A multi-stage process including transient polyploidization and EMT precedes the emergence of chemoresistent ovarian carcinoma cells with a dedifferentiated and pro-inflammatory secretory phenotype
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Verena Rohnalter1, Katrin Roth2, Florian Finkernagel1, Till Adhikary1, Julia Obert1, Kristina Dorzweiler1, Maike Bensberg1, Sabine Müller-Brüsselbach1, Rolf Müller1
1Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology, Philipps University, Marburg 35043, Germany
2Cell Imaging Core Facility, Center for Tumor Biology and Immunology, Philipps University, Marburg 35043, Germany
Rolf Müller, e-mail: firstname.lastname@example.org
Keywords: chemoresistance, giant cancer cells, polyploidy, senescence-associated secretory phenotype (SASP), epithelial-mesenchymal transition (EMT)
Received: July 28, 2015 Accepted: October 06, 2015 Published: October 19, 2015
DNA-damaging drugs induce a plethora of molecular and cellular alterations in tumor cells, but their interrelationship is largely obscure. Here, we show that carboplatin treatment of human ovarian carcinoma SKOV3 cells triggers an ordered sequence of events, which precedes the emergence of mitotic chemoresistant cells. The initial phase of cell death after initiation of carboplatin treatment is followed around day 14 by the emergence of a mixed cell population consisting of cycling, cell cycle-arrested and senescent cells. At this stage, giant cells make up >80% of the cell population, p21 (CDKN1A) in strongly induced, and cell numbers remain nearly static. Subsequently, cell death decreases, p21 expression drops to a low level and cell divisions increase, including regular mitoses of giant cells and depolyploidization by multi-daughter divisions. These events are accompanied by the upregulation of stemness markers and a pro-inflammatory secretory phenotype, peaking after approximately 14 days of treatment. At the same time the cells initiate epithelial to mesenchymal transition, which over the subsequent weeks continuously increases, concomitantly with the emergence of highly proliferative, migratory, dedifferentiated, pro-inflammatory and chemoresistant cells (SKOV3-R). These cells are anchorage-independent and grow in a 3D collagen matrix, while cells on day 14 do not survive under these conditions, indicating that SKOV3-R cells were generated thereafter by the multi-stage process described above. This process was essentially recapitulated with the ovarian carcinoma cell line IGROV-1. Our observations suggest that transitory cells characterized by polyploidy, features of stemness and a pro-inflammatory secretory phenotype contribute to the acquisition of chemoresistance.
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