title: Assessing angiogenic responses induced by primary human prostate stromal cells in a three-dimensional fibrin matrix assay.
abstract: Accurate modeling of angiogenesis in vitro is essential for guiding the preclinical development of novel anti-angiogenic agents and treatment strategies. The formation of new blood vessels is a multifactorial and multi-stage process dependent upon paracrine factors produced by stromal cells in the local microenvironment. Mesenchymal stem cells (MSCs) are multipotent cells in adults that can be recruited to sites of inflammation and tissue damage where they aid in wound healing through regenerative, trophic, and immunomodulatory properties. Primary stromal cultures derived from human bone marrow, normal prostate, or prostate cancer tissue are highly enriched in MSCs and stromal progenitors. Using conditioned media from these primary cultures, a robust pro-angiogenic response was observed in a physiologically-relevant three-dimensional fibrin matrix assay. To evaluate the utility of this assay, the allosteric HDAC4 inhibitor tasquinimod and the anti-VEGF monoclonal antibody bevacizumab were used as model compounds with distinct mechanisms of action. While both agents had a profound inhibitory effect on endothelial sprouting, only bevacizumab induced significant regression of established vessels. Additionally, the pro-angiogenic properties of MSCs derived from prostate cancer patients provides further evidence that selective targeting of this population may be of therapeutic benefit.
authors.affiliation: Department of Oncology, Prostate Cancer Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: W Nathaniel
authors.initials: WN
authors.lastname: Brennen
authors.affiliation: Department of Oncology, Prostate Cancer Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Huong
authors.initials: H
authors.lastname: Nguyen
authors.affiliation: Department of Oncology, Prostate Cancer Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Dalrymple
authors.affiliation: Department of Oncology, Prostate Cancer Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Reppert-Gerber
authors.affiliation: Department of Oncology, Prostate Cancer Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jeesun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Oncology, Prostate Cancer Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
authors.affiliation: Department of Oncology, Prostate Cancer Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Present Address: Department of Internal Medicine, Division of Hematology/Oncology, UT Southwestern, Dallas, TX, USA.
authors.forename: Hans
authors.initials: H
authors.lastname: Hammers
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000068258:Bevacizumab / Q000494:pharmacology; D002478:Cells, Cultured; D005337:Fibrin; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011467:Prostate / Q000166:cytology*; D015363:Quinolones / Q000494:pharmacology; D055153:Stem Cell Niche
chemical_list: D020533:Angiogenesis Inhibitors; D015363:Quinolones; D000068258:Bevacizumab; C516109:tasquinimod; D005337:Fibrin
keywords: angiogenesis; mesenchymal stem cells (MSC); prostate; stroma; stromal paracrine factors