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

Abstract

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.

In Ovarian Cancer Multicellular Spheroids, Platelet Releasate Promotes Growth, Expansion of ALDH+ and CD133+ Cancer Stem Cells, and Protection against the Cytotoxic Effects of Cisplatin, Carboplatin and Paclitaxel

“…PR contains several growth factors that have been involved in OvCa progression, including CSCs expansion and drug resistance ( Supplemental Table S2 )—EGF, secreted by M2-like TAMs, activates the EGFR-ERK signaling pathway and promotes the progression of OvCa [ 45 , 46 ]; EGFR blockade targets ALDH-CSCs and reverses cisplatin resistance [ 47 , 48 , 49 ]; anti-IGF-1R-targeted strategies potentiate the efficacy of platinum-based chemotherapy [ 50 , 51 ]; PDGF, secreted by mesenchymal stromal cells (MSCs), induces platinum resistance and CSC enrichment (CD133, and ALDH in OvCa heterospheroids) [ 52 ]; TGFβ increases OvCa growth [ 18 , 22 , 53 ] and its neutralization potentiates tumor immunity and decreases OvCa progression [ 54 , 55 ]; CCL5 and CCR5 are mainly expressed by CD133+ OvCa stem-like cells [ 56 ], CCL2/CCL5, secreted by stromal cells, induces IL-6/PYK2-dependent chemoresistance in OvCa cells [ 57 ] and cisplatin, by inducing the secretion of CCL5 by cancer-associated fibroblasts (CAFs), promotes cisplatin resistance [ 16 ]. Thus, the interaction of OvCa cells with platelets [ 20 ] and their products may contribute to the expansion of ovarian CSCs, as well as to decreased drug activity and consequently to tumor progression [ 58 ].…”

Role of cancer‑associated fibroblasts in the resistance to antitumor therapy, and their potential therapeutic mechanisms in non‑small cell lung cancer (Review)

“…Though CAFs lack specific markers, literature reports that CAF markers may possess organs heterogeneity, and that CAFs expressing the same marker may possess different functions in different organs. For example, in ovarian cancer, PDGF-R+ CAFs promote tumor progression by remodeling the ECM ( 51 ). However, CAFs expressing PDGF increase the levels of the Puma in myofibroblasts, which subsequently activates Bak, a pro-apoptotic protein that induce cholangiocarcinoma cell apoptosis ( 52 ).…”

Mesenchymal Stem Cells for Mitigating Radiotherapy Side Effects

“…The tumor involves a chronic inflammatory process that recruits endogenous or exogenous MSCs [ 142 , 143 ]. Homed MSCs promote angiogenesis [ 144 ] and interact with CSC enhancing the growth [ 145 ] and chemoresistance [ 146 ] of CSC. The tumor exploits MSCs’ unique immunosuppression nature, allowing malignant cells to escape recognition and clearance by the immune system [ 147 , 148 , 149 ].…”