Receptor tyrosine kinases expressed in metastatic colon cancer

Abstract

Using a PCR-based cloning technique, we have isolated a series of DNA fragments coding for tyrosine kinases that are expressed in a metastatic human colon tumor, and have subsequently analyzed their expression pattern at the protein level in human tumors. We identified both the alpha and the beta forms of the platelet-derived growth factor receptor (PDGFR), axl and 8 other genes, including 3 cytoplasmic tyrosine kinases. To study their expression in human colon cancer, we performed Western blots of matched sets of normal tissues and of carcinomas from the same patient. These revealed that the alpha-PDGFR migrates predominantly as a 200-kDa band in 8/8 normal tissues, and as a 170-kDa band in 17/17 malignant tissues, as well as in colonic polyps, suggesting that expression of an isoform of this receptor may be a marker for the progression of colon cancer. Additional studies showed that the Axl receptor tyrosine kinase was expressed at 10-fold higher levels in a peritoneal metastatic nodule than in other normal and malignant tissues. Immunohistochemistry revealed Axl over-expression specifically in the malignant cells of the tumor. This indicates that over-expression and possibly a differential processing event of tyrosine kinase receptors may be involved in colon cancer, and that they are potential markers for the progression of this disease.

E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines

“…AXL is a member of a family of receptor tyrosine kinases characterised by an extracellular domain resembling cell adhesion molecules and an intracellular conserved tyrosine kinase domain. Its upregulation in the 'FibroblasticTumour' cluster is in agreement with the reported elevated expression in highly metastatic osteosarcoma cell lines (Nakano et al, 2003) and metastatic tumours including colon cancer, gastric cancer and melanoma (Quong et al, 1994;Craven et al, 1995;Wu et al, 2002).…”

AXL regulates mesothelioma proliferation and invasiveness

“…Herein, we used phosphotyrosine immunoaffinity and mass spectrometry to identify activated tyrosine kinase proteins in mesothelioma (Figure 1): these studies demonstrated AXL activation, which we show to be a frequent event in mesothelioma cell lines and mesothelioma surgical specimens, but not in normal mesothelial cells. Notably, AXL expression, overall, was even stronger in mesothelioma than in various other cancer types that have been reported to feature high levels of AXL expression (Figure 2a)-including prostate cancer, melanoma and colon carcinoma (Quong et al, 1994;Craven et al, 1995;Jacob et al, 1999). We show that AXL expression and activation are particularly strong in the spindle-cell subtypes of mesothelioma, which are known to be associated with short survival (Figure 2c).…”

“…We show that AXL expression and activation are particularly strong in the spindle-cell subtypes of mesothelioma, which are known to be associated with short survival (Figure 2c). Various recent studies implicate AXL as an oncogenic factor in advanced solid tumors: AXL is overexpressed in highly invasive lung adenocarcinoma cell lines, metastatic DU145 prostate cancer models and metastatic colon tumors (Craven et al, 1995;Jacob et al, 1999;Shieh et al, 2005). These and other studies suggest that AXL overexpression promotes invasiveness (Lay et al, 2007;Tai et al, 2008;Li et al, 2009).…”

“…AXL was first identified as a transforming gene in chronic myeloid leukemia (Janssen et al, 1991;O'Bryan et al, 1991), but is also overexpressed in metastatic colon and prostate cancer, thyroid carcinoma, breast cancer and melanoma (Quong et al, 1994;Craven et al, 1995;Ito et al, 1999;Jacob et al, 1999;Meric et al, 2002). Various studies have demonstrated roles of GAS6/AXL in regulating cell growth and survival in normal and cancer cells (Stitt et al, 1995;Wimmel et al, 2001).…”

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

“…Dysregulation of Axl or its ligand Gas6 is implicated in the pathogenesis of a variety of human cancers. Overexpression of Axl has been reported in a wide array of human cancers (Craven et al, 1995;Ito et al, 1999;Berclaz et al, 2001;Sun et al, 2004;Shieh et al, 2005) and is associated with invasiveness and metastasis in lung (Shieh et al, 2005), prostate (Sainaghi et al, 2005), breast (Meric et al, 2002;Zhang et al, 2008), gastric (Wu et al, 2002) and pancreatic (Koorstra et al, 2009) cancers, renal cell carcinoma (Chung et al, 2003) as well as glioblastoma (Hutterer et al, 2008). Recently, by profiling of phosphotyrosine signaling, activated Axl protein was detected in about 5% primary tumors of non-small-cell lung cancer (NSCLC) (Rikova et al, 2007).…”