title: A novel model for evaluating therapies targeting human tumor vasculature and human cancer stem-like cells.
abstract: Human tumor vessels express tumor vascular markers (TVM), proteins that are not expressed in normal blood vessels. Antibodies targeting TVMs could act as potent therapeutics. Unfortunately, preclinical in vivo studies testing anti-human TVM therapies have been difficult to do due to a lack of in vivo models with confirmed expression of human TVMs. We therefore evaluated TVM expression in a human embryonic stem cell-derived teratoma (hESCT) tumor model previously shown to have human vessels. We now report that in the presence of tumor cells, hESCT tumor vessels express human TVMs. The addition of mouse embryonic fibroblasts and human tumor endothelial cells significantly increases the number of human tumor vessels. TVM induction is mostly tumor-type-specific with ovarian cancer cells inducing primarily ovarian TVMs, whereas breast cancer cells induce breast cancer specific TVMs. We show the use of this model to test an anti-human specific TVM immunotherapeutics; anti-human Thy1 TVM immunotherapy results in central tumor necrosis and a three-fold reduction in human tumor vascular density. Finally, we tested the ability of the hESCT model, with human tumor vascular niche, to enhance the engraftment rate of primary human ovarian cancer stem-like cells (CSC). ALDH(+) CSC from patients (n = 6) engrafted in hESCT within 4 to 12 weeks whereas none engrafted in the flank. ALDH(-) ovarian cancer cells showed no engraftment in the hESCT or flank (n = 3). Thus, this model represents a useful tool to test anti-human TVM therapy and evaluate in vivo human CSC tumor biology.
authors.affiliation: Cellular and Molecular Biology Program, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Department of Internal Medicine, Division Hematology-Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Burgos-Ojeda
authors.forename: Karen
authors.initials: K
authors.lastname: McLean
authors.forename: Shoumei
authors.initials: S
authors.lastname: Bai
authors.forename: Heather
authors.initials: H
authors.lastname: Pulaski
authors.forename: Yusong
authors.initials: Y
authors.lastname: Gong
authors.forename: Ines
authors.initials: I
authors.lastname: Silva
authors.forename: Karl
authors.initials: K
authors.lastname: Skorecki
authors.forename: Maty
authors.initials: M
authors.lastname: Tzukerman
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Buckanovich
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D053595:Embryonic Stem Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000922:Immunotoxins / Q000008:administration & dosage / Q000276:immunology; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013724:Teratoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D000922:Immunotoxins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C485631:HEY1 protein, human