MSC stimulate ovarian tumor growth during intercellular communication but reduce tumorigenicity after fusion with ovarian cancer cells

Abstract

The tumor microenvironment enables important cellular interactions between cancer cells and recruited adjacent populations including mesenchymal stroma/stem cells (MSC). In vivo cellular interactions of primary human MSC in co-culture with human SK-OV-3 ovarian cancer cells revealed an increased tumor growth as compared to mono-cultures of the ovarian cancer cells. Moreover, the presence of MSC stimulated formation of liver metastases. Further interactions of MSC with the ovarian cancer cells resulted in the formation of hybrid cells by cell fusion. Isolation and single cell cloning of these hybrid cells revealed two differentially fused ovarian cancer cell populations termed SK-hyb1 and SK-hyb2. RNA microarray analysis demonstrated expression profiles from both parental partners whereby SK-hyb1 were attributed with more SK-OV-3 like properties and SK-hyb2 cells displayed more similarities to MSC. Both ovarian cancer hybrid populations exhibited reduced proliferative capacity compared to the parental SK-OV-3 cells. Moreover, the fused populations failed to develop tumors in NODscid mice. Together, these data suggested certain stimulatory effects on ovarian tumor growth in the presence of MSC. Conversely, fusion of MSC with SK-OV-3 cells contributed to the generation of new cancer hybrid populations displaying a significantly reduced tumorigenicity.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0279-1) contains supplementary material, which is available to authorized users.

Anti-Tumor Effects of Exosomes Derived from Drug-Incubated Permanently Growing Human MSC

“…Previous work has demonstrated that a variety of different MSC from primary cultures exhibit mutual interactions with cancer cells of breast and ovarian tumors in vitro and in vivo [ 25 , 26 , 27 ]. In addition to direct cell-to-cell contacts, further cellular communication was performed via indirect mechanisms by release of biological factors and/or small vesicles.…”

“…Total RNA was isolated from the tumor tissues and the organs using the RNeasy Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions. An amount of 1 µg of RNA was reverse-transcribed into cDNA, and reactions were performed with corresponding primers (mCherry: sense 5′-TTC ATG TAC GGC TCC AAG GC-3′; antisense 5′-CTG CTT GAT CTC GCC CTT CA-3′; amplification product 297 bp; GAPDH as a control: sense 5′-ACC ACA GTC CAT GCC ATC AC-3′; antisense 5′-TCC ACC ACC CTG TTG CTG TA-3′; amplification product 452 bp) specifically as described previously [ 27 ]. Aliquots of 25 µL of each RT-PCR product were separated on a 2% agarose gel including the standard GeneRuler 100 bp DNA Ladder (ThermoFisher Scientific, Schwerte, Germany) and visualized by GelRedTM (Biotium Inc., Hayward, CA, USA) staining.…”

DEAD-Box Helicase 4 (Ddx4)+ Stem Cells Sustain Tumor Progression in Non-Serous Ovarian Cancers

“…MSCs are generally assumed to support the tumor cell proliferation [ 26 , 27 ]. Thus, to investigate the modulation of tumor cell viability and proliferation by ML cells, we co-cultured A2780 population with ML-Ddx4 + cells derived from either healthy ovaries or NS-EOCs, separated by pored inserts and, at different time points of the culture, namely 24 (T1), 48 (T2), and 72 (T3) h, we measured the extent of cell divisions in A2780 cells by the carboxyfluoresceinsuccinimidyl ester (CFSE) assay.…”

“…The potential capability of MSCs to support tumor cell proliferation has been widely proved in most solid malignancies [ 26 , 27 ] including OC. In this regard, the cross-talk between mesenchymal and tumor cells has been shown to induce transcriptomic changes in the latter, characterized by the upregulation of genes involved in cell proliferation, migration and invasiveness that ultimately lead to the acquisition of a pro-metastatic phenotype [ 49 ].…”

Effect of umbilical cord mesenchymal stem cells in human ovarian cancer SKOV3 cells

“…However, there are relatively few reports on the effects of umbilical cord mesenchymal stem cells on ovarian cancer cells, and there are different opinions. Some studies have shown that co-culture of mesenchymal stem cells and human SKOV3 ovarian cancer cells can promote apoptosis, and The fusion of SKOV3 cells can also significantly reduce tumorigenicity [13] . The PI3K / AKT signaling pathway is one of the important signal transduction pathways in cells, and plays an important role in inhibiting apoptosis, regulating the cell cycle, and promoting cell invasion and metastasis [14] .…”