TY - JOUR
T1 - The Potential of PSMA as a Vascular Target in TNBC
AU - Heesch, A.
AU - Ortmanns, L.
AU - Maurer, J.
AU - Stickeler, E.
AU - Sahnoun, S.E.M.
AU - Mottaghy, F.M.
AU - Morgenroth, A.
N1 - Funding Information:
This research was funded by Deutsche Krebshilfe (project number: 70113779 and 70113780) and Deutsche Forschungsgemeinschaft in the framework of the Research Training Group ‘Tumor-targeted Drug Delivery’ (project number: 331065168).
Publisher Copyright:
© 2023 by the authors.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - Recent studies proving prostate-specific membrane antigen (PSMA) expression on triple-negative breast cancer (TNBC) cells and adjacent endothelial cells suggest PSMA as a promising target for therapy of until now not-targetable cancer entities. In this study, PSMA and its isoform expression were analyzed in different TNBC cells, breast cancer stem cells (BCSCs), and tumor-associated endothelial cells. PSMA expression was detected in 91% of the investigated TNBC cell lines. The PSMA splice isoforms were predominantly found in the BCSCs. Tumor-conditioned media from two TNBC cell lines, BT-20 (high full-length PSMA expression, PSMA Delta 18 expression) and Hs578T (low full-length PSMA expression, no isoform expression), showed significant pro-angiogenic effect with induction of tube formation in endothelial cells. All TNBC cell lines induced PSMA expression in human umbilical vein endothelial cells (HUVEC). Significant uptake of radiolabeled ligand [Ga-68]Ga-PSMA was detected in BCSC1 (4.2%), corresponding to the high PSMA expression. Moreover, hypoxic conditions increased the uptake of radiolabeled ligand [Lu-177]Lu-PSMA in MDA-MB-231 (0.4% vs. 3.4%, under hypoxia and normoxia, respectively) and MCF-10A (0.3% vs. 3.0%, under normoxia and hypoxia, respectively) significantly (p < 0.001). [Lu-177]Lu-PSMA-induced apoptosis rates were highest in BT-20 and MDA-MB-231 associated endothelial cells. Together, these findings demonstrate the potential of PSMA-targeted therapy in TNBC.
AB - Recent studies proving prostate-specific membrane antigen (PSMA) expression on triple-negative breast cancer (TNBC) cells and adjacent endothelial cells suggest PSMA as a promising target for therapy of until now not-targetable cancer entities. In this study, PSMA and its isoform expression were analyzed in different TNBC cells, breast cancer stem cells (BCSCs), and tumor-associated endothelial cells. PSMA expression was detected in 91% of the investigated TNBC cell lines. The PSMA splice isoforms were predominantly found in the BCSCs. Tumor-conditioned media from two TNBC cell lines, BT-20 (high full-length PSMA expression, PSMA Delta 18 expression) and Hs578T (low full-length PSMA expression, no isoform expression), showed significant pro-angiogenic effect with induction of tube formation in endothelial cells. All TNBC cell lines induced PSMA expression in human umbilical vein endothelial cells (HUVEC). Significant uptake of radiolabeled ligand [Ga-68]Ga-PSMA was detected in BCSC1 (4.2%), corresponding to the high PSMA expression. Moreover, hypoxic conditions increased the uptake of radiolabeled ligand [Lu-177]Lu-PSMA in MDA-MB-231 (0.4% vs. 3.4%, under hypoxia and normoxia, respectively) and MCF-10A (0.3% vs. 3.0%, under normoxia and hypoxia, respectively) significantly (p < 0.001). [Lu-177]Lu-PSMA-induced apoptosis rates were highest in BT-20 and MDA-MB-231 associated endothelial cells. Together, these findings demonstrate the potential of PSMA-targeted therapy in TNBC.
KW - triple-negative breast cancer
KW - prostate-specific membrane antigen
KW - angiogenesis
KW - tumor-endothelial crosstalk
KW - ALTERNATIVELY SPLICED VARIANTS
KW - GROWTH-FACTOR EXPRESSION
KW - NEGATIVE BREAST-CANCER
KW - MEMBRANE ANTIGEN PSMA
KW - PROSTATE-CANCER
KW - PHASE-II
KW - ANGIOGENESIS
KW - FOLATE
KW - INTERNALIZATION
KW - PROLIFERATION
U2 - 10.3390/cells12040551
DO - 10.3390/cells12040551
M3 - Article
C2 - 36831218
SN - 2073-4409
VL - 12
JO - Cells
JF - Cells
IS - 4
M1 - 551
ER -