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  • 1
    Publication Date: 2014-02-21
    Description: Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paolino, Magdalena -- Choidas, Axel -- Wallner, Stephanie -- Pranjic, Blanka -- Uribesalgo, Iris -- Loeser, Stefanie -- Jamieson, Amanda M -- Langdon, Wallace Y -- Ikeda, Fumiyo -- Fededa, Juan Pablo -- Cronin, Shane J -- Nitsch, Roberto -- Schultz-Fademrecht, Carsten -- Eickhoff, Jan -- Menninger, Sascha -- Unger, Anke -- Torka, Robert -- Gruber, Thomas -- Hinterleitner, Reinhard -- Baier, Gottfried -- Wolf, Dominik -- Ullrich, Axel -- Klebl, Bert M -- Penninger, Josef M -- W 1101/Austrian Science Fund FWF/Austria -- England -- Nature. 2014 Mar 27;507(7493):508-12. doi: 10.1038/nature12998. Epub 2014 Feb 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria. ; Lead Discovery Center GmbH, D-44227 Dortmund, Germany. ; Medical University Innsbruck, 6020 Innsbruck, Austria. ; Department of Microbiology and Immunology, Brown University, Providence, Rhode Island 02912, USA. ; School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Perth, Australia. ; Max-Planck, Institute for Biochemistry, Department of Molecular Biology, D-82152 Martinsried, Germany. ; 1] Medical University Innsbruck, 6020 Innsbruck, Austria [2] Internal Medicine III, University Hospital Bonn, 53127 Bonn, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24553136" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/deficiency/genetics/*metabolism ; Animals ; Anticoagulants/pharmacology/therapeutic use ; Female ; Killer Cells, Natural/drug effects/*immunology/metabolism ; Male ; Mammary Neoplasms, Experimental/drug therapy/genetics/immunology/*pathology ; Melanoma, Experimental/drug therapy/genetics/immunology/*pathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neoplasm Metastasis/drug therapy/*immunology/prevention & control ; Proto-Oncogene Proteins/antagonists & inhibitors/metabolism ; Proto-Oncogene Proteins c-cbl/deficiency/genetics/*metabolism ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors/*metabolism ; Ubiquitin-Protein Ligases/deficiency/genetics/*metabolism ; Ubiquitination ; Warfarin/pharmacology/therapeutic use
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] The fragile site FRA11B has been localized to the p(CCG)n repeat of the CBL2 proto-oncogene. A proportion of Jacobsen (11q−) syndrome patients inherited a chromosome carrying a CBL2 p(CCG)n expansion, which was truncated close to FRA11B. ...
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    ISSN: 1744-313X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology , Medicine
    Notes: Murine alloantisera to lymphocyte (Ly) alloantigens also contain antibodies to murine leukaemia viruses (MuLV) in high titre. A number of such sera were extensively absorbed with ecotropic AKR murine leukaemia virus to remove contaqiminating anti-MuLV antibodies. The virus-absorbed and unabsorbed antisera wre then examined by the radioimmune precipitation (RIP) assay for anti-MuLV antibodies, and for anti-Ly antibodies by cytotoxicity assays against specific target cells. The results presented here demonstrate that whilst virus absorption markdely reduced the anti-viraql titres of the alloantisera they ahd no effect on the anti-Ly titres of any of them. This indicated that none of the Ly antigens which was examined cross reacts with the antigens of ecotropic AKR-MuLV and further suggest that Ly antigens are not encoded by the genes of endogenous ecotropic MuLVs. It was also demonstrated that the majority of the constaninating anti-MuLV antibodies present in anti-Ly-6.2 proteins of the virus.
    Type of Medium: Electronic Resource
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