Cell Fusion of Mesenchymal Stem/Stromal Cells and Breast Cancer Cells Leads to the Formation of Hybrid Cells Exhibiting Diverse and Individual (Stem Cell) Characteristics

Abstract

Cancer is one of the most common diseases worldwide, and treatment bears many challenges such as drug and radioresistance and formation of metastases. These difficulties are due to tumor heterogeneity, which has many origins. One may be cell fusion, a process that is relevant in both physiological (e.g., wound healing) and pathophysiological (cancer and viral infection) processes. In this study, we examined if cell fusion between mesenchymal stem/stromal cells (MSCs) and breast cancer (BC) cells occurs and if newly generated hybrid cells may exhibit cancer stem/initiating cell (CS/IC) characteristics. Therefore, several methods such as mammosphere assay, AldeRed assay, flow cytometry (CD24, CD44, CD104) and Western blot analysis (of epithelial to mesenchymal transition markers such as SNAIL, SLUG and Twist) were applied. In short, four different hybrid clones, verified by short tandem repeat (STR) analysis, were analyzed; each expressed an individual phenotype that seemed not to be explicitly related to either a more stem cell or cancer cell phenotype. These results show that cancer cells and MSCs are able to fuse spontaneously in vitro, thereby giving rise to hybrid cells with new properties, which likely indicate that cell fusion may be a trigger for tumor heterogeneity.

Cell–Cell Fusion and the Roads to Novel Properties of Tumor Hybrid Cells

“…Moreover, hybrids exhibited increased expression levels of the stem cell transcription factors Oct4, Sox2, Nanog, Kif4 as well as Bmi1, suggesting that they may have acquired stem cell-like properties [27]. Similar data were presented by Dörnen et al demonstrating that the fusion of MSCs and breast cancer cells led to the formation of tumor hybrids exhibiting diverse and individual (stem cell) characteristics [40]. In vitro and in vivo studies of Melzer and colleagues showed that human MSCs could fuse with human breast cancer cells and that tumor hybrids possessed an enhanced metastatic capacity to distant organs in a much shorter period of time than the parental breast cancer cells [60,61,65].…”

“…Most studies focusing on heterotypic cell-cell fusion events have investigated tumor hybrids that were derived from cancer cells and macrophages or stem cells. This might be attributed to the fact that both macrophages and stem cells possess fusogenic capacities [20][21][22][23][24][25][26][27][30][31][32][33][34][35][36][38][39][40]52]. For instance, it is well known that macrophages give rise to multinucleated osteoclasts through hybridization [7,53,54] and that stem cells could restore degenerated tissues by cell-cell fusion [55][56][57][58].…”

Relevance of circulating hybrid cells as a non-invasive biomarker for myriad solid tumors

“…Beyond providing insight on tumor protein expression, our detection of mutant KRAS genes in CHCs isolated from a patient with PDAC highlights their promise as source of genomic material to facilitate tumor profiling for clinically actionable oncogenic alterations. Given that KRAS mutations were only identified in a subset of CHCs underscores there is much that remains to be understood about hybrid cell biology, including the degree to which hybrid cells retain each parent genome and the process of ploidy reduction 55 . Additionally, evidence exists of allele recombination between parent genomes resulting in genetically distinct hybrid cells and contributes to the heterogeneity of hybrid cell populations 56 .…”

Cancer Cell Fusion and Post-Hybrid Selection Process (PHSP)

“…This assumption would be in agreement with data revealing that fusion of non-transformed cells could give rise to transformed and tumorigenic hybrids exhibiting CS/IC properties [ 70 , 97 , 142 ]. Moreover, cancer cells could also acquire CS/IC properties by fusion with stem cells as demonstrated in several studies [ 22 , 26 , 29 , 44 , 143 , 144 , 162 , 163 ]. In more detail, gene expression analysis of hybrids after fusion of lung-cancer cells with MSC revealed markedly increased expression levels of the cancer stem-cell markers CD44 and CD133 and the overall stemness markers Oct4, Nanog, Sox2, Kif4 and Bmi1, which supports the assumption that cancer cells may acquire CS/IC properties through fusion with stem cells [ 26 ].…”

“…However, these processes may not be mutually exclusive. As discussed above, some studies suggested that cancer cells could acquire CS/ICs properties via cell fusion [ 22 , 26 , 29 , 44 , 143 , 144 , 162 , 163 ]. If so, cell-fusion-derived CS/ICs would not only be more tumorigenic and metastatogenic, but should also acquire an increased resistance against radiation and cytotoxic compounds according to the defined characteristics of cancer stem cells [ 160 , 161 , 178 , 179 , 180 ].…”