Carcinoma-Associated Mesenchymal Stem Cells Promote Chemoresistance in Ovarian Cancer Stem Cells via PDGF Signaling

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 chemo...

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Veröffentlicht in:Cancers 2020-07, Vol.12 (8), p.2063
Hauptverfasser: Raghavan, Shreya, Snyder, Catherine S., Wang, Anni, McLean, Karen, Zamarin, Dmitriy, Buckanovich, Ronald J., Mehta, Geeta
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container_issue 8
container_start_page 2063
container_title Cancers
container_volume 12
creator Raghavan, Shreya
Snyder, Catherine S.
Wang, Anni
McLean, Karen
Zamarin, Dmitriy
Buckanovich, Ronald J.
Mehta, Geeta
description 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.
doi_str_mv 10.3390/cancers12082063
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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.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers12082063</identifier><identifier>PMID: 32726910</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Ascites ; Cancer therapies ; Cell self-renewal ; Chemoprotection ; Chemoresistance ; Chemotherapy ; Cytokines ; Drug dosages ; Drug resistance ; Drug therapy ; Flow cytometry ; Gene expression ; Genotype &amp; phenotype ; Health aspects ; Hedgehog protein ; Kinases ; Medical prognosis ; Mesenchymal stem cells ; Metastases ; Metastasis ; Observations ; Ovarian cancer ; Paracrine signalling ; Patient outcomes ; Phenotypes ; Platelet-derived growth factor ; Platinum ; Spheroids ; Stem cells ; Stromal cells ; Tumor cells</subject><ispartof>Cancers, 2020-07, Vol.12 (8), p.2063</ispartof><rights>COPYRIGHT 2020 MDPI AG</rights><rights>2020. 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source Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central
subjects Ascites
Cancer therapies
Cell self-renewal
Chemoprotection
Chemoresistance
Chemotherapy
Cytokines
Drug dosages
Drug resistance
Drug therapy
Flow cytometry
Gene expression
Genotype & phenotype
Health aspects
Hedgehog protein
Kinases
Medical prognosis
Mesenchymal stem cells
Metastases
Metastasis
Observations
Ovarian cancer
Paracrine signalling
Patient outcomes
Phenotypes
Platelet-derived growth factor
Platinum
Spheroids
Stem cells
Stromal cells
Tumor cells
title Carcinoma-Associated Mesenchymal Stem Cells Promote Chemoresistance in Ovarian Cancer Stem Cells via PDGF Signaling
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