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         headline:A compact VEGF signature associated with distant metastases and poor outcomes
         description:Tumor metastases pose the greatest threat to a patient's survival, and thus, understanding the biology of disseminated cancer cells is critical for developing effective therapies. Microarrays and immunohistochemistry were used to analyze primary breast tumors, regional (lymph node) metastases, and distant metastases in order to identify biological features associated with distant metastases. When compared with each other, primary tumors and regional metastases showed statistically indistinguishable gene expression patterns. Supervised analyses comparing patients with distant metastases versus primary tumors or regional metastases showed that the distant metastases were distinct and distinguished by the lack of expression of fibroblast/mesenchymal genes, and by the high expression of a 13-gene profile (that is, the 'vascular endothelial growth factor (VEGF) profile') that included VEGF, ANGPTL4, ADM and the monocarboxylic acid transporter SLC16A3. At least 8 out of 13 of these genes contained HIF1α binding sites, many are known to be HIF1α-regulated, and expression of the VEGF profile correlated with HIF1α IHC positivity. The VEGF profile also showed prognostic significance on tests of sets of patients with breast and lung cancer and glioblastomas, and was an independent predictor of outcomes in primary breast cancers when tested in models that contained other prognostic gene expression profiles and clinical variables. These data identify a compact in vivo hypoxia signature that tends to be present in distant metastasis samples, and which portends a poor outcome in multiple tumor types. This signature suggests that the response to hypoxia includes the ability to promote new blood and lymphatic vessel formation, and that the dual targeting of multiple cell types and pathways will be needed to prevent metastatic spread.
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            Vascular Endothelial Growth Factor Signature
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      headline:A compact VEGF signature associated with distant metastases and poor outcomes
      description:Tumor metastases pose the greatest threat to a patient's survival, and thus, understanding the biology of disseminated cancer cells is critical for developing effective therapies. Microarrays and immunohistochemistry were used to analyze primary breast tumors, regional (lymph node) metastases, and distant metastases in order to identify biological features associated with distant metastases. When compared with each other, primary tumors and regional metastases showed statistically indistinguishable gene expression patterns. Supervised analyses comparing patients with distant metastases versus primary tumors or regional metastases showed that the distant metastases were distinct and distinguished by the lack of expression of fibroblast/mesenchymal genes, and by the high expression of a 13-gene profile (that is, the 'vascular endothelial growth factor (VEGF) profile') that included VEGF, ANGPTL4, ADM and the monocarboxylic acid transporter SLC16A3. At least 8 out of 13 of these genes contained HIF1α binding sites, many are known to be HIF1α-regulated, and expression of the VEGF profile correlated with HIF1α IHC positivity. The VEGF profile also showed prognostic significance on tests of sets of patients with breast and lung cancer and glioblastomas, and was an independent predictor of outcomes in primary breast cancers when tested in models that contained other prognostic gene expression profiles and clinical variables. These data identify a compact in vivo hypoxia signature that tends to be present in distant metastasis samples, and which portends a poor outcome in multiple tumor types. This signature suggests that the response to hypoxia includes the ability to promote new blood and lymphatic vessel formation, and that the dual targeting of multiple cell types and pathways will be needed to prevent metastatic spread.
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            name:University of North Carolina at Chapel Hill
            address:
               name:Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA
               type:PostalAddress
            type:Organization
            name:University of North Carolina at Chapel Hill
            address:
               name:Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, USA
               type:PostalAddress
            type:Organization
      name:Daniel S Oh
      affiliation:
            name:University of North Carolina at Chapel Hill
            address:
               name:Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA
               type:PostalAddress
            type:Organization
            name:University of North Carolina at Chapel Hill
            address:
               name:Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, USA
               type:PostalAddress
            type:Organization
      name:Matthew G Ewend
      affiliation:
            name:University of North Carolina at Chapel Hill
            address:
               name:Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA
               type:PostalAddress
            type:Organization
            name:University of North Carolina at Chapel Hill
            address:
               name:Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, USA
               type:PostalAddress
            type:Organization
      name:Lisa A Carey
      affiliation:
            name:University of North Carolina at Chapel Hill
            address:
               name:Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA
               type:PostalAddress
            type:Organization
            name:University of North Carolina at Chapel Hill
            address:
               name:Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, USA
               type:PostalAddress
            type:Organization
      name:Subbaya Subramanian
      affiliation:
            name:Stanford University Medical Center
            address:
               name:Department of Pathology, Stanford University Medical Center, Stanford, USA
               type:PostalAddress
            type:Organization
      name:Robert West
      affiliation:
            name:Stanford University Medical Center
            address:
               name:Department of Pathology, Stanford University Medical Center, Stanford, USA
               type:PostalAddress
            type:Organization
      name:Francis Ikpatt
      affiliation:
            name:Committees on Genetics and Cancer Biology, University of Chicago
            address:
               name:Section of Hematology/Oncology, Department of Medicine, Committees on Genetics and Cancer Biology, University of Chicago, Chicago, USA
               type:PostalAddress
            type:Organization
      name:Olufunmilayo I Olopade
      affiliation:
            name:Committees on Genetics and Cancer Biology, University of Chicago
            address:
               name:Section of Hematology/Oncology, Department of Medicine, Committees on Genetics and Cancer Biology, University of Chicago, Chicago, USA
               type:PostalAddress
            type:Organization
      name:Matt van de Rijn
      affiliation:
            name:Stanford University Medical Center
            address:
               name:Department of Pathology, Stanford University Medical Center, Stanford, USA
               type:PostalAddress
            type:Organization
      name:Charles M Perou
      affiliation:
            name:University of North Carolina at Chapel Hill
            address:
               name:Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA
               type:PostalAddress
            type:Organization
            name:University of North Carolina at Chapel Hill
            address:
               name:Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, USA
               type:PostalAddress
            type:Organization
            name:University of North Carolina at Chapel Hill
            address:
               name:Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA
      name:Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, USA
      name:Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA
      name:Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA
      name:Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, USA
      name:Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA
      name:Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, USA
      name:Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA
      name:Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, USA
      name:Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA
      name:Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, USA
      name:Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA
      name:Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, USA
      name:Department of Pathology, Stanford University Medical Center, Stanford, USA
      name:Department of Pathology, Stanford University Medical Center, Stanford, USA
      name:Section of Hematology/Oncology, Department of Medicine, Committees on Genetics and Cancer Biology, University of Chicago, Chicago, USA
      name:Section of Hematology/Oncology, Department of Medicine, Committees on Genetics and Cancer Biology, University of Chicago, Chicago, USA
      name:Department of Pathology, Stanford University Medical Center, Stanford, USA
      name:Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA
      name:Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, USA
      name:Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, USA

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