Identification of Metastasis-Associated Receptor Tyrosine Kinases in Non–Small Cell Lung Cancer

University of Cologne, Köln, North Rhine-Westphalia, Germany
Cancer Research (Impact Factor: 9.28). 04/2005; 65(5):1778-82. DOI: 10.1158/0008-5472.CAN-04-3388
Source: PubMed

ABSTRACT Development of distant metastasis after tumor resection is the leading cause of death in early-stage non-small cell lung cancer (NSCLC). Receptor tyrosine kinases (RTK) are involved in tumorigenesis but only few RTKs have been systematically studied in NSCLC. Here, we provide quantitative real-time reverse transcription-PCR expression data of all RTKs (n=56) in primary tumors of 70 patients with early-stage (I-IIIA) NSCLC. Overall, 33 RTKs were expressed in at least 25% of the patients. Several RTKs were significantly expressed higher in tumors that ultimately metastasized. The hazard risk for metastasis development in stage I/II disease was increased at least 3-fold for tumors with high expression levels of insulin receptor, neurotrophic tyrosine receptor kinase 1, epidermal growth factor receptor, ERBB2, ERBB3, platelet-derived growth factor receptor beta, fibroblast growth factor receptor 1, or leukocyte tyrosine kinase. Relative risks were reduced 3-fold by expression of EPHB6 or DKFZ1. Three members of the epidermal growth factor receptor family were associated with a high risk of metastasis, emphasizing the validity of our data. High ERBB3 expression was significantly associated with decreased survival. Taken together, our genome-wide RTK expression map uncovered the previously unknown value of several RTKs as potential markers for prognosis and metastasis prediction in early-stage NSCLC. The identified RTKs represent promising novel candidates for further functional analyses.

Download full-text


Available from: Sven Diederichs, Jan 09, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast cancer mortality in women is largely attributed to the metastasis of primary breast tumors. We have analysed the function of EphB6, a kinase-deficient receptor, in the invasive phenotype of breast cancer cell lines. We have demonstrated the loss of EphB6 protein in invasive breast carcinoma cell lines and absence of EphB6 transcript in a metastatic breast tumor specimen. The function of EphB6 in invasiveness was confirmed by the ability of EphB6 protein to decrease the in vitro invasiveness of MDA-MB-231, MDA-MB-435 and BT549 cells transfected with an EphB6 expression construct. In MDA-MB-231 cells, the decreased invasiveness appeared to be mediated by decreased transcript levels of matrix metalloproteinase (MMP)7 and MMP19, and increased transcript levels of tissue inhibitors of metalloproteinase 2. In addition to affecting invasiveness phenotype, EphB6 overexpression was also responsible for altering the growth rate and colony-forming efficiency of MCF-7 and MDA-MB-231 cells in a cell-line-specific manner. We suggest that the significant decrease in the invasiveness of MDA-MB-231 and other cell lines transfected with EphB6 is likely occurring by the ability of EphB6 to transduce signals to the nucleus and altering relevant gene expression.
    Oncogene 03/2009; 28(14):1706-13. DOI:10.1038/onc.2009.18 · 8.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor gangliosides, and tumor cell proliferation and signaling
  • [Show abstract] [Hide abstract]
    ABSTRACT: The fibroblast growth factors (FGFs) are a large family of peptide growth factors playing essential roles in embryonic development, tissue maintenance and wound healing. FGFs interact with target cells by binding to four high-affinity receptor tyrosine kinases (RTK) termed FGFR1-4. Based on the proliferative and anti-apoptotic as well as pro-angiogenic functions of the FGF/FGFR signal module, it is not surprising that deregulations occur at multiple levels in many types of human cancer. Recently, it got obvious that FGF/FGFR signals might also be hyperactivated in non-small cell lung cancer (NSCLC) by diverse molecular mechanisms leading to autocrine support of tumour cell proliferation, migration and survival as well as paracrine activities including neo-angiogenesis. Additionally, FGF/FGFR signals turned out to be involved in therapy resistance against not only classical chemotherapy but also novel targeted anti-NSCLC agents like inhibitors of the epidermal growth factor receptor (EGFR). This suggests that FGF/FGFR inhibitors might represent a novel component for combined NSCLC therapy approaches. KeywordsFibroblast growth factor-FGFR-non-small cell lung cancer-autocrine loop-targeted therapy
    memo - Magazine of European Medical Oncology 04/2010; 3(1):23-26. DOI:10.1007/s12254-010-0182-y