Clinical Research Papers:
Co-expression of MET and CD47 is a novel prognosticator for survival of luminal-type breast cancer patients
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Irène Baccelli1,2,*, Albrecht Stenzinger3,*, Vanessa Vogel1,2,3, Berit Maria Pfitzner4, Corinna Klein1,2, Markus Wallwiener5, Martina Scharpff5, Massimo Saini1,2, Tim Holland-Letz6, Hans-Peter Sinn3, Andreas Schneeweiss5, Carsten Denkert4,7, Wilko Weichert3,5,7,*, Andreas Trumpp1,2,7,*
1Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
2Divison of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
3Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany
4Institute of Pathology, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
5National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany
6Department of Biostatistics, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld TP4, 69120 Heidelberg, Germany
7German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
*These authors contributed equally to the study
Keywords: breast cancer, prognosis, biomarker, CD47, MET, metastasis, circulating tumor cells, metastasis-stem cell.
Received: June 26, 2014 Accepted: August 23, 2014 Published: September 02, 2014
Although luminal-type primary breast cancer can be efficiently treated, development of metastatic disease remains a significant clinical problem. We have previously shown that luminal-type circulating tumor cells (CTCs) co-expressing the tyrosine-kinase MET and CD47, a ligand involved in cancer cell evasion from macrophage scavenging, are able to initiate metastasis in xenografts. Here, we investigated the clinical relevance of MET-CD47 co-expression in 255 hormone receptor positive breast tumors by immunohistochemistry and found a 10.3-year mean overall-survival difference between MET-CD47 double-positive and double-negative patients (p<0.001). MET-CD47 co-expression defined a novel independent prognosticator for overall-survival by multivariate analysis (Cox proportional hazards model: HR: 4.1, p<0.002) and CD47 expression alone or in combination with MET was strongly associated with lymph node metastasis. Furthermore, flow cytometric analysis of metastatic patient blood revealed consistent presence of MET+CD47+ CTCs (range 0.8 - 33.3% of CTCs) and their frequency was associated with increased metastatic spread. Finally, primary uncultured CTCs with high MET+CD47+ content showed an enhanced capacity to initiate metastasis in mice. Detection and targeting of MET and CD47 may thus provide a rational basis for risk stratification and treatment of patients with luminal-type breast cancer.
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