Assessing angiogenic responses induced by primary human prostate stromal cells in a three-dimensional fibrin matrix assay

// W. Nathaniel Brennen 1 , Huong Nguyen 1 , Susan L. Dalrymple 1 , Stephanie Reppert-Gerber 1 , Jeesun Kim 1 , John T. Isaacs 1 , Hans Hammers 1, 2 1 Department of Oncology, Prostate Cancer Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA 2 Present Address: Department of Internal Medicine, Division of Hematology/Oncology, UT Southwestern, Dallas, TX, USA Correspondence to: Hans Hammers, email: hans.hammers@utsouthwestern.edu Keywords: angiogenesis, stroma, mesenchymal stem cells (MSC), prostate, stromal paracrine factors Received: June 01, 2016 Accepted: August 10, 2016 Published: August 17, 2016 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.