TY - JOUR
T1 - A new model of multi-visceral and bone metastatic prostate cancer with perivascular niche targeting by a novel endothelial specific adenoviral vector
AU - Lu, Zhi Hong
AU - Kaliberov, Sergey
AU - Sohn, Rebecca E.
AU - Kaliberova, Lyudmila
AU - Du, Yingqiu
AU - Prior, Julie L.
AU - Leib, Daniel J.
AU - Chauchereau, Anne
AU - Sehn, Jennifer K.
AU - Curiel, David T.
AU - Arbeit, Jeffrey M.
N1 - Funding Information:
The IGR-CaP1 cells are available via MTA from the Pasteur Institute (Paris) (CNCM 1-4126). The authors also thank Matthew Silva and Deborah Novak for their comments and suggestions. Grant support was from R01CA159959, R01CA154697, and NIH P50 CA094056 to JMA, DTC, and D. Piwnica-Worms/S. Achilefu respectively, with additional support from the Midwest Stone Foundation, the BJC Foundation, and St. Louis Men's Club to JMA. The bone histology and morphology work was supported by funding to the Washington University Musculoskeletal Core grants, T32AR060791, and P30AR057235.
PY - 2017
Y1 - 2017
N2 - While modern therapies for metastatic prostate cancer (PCa) have improved survival they are associated with an increasingly prevalent entity, aggressive variant PCa (AVPCa), lacking androgen receptor (AR) expression, enriched for cancer stem cells (CSCs), and evidencing epithelial-mesenchymal plasticity with a varying extent of neuroendocrine transdifferentiation. Parallel work revealed that endothelial cells (ECs) create a perivascular CSC niche mediated by juxtacrine and membrane tethered signaling. There is increasing interest in pharmacological metastatic niche targeting, however, targeted access has been impossible. Here, we discovered that the Gleason 7 derived, androgen receptor negative, IGR-CaP1 cell line possessed some but not all of the molecular features of AVPCa. Intracardiac injection into NOD/ SCID/IL2Rg-/- (NSG) mice produced a completely penetrant bone, liver, adrenal, and brain metastatic phenotype; noninvasively and histologically detectable at 2 weeks, and necessitating sacrifice 4-5 weeks post injection. Bone metastases were osteoblastic, and osteolytic. IGR-CaP1 cells expressed the neuroendocrine marker synaptophysin, near equivalent levels of vimentin and e-cadherin, all of the EMT transcription factors, and activation of NOTCH and WNT pathways. In parallel, we created a new triple-targeted adenoviral vector containing a fiber knob RGD peptide, a hexon mutation, and an EC specific ROBO4 promoter (Ad.RGD.H5/3.ROBO4). This vector was expressed in metastatic microvessels tightly juxtaposed to IGR-CaP1 cells in bone and visceral niches. Thus, the combination of IGR-CaP1 cells and NSG mice produces a completely penetrant metastatic PCa model emulating end-stage human disease. In addition, the metastatic niche access provided by our novel Ad vector could be therapeutically leveraged for future disease control or cure.
AB - While modern therapies for metastatic prostate cancer (PCa) have improved survival they are associated with an increasingly prevalent entity, aggressive variant PCa (AVPCa), lacking androgen receptor (AR) expression, enriched for cancer stem cells (CSCs), and evidencing epithelial-mesenchymal plasticity with a varying extent of neuroendocrine transdifferentiation. Parallel work revealed that endothelial cells (ECs) create a perivascular CSC niche mediated by juxtacrine and membrane tethered signaling. There is increasing interest in pharmacological metastatic niche targeting, however, targeted access has been impossible. Here, we discovered that the Gleason 7 derived, androgen receptor negative, IGR-CaP1 cell line possessed some but not all of the molecular features of AVPCa. Intracardiac injection into NOD/ SCID/IL2Rg-/- (NSG) mice produced a completely penetrant bone, liver, adrenal, and brain metastatic phenotype; noninvasively and histologically detectable at 2 weeks, and necessitating sacrifice 4-5 weeks post injection. Bone metastases were osteoblastic, and osteolytic. IGR-CaP1 cells expressed the neuroendocrine marker synaptophysin, near equivalent levels of vimentin and e-cadherin, all of the EMT transcription factors, and activation of NOTCH and WNT pathways. In parallel, we created a new triple-targeted adenoviral vector containing a fiber knob RGD peptide, a hexon mutation, and an EC specific ROBO4 promoter (Ad.RGD.H5/3.ROBO4). This vector was expressed in metastatic microvessels tightly juxtaposed to IGR-CaP1 cells in bone and visceral niches. Thus, the combination of IGR-CaP1 cells and NSG mice produces a completely penetrant metastatic PCa model emulating end-stage human disease. In addition, the metastatic niche access provided by our novel Ad vector could be therapeutically leveraged for future disease control or cure.
KW - Adenovirus
KW - Endothelial
KW - Metastasis
KW - Niche
KW - Prostate
UR - http://www.scopus.com/inward/record.url?scp=85012900040&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.14699
DO - 10.18632/oncotarget.14699
M3 - Article
C2 - 28103576
AN - SCOPUS:85012900040
VL - 8
SP - 12272
EP - 12289
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 7
ER -