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.

Naike Casagrande,Alfonso Colombatti,Cinzia Borghese,Cristina Durante,Francesco Agostini,Mario Mazzucato,Donatella Aldinucci

doi:10.3390/ijms22063019

Abstract

A high platelet count is associated with a poor prognosis in ovarian cancer (OvCa). Despite good clinical responses with platinating agents in combination with taxanes, numerous OvCa patients relapse due to chemotherapy resistance. Here, we report that treatment of OvCa cells A2780, OVCAR5 and MDAH with releasate from activated platelets (PR) promoted multicellular tumor spheroid (MCTS) formation. These OvCa-MCTSs had increased percentages of CD133+ and aldehyde dehydrogenase (ALDH)+ cells, bona fide markers of OvCa cancer stem cells (CSCs). PR increased OVCAR5- and MDAH-MCTS viability and decreased the cytotoxic and pro-apoptotic effects of paclitaxel, cisplatin and carboplatin. PR increased the volume of spontaneously formed OVCAR8-MCTSs and counteracted their size reduction due to cisplatin, carboplatin and paclitaxel treatment. PR promoted the survival of ALDH+ and CD133+ OvCa cells during cisplatin, carboplatin and paclitaxel treatment. In conclusion, molecules and growth factors released by activated platelets (EGF, PDGF, TGF-β, IGF and CCL5) may protect tumor cells from chemotherapy by promoting the expansion of ALDH+ and CD133+ OvCa-CSCs, favoring drug resistance and tumor relapse.

Highlights

An increased platelet count is correlated with poor disease-free survival (DFS) and overall survival in various cancers [1,2,3], including ovarian cancer (OvCa) [4,5,6,7]
OvCa patients are responsive to chemotherapy at first; the main obstacles for successful chemotherapy are represented by drug toxicity and drug resistance [23]
Drug resistance can be intrinsic, acquired or achieved by the aggregation of tumor cells as spheroids or heterospheroids. These aggregates of tumor cells, called multicellular tumor spheroids (MCTSs) are less sensitive to anticancer drugs and are capable of disseminating in the peritoneum to form metastasis [30,31,32], and are found in malignant ascites formed in late-stage OvCa patients with peritoneal carcinomatosis

Summary

Introduction

An increased platelet count is correlated with poor disease-free survival (DFS) and overall survival in various cancers [1,2,3], including ovarian cancer (OvCa) [4,5,6,7]. Platelets and molecules secreted by platelets affect tumor growth, metastasis and anticancer drug activity [8,9,10,11,12]. Tumor cells can stimulate platelet production and activation, leading to an abnormally increased number of platelets in the blood (thrombocytosis) and to the release of growth factors, cytokines, chemokines and vesicular signals, collectively termed “platelet releasate” (PR) [12,13,14]. The co-culture of platelets with OvCa cells increased tridimensional multicellular tumor spheroid (MCTS) formation, with the expression of metastasis-initiating cell markers and migration [20], which was inhibited by aspirin [21]. PR increased tumor growth and decreased docetaxel activity in OvCa xenograft models [5]

Methods

Results

Conclusion