title: Exosomal Annexin II Promotes Angiogenesis and Breast Cancer Metastasis.
abstract: Tumor-derived exosomes are emerging mediators of tumorigenesis and tissue-specific metastasis. Proteomic profiling has identified Annexin II as one of the most highly expressed proteins in exosomes; however, studies focused on the biological role of exosomal Annexin II (exo-Anx II) are still lacking. In this study, mechanistic insight was sought regarding exo-Anx II and its function in angiogenesis and breast cancer metastasis. Multiple in vitro and in vivo techniques were used to study the role of exo-Anx II in angiogenesis. Using atomic force microscopy and Western blotting, exo-Anx II expression was characterized in normal and breast cancer cells. In addition, organ-specific metastatic breast cancer cells and animal models were used to define the role exo-Anx II in breast cancer metastasis. Results revealed that exo-Anx II expression is significantly higher in malignant cells than normal and premetastatic breast cancer cells. In vitro and in vivo studies demonstrated that exo-Anx II promotes tPA-dependent angiogenesis. Furthermore, in vivo analysis indicated that metastatic exosomes create a favorable microenvironment for metastasis, and exo-Anx II plays an important role in this process, as priming with Anx II-depleted exosomes reduces brain (∼4-fold) and lung (∼2-fold) metastasis. Upon delineating the mechanism, it was discovered that exo-Anx II causes macrophage-mediated activation of the p38MAPK, NF-κB, and STAT3 pathways and increased secretion of IL6 and TNFα. These data demonstrate an important role for exo-Anx II in breast cancer pathogenesis.
  
  
  
  Exosome-associated Annexin II plays an important role in angiogenesis and breast cancer metastasis, which can be exploited as a potential biomarker as well as a therapeutic target for diagnosis and treatment of metastatic breast cancer. Mol Cancer Res; 15(1); 93-105. ©2016 AACR.
authors.affiliation: Department of Molecular and Medical Genetics, University of North Texas Health Science Center, Fort Worth, Texas. sayantan.maji@live.unthsc.edu.|Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, Texas.
authors.forename: Sayantan
authors.initials: S
authors.lastname: Maji
authors.affiliation: Department of Molecular and Medical Genetics, University of North Texas Health Science Center, Fort Worth, Texas.|Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, Texas.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Chaudhary
authors.affiliation: Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas.
authors.forename: Irina
authors.initials: I
authors.lastname: Akopova
authors.affiliation: Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas.
authors.forename: Phung M
authors.initials: PM
authors.lastname: Nguyen
authors.affiliation: Plaza Medical Center of Fort Worth, Fort Worth, Texas.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hare
authors.affiliation: Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas.
authors.forename: Ignacy
authors.initials: I
authors.lastname: Gryczynski
authors.affiliation: Department of Molecular and Medical Genetics, University of North Texas Health Science Center, Fort Worth, Texas.|Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, Texas.|Texas Center for Health Disparities, University of North Texas Health Science Center, Fort Worth, Texas.
authors.forename: Jamboor K
authors.initials: JK
authors.lastname: Vishwanatha
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000378:metabolism*; D001932:Brain Neoplasms / Q000473:pathology / Q000556:secondary*; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D017785:Photons; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017306:Annexin A2; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D048051:p38 Mitogen-Activated Protein Kinases; D010959:Tissue Plasminogen Activator