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Bartolini, Alice; Cardaci, Sabrina; Lamba, Simona; Oddo, Daniele; Marchiò, Caterina; Cassoni, Paola; Amoreo, Carla Azzurra; Corti, Giorgio; Testori, Alessandro; Bussolino, Federico; Pasqualini, Renata; Arap, Wadih; Corà, Davide; Di Nicolantonio, Federica; Marchiò, Serena

BCAM and LAMA5 Mediate the Recognition between Tumor Cells and the Endothelium in the Metastatic Spreading of KRAS-Mutant Colorectal Cancer

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  • Medientyp: E-Artikel
  • Titel: BCAM and LAMA5 Mediate the Recognition between Tumor Cells and the Endothelium in the Metastatic Spreading of KRAS-Mutant Colorectal Cancer
  • Beteiligte: Bartolini, Alice; Cardaci, Sabrina; Lamba, Simona; Oddo, Daniele; Marchiò, Caterina; Cassoni, Paola; Amoreo, Carla Azzurra; Corti, Giorgio; Testori, Alessandro; Bussolino, Federico; Pasqualini, Renata; Arap, Wadih; Corà, Davide; Di Nicolantonio, Federica; Marchiò, Serena
  • Erschienen: American Association for Cancer Research (AACR), 2016
  • Erschienen in: Clinical Cancer Research
  • Sprache: Englisch
  • DOI: 10.1158/1078-0432.ccr-15-2664
  • ISSN: 1557-3265; 1078-0432
  • Schlagwörter: Cancer Research ; Oncology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:p>Purpose: KRAS mutations confer adverse prognosis to colorectal cancer, and no targeted therapies have shown efficacy in this patient subset. Paracrine, nongenetic events induced by KRAS-mutant tumor cells are expected to result in specific deregulation and/or relocation of tumor microenvironment (TME) proteins, which in principle can be exploited as alternative therapeutic targets.</jats:p> <jats:p>Experimental Design: A multimodal strategy combining ex vivo/in vitro phage display screens with deep-sequencing and bioinformatics was applied to uncover TME-specific targets in KRAS-mutant hepatic metastasis from colorectal cancer. Expression and localization of BCAM and LAMA5 were validated by immunohistochemistry in preclinical models of human hepatic metastasis and in a panel of human specimens (n = 71). The antimetastatic efficacy of two BCAM-mimic peptides was evaluated in mouse models. The role of BCAM in the interaction of KRAS-mutant colorectal cancer cells with TME cells was investigated by adhesion assays.</jats:p> <jats:p>Results: BCAM and LAMA5 were identified as molecular targets within both tumor cells and TME of KRAS-mutant hepatic metastasis from colorectal cancer, where they were specifically overexpressed. Two BCAM-mimic peptides inhibited KRAS-mutant hepatic metastasis in preclinical models. Genetic suppression and biochemical inhibition of either BCAM or LAMA5 impaired adhesion of KRAS-mutant colorectal cancer cells specifically to endothelial cells, whereas adhesion to pericytes and hepatocytes was unaffected.</jats:p> <jats:p>Conclusions: These data show that the BCAM/LAMA5 system plays a functional role in the metastatic spreading of KRAS-mutant colorectal cancer by mediating tumor–TME interactions and as such represents a valuable therapeutic candidate for this large, currently untreatable patient group. Clin Cancer Res; 22(19); 4923–33. ©2016 AACR.</jats:p>
  • Zugangsstatus: Freier Zugang