TY - JOUR
T1 - Assessing angiogenic responses induced by primary human prostate stromal cells in a three-dimensional fibrin matrix assay
AU - Brennen, W. Nathaniel
AU - Nguyen, Huong
AU - Dalrymple, Susan L.
AU - Reppert-Gerber, Stephanie
AU - Kim, Jeesun
AU - Isaacs, John T.
AU - Hammers, Hans
N1 - Funding Information:
The authors would like to acknowledge the following sources of financial support: Prostate Cancer Foundation Young Investigator Awards (WNB, HH), Allegheny Health Network-Hopkins Cancer Research Fund (WNB), Maryland Cigarette Restitution Fund (WNB), SKCCC CCSG developmental funds [P30 CA006973, (WNB)], NIH-Prostate SPORE Grant [P50 CA058236, (JTI)], Movember Prostate Cancer Foundation Challenge Award (JTI), and the Department of Defense [W81XWH-13-1-0304, (JTI); CA140917, (HH)]. We would also like to acknowledge the Tissue Services Core and Cell Imaging Facility supported by the SKCCC CCSG (P30 CA006973), and the use of tissues procured by the National Disease Research Interchange (NDRI) with support from NIH grant 2U2 OD011158.The authors would like to acknowledge the following sources of financial support: Prostate Cancer Foundation Young Investigator Awards (WNB, HH), Allegheny Health Network-Hopkins Cancer Research Fund (WNB), Maryland Cigarette Restitution Fund (WNB), SKCCC CCSG developmental funds Eugene P. Frenkel M.D. Scholarship at UT Southwestern (HH) [P30 CA006973, (WNB)], NIH-Prostate SPORE Grant [P50 CA058236, (JTI)], Movember Prostate Cancer Foundation Challenge Award (JTI), and the Department of Defense [W81XWH-13-1-0304, (JTI); CA140917, (HH)].
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Mesenchymal stem cells (MSC)
KW - Prostate
KW - Stroma
KW - Stromal paracrine factors
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U2 - 10.18632/oncotarget.11347
DO - 10.18632/oncotarget.11347
M3 - Article
C2 - 27542256
AN - SCOPUS:84995388864
SN - 1949-2553
VL - 7
SP - 71298
EP - 71308
JO - Oncotarget
JF - Oncotarget
IS - 44
ER -