and Gas6 protein were also increased in cells cultured in high glucose (30 mM) or methylglyoxal (200 µM). Gas6 treatment increased the expression and secretion of TGF-β1 protein, a key regulator of extracellular matrix expression in the glomeruli of diabetic kidneys. Immunohistochemical analyses of glomeruli from 20-week-old ZDF rats exhibited increased Axl protein expression. Rottlerin, a selective PKC-δ inhibitor, completely blocked Gas6-induced TGF-β1 expression. These data suggest that LDL modified by glycoxidation may mediate Axl/Gas6 pathway activation, and this mechanism may play a significant role in the pathogenesis of diabetic nephropathy.
    PLoS ONE 11/2012; 7(11):e50297. DOI:10.1371/journal.pone.0050297 · 3.23 Impact Factor
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