TY - JOUR
T1 - Carcinoma-associated mesenchymal stem cells promote chemoresistance in ovarian cancer stem cells via pdgf signaling
AU - Raghavan, Shreya
AU - Snyder, Catherine S.
AU - Wang, Anni
AU - McLean, Karen
AU - Zamarin, Dmitriy
AU - Buckanovich, Ronald J.
AU - Mehta, Geeta
N1 - Funding Information:
Funding: This work is supported primarily by the American Cancer Society Research Scholar Award RSG-19-003-01-CCE (G.M.), DOD OCRP Early Career Investigator Award W81XWH-13-1-0134 (G.M.), DOD Pilot award W81XWH-16-1-0426 (G.M.), DOD Investigator Initiated award W81XWH-18-0346 (G.M.), Rivkin Center for Ovarian Cancer (G.M.), Michigan Ovarian Cancer Alliance (G.M.), NIH/NIDCR Tissue Engineering and Regeneration Training Grant T32DE00007057 (S.R.) and the Rackham Research Grant (C.S.S.). Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award number P30CA046592.
Funding Information:
This work is supported primarily by the American Cancer Society Research Scholar Award RSG-19-003-01-CCE (G.M.), DOD OCRP Early Career Investigator Award W81XWH-13-1-0134 (G.M.), DOD Pilot award W81XWH-16-1-0426 (G.M.), DOD Investigator Initiated award W81XWH-18-0346 (G.M.), Rivkin Center for Ovarian Cancer (G.M.), Michigan Ovarian Cancer Alliance (G.M.), NIH/NIDCR Tissue Engineering and Regeneration Training Grant T32DE00007057 (S.R.) and the Rackham Research Grant (C.S.S.). Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award number P30CA046592. The authors acknowledge the efforts of Joel Whitfield from the Immunological Monitoring Core at the Rogel Cancer Center, for performing ELISA measurements. The authors are thankful to Mark Savary at the Flow Cytometry Core for technical assistance in performing fluorescent activated cell sorting. The authors are thankful to Elise M.-A. Fleck for conducting preliminary experiments. The authors are also grateful to Pooja Mehta and Michael Bregenzer for their contribution to this work.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/8
Y1 - 2020/8
N2 - Within the ovarian cancer tumor microenvironment, cancer stem-like cells (CSC) interact with carcinoma associated mesenchymal stem/stromal cells (CA-MSC) through multiple secreted cytokines and growth factors. These paracrine interactions have been revealed to cause enrichment of CSC and their chemoprotection; however, it is still not known if platelet-derived growth factor (PDGF) signaling is involved in facilitating these responses. In order to probe this undiscovered bidirectional communication, we created a model of ovarian malignant ascites in the three-dimensional (3D) hanging drop heterospheroid array, with CSC and CA-MSC. We hypothesized that PDGF secretion by CA-MSC increases self-renewal, migration, epithelial to mesenchymal transition (EMT) and chemoresistance in ovarian CSC. Our results indicate that PDGF signaling in the CSC-MSC heterospheroids significantly increased stemness, metastatic potential and chemoresistance of CSC. Knockdown of PDGFB in MSC resulted in abrogation of these phenotypes in the heterospheroids. Our studies also reveal a cross-talk between PDGF and Hedgehog signaling in ovarian cancer. Overall, our data suggest that when the stromal signaling via PDGF to ovarian CSC is blocked in addition to chemotherapy pressure, the tumor cells are significantly more sensitive to chemotherapy. Our results emphasize the importance of disrupting the signals from the microenvironment to the tumor cells, in order to improve response rates. These findings may lead to the development of combination therapies targeting stromal signaling (such as PDGF and Hedgehog) that can abrogate the tumorigenic, metastatic and platinum resistant phenotypes of ovarian CSC through additional investigations.
AB - Within the ovarian cancer tumor microenvironment, cancer stem-like cells (CSC) interact with carcinoma associated mesenchymal stem/stromal cells (CA-MSC) through multiple secreted cytokines and growth factors. These paracrine interactions have been revealed to cause enrichment of CSC and their chemoprotection; however, it is still not known if platelet-derived growth factor (PDGF) signaling is involved in facilitating these responses. In order to probe this undiscovered bidirectional communication, we created a model of ovarian malignant ascites in the three-dimensional (3D) hanging drop heterospheroid array, with CSC and CA-MSC. We hypothesized that PDGF secretion by CA-MSC increases self-renewal, migration, epithelial to mesenchymal transition (EMT) and chemoresistance in ovarian CSC. Our results indicate that PDGF signaling in the CSC-MSC heterospheroids significantly increased stemness, metastatic potential and chemoresistance of CSC. Knockdown of PDGFB in MSC resulted in abrogation of these phenotypes in the heterospheroids. Our studies also reveal a cross-talk between PDGF and Hedgehog signaling in ovarian cancer. Overall, our data suggest that when the stromal signaling via PDGF to ovarian CSC is blocked in addition to chemotherapy pressure, the tumor cells are significantly more sensitive to chemotherapy. Our results emphasize the importance of disrupting the signals from the microenvironment to the tumor cells, in order to improve response rates. These findings may lead to the development of combination therapies targeting stromal signaling (such as PDGF and Hedgehog) that can abrogate the tumorigenic, metastatic and platinum resistant phenotypes of ovarian CSC through additional investigations.
KW - 3D spheroids
KW - Cancer stem-like cells (CSC)
KW - Carcinoma associated mesenchymal stem cells (CA-MSC)
KW - Chemoresistance
KW - Heterospheroids
KW - High grade serous ovarian cancers
KW - Ovarian cancer
KW - Platelet derived growth factor (PDGF)
KW - Stemness
KW - Stromal cells
KW - Tumoroids
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U2 - 10.3390/cancers12082063
DO - 10.3390/cancers12082063
M3 - Article
AN - SCOPUS:85088790872
VL - 12
SP - 1
EP - 21
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 8
M1 - 2063
ER -