Abstract
BackgroundThe biological phenomenon of cell fusion has been associated with cancer progression since it was determined that normal cell × tumor cell fusion-derived hybrid cells could exhibit novel properties, such as enhanced metastatogenic capacity or increased drug resistance, and even as a mechanism that could give rise to cancer stem/initiating cells (CS/ICs). CS/ICs have been proposed as cancer cells that exhibit stem cell properties, including the ability to (re)initiate tumor growth.MethodsFive M13HS hybrid clone cells, which originated from spontaneous cell fusion events between M13SV1-EGFP-Neo human breast epithelial cells and HS578T-Hyg human breast cancer cells, and their parental cells were analyzed for expression of stemness and EMT-related marker proteins by Western blot analysis and confocal laser scanning microscopy. The frequency of ALDH1-positive cells was determined by flow cytometry using AldeRed fluorescent dye. Concurrently, the cells’ colony forming capabilities as well as the cells’ abilities to form mammospheres were investigated. The migratory activity of the cells was analyzed using a 3D collagen matrix migration assay.ResultsM13HS hybrid clone cells co-expressed SOX9, SLUG, CK8 and CK14, which were differently expressed in parental cells. A variation in the ALDH1-positive putative stem cell population was observed among the five hybrids ranging from 1.44% (M13HS-7) to 13.68% (M13HS-2). In comparison to the parental cells, all five hybrid clone cells possessed increased but also unique colony formation and mammosphere formation capabilities. M13HS-4 hybrid clone cells exhibited the highest colony formation capacity and second highest mammosphere formation capacity of all hybrids, whereby the mean diameter of the mammospheres was comparable to the parental cells. In contrast, the largest mammospheres originated from the M13HS-2 hybrid clone cells, whereas these cells’ mammosphere formation capacity was comparable to the parental breast cancer cells. All M13HS hybrid clones exhibited a mesenchymal phenotype and, with the exception of one hybrid clone, responded to EGF with an increased migratory activity.ConclusionFusion of human breast epithelial cells and human breast cancer cells can give rise to hybrid clone cells that possess certain CS/IC properties, suggesting that cell fusion might be a mechanism underlying how tumor cells exhibiting a CS/IC phenotype could originate.
Highlights
The biological phenomenon of cell fusion has been associated with cancer progression since it was determined that normal cell × tumor cell fusion-derived hybrid cells could exhibit novel properties, such as enhanced metastatogenic capacity or increased drug resistance, and even as a mechanism that could give rise to cancer stem/initiating cells (CS/Cancer stem/initiating cells (ICs))
Hybrid cells derived from human breast epithelial cells and human breast cancer cells express mammary stemness factors Cell fusion has been considered as a possible mechanism for how cancer stem/initiating cells (CS/ICs) could evolve [14]
Since M13SV1-EGFPNeo human breast epithelial cells exhibit stem-like properties [24], five distinct M13HS hybrid cell clones (M13HS-1, −2, −4, −7, and −8), which were derived from spontaneous cell fusion events between M13SV1EGFP-Neo cells and human HS578T-Hyg breast cancer cells [15], were analyzed for the expression of SOX9 and SLUG, which cooperatively determine the mammary stem cell state [26], and for the luminal and basal markers cytokeratin 8 (CK8) and CK14 [27]
Summary
The biological phenomenon of cell fusion has been associated with cancer progression since it was determined that normal cell × tumor cell fusion-derived hybrid cells could exhibit novel properties, such as enhanced metastatogenic capacity or increased drug resistance, and even as a mechanism that could give rise to cancer stem/initiating cells (CS/ICs). Analysis of a cell line derived from a human breast adenocarcinoma xenograft revealed that approximately 30% of the cells had mixed mouse and human chromosomes, among which 8% carried mouse/human translocations, indicating that the hybrid cells originated by spontaneous fusion between the malignant human epithelium and normal host mouse stroma [6] Such transformed stroma-derived cells were tumorigenic with histopathologic features of malignancy, suggesting the impact of cell fusion in tumor progression [6]. Treatment of mice with Epirubicin was correlated with an increased frequency of hybrid cells (up to 12%) in the outer section of the tumor [13], indicating that chemotherapy might promote the origin of drug-resistant cancer hybrid cells
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