Characterization of hybrid cells derived from spontaneous fusion events between breast epithelial cells exhibiting stem-like characteristics and breast cancer cells

Dittmar, Thomas; Schwitalla, Sarah; Seidel, Jeanette; Haverkampf, Sonja; Reith, Georg; Meyer-Staeckling, Sönke; Brandt, Burkhard; Niggemann, Bernd; Zänker, Kurt S.

doi:10.1007/s10585-010-9359-3

Cited by 62 publications

(105 citation statements)

References 49 publications

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Section: Resultsmentioning

confidence: 99%

“…Both hybrid clones derived from spontaneous fusion events between M13SV1-EGFP-Neo cells and MDA-MB-435-Hyg cells and were isolated by a dual antibiotic selection procedure [7]. Parental cells were co-cultured for 24 h prior to addition of antibiotics [7]. The origin of hybrid cells by cell fusion and not horizontal gene transfer was proven by short tandem repeat (STR) analysis, whereby specific sequences on different chromosomes were analyzed.…”

Section: Resultsmentioning

confidence: 99%

“…Analysis of the gene expression profile of hybrid cells showed that these cells retain a transcriptome identity characteristic of both parental derivatives, while also expressing a unique subset of transcripts, which may have important consequences for tumorigenesis and metastogenesis [28]. A unique gene expression pattern was further described for hybrid cells derived from weakly malignant Cloudman S91 melanoma cells and macrophages [30,31], human breast epithelial cells exhibiting stem cell characteristics and breast cancer cells [7], and murine 67NR mammary carcinoma cells and mouse bone marrow-derived cells (BMDCs) [8]. Rizvi and colleagues provided evidence that murine BMDCs restore murine intestinal tissue in a long term repopulation fashion suggesting that BMDCs have fused with intestinal stem and/or progenitor cells [29].…”

Section: Introductionmentioning

confidence: 99%

“…These cells were characterised by a nearly doubled chromosomal number and an increased proliferation rate [10] as well as a unique gene expression profile concomitant with an altered migratory behaviour [7]. In the present work we analysed the role of three major cell migration related signal transduction cascades - PLC-γ1, PI3K/AKT, RAS-RAF-MAPK - in two hybrid cell lines and their parental cells.…”

Section: Introductionmentioning

confidence: 99%

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Hybrid cells derived from breast epithelial cell/breast cancer cell fusion events show a differential RAF-AKT crosstalk

et al. 2012

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BackgroundThe biological phenomenon of cell fusion has been linked to several characteristics of tumour progression, including an enhanced metastatogenic capacity and an enhanced drug resistance of hybrid cells. We demonstrated recently that M13SV1-EGFP-Neo breast epithelial cells exhibiting stem cell characteristics spontaneously fused with MDA-MB-435-Hyg breast cancer cells, thereby giving rise to stable M13MDA435 hybrid cells, which are characterised by a unique gene expression profile and migratory behaviour. Here we investigated the involvement of the PLC-β/γ1, PI3K/AKT and RAS-RAF-ERK signal transduction cascades in the EGF and SDF-1α induced migration of two M13MDA435 hybrid cell clones in comparison to their parental cells.ResultsAnalysis of the migratory behaviour by using the three-dimensional collagen matrix migration assay showed that M13SV1-EGFP-Neo cells as well as M13MDA435 hybrid cells, but not the breast cancer cell line, responded to EGF stimulation with an increased locomotory activity. By contrast, SDF-1α solely stimulated the migration of M13SV1-EGFP-Neo cells, whereas the migratory activity of the other cell lines was blocked. Analysis of signal transduction cascades revealed a putative differential RAF-AKT crosstalk in M13MDA435-1 and -3 hybrid cell clones. The PI3K inhibitor Ly294002 effectively blocked the EGF induced migration of M13MDA435-3 hybrid cells, whereas the EGF induced locomotion of M13MDA435-1 hybrid cells was markedly increased. Analysis of RAF-1 S259 phosphorylation, being a major mediator of the negative regulation of RAF-1 by AKT, showed decreased pRAF-1 S259 levels in LY294002 treated M13MDA435-1 hybrid cells. By contrast, pRAF-1 S259 levels remained unaltered in the other cell lines. Inhibition of PI3K/AKT signalling by Ly294002 relieves the AKT mediated phosphorylation of RAF-1, thereby restoring MAPK signalling.ConclusionsHere we show that hybrid cells could evolve exhibiting a differential active RAF-AKT crosstalk. Because PI3K/AKT signalling has been chosen as a target for anti-cancer therapies our data might point to a possible severe side effect of AKT targeted cancer therapies. Inhibition of PI3K/AKT signalling in RAF-AKT crosstalk positive cancer (hybrid) cells could result in a progression of these cells. Thus, not only the receptor (activation) status, but also the activation of signal transduction molecules should be analysed thoroughly prior to therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hybrid cells derived from breast epithelial cell/breast cancer cell fusion events show a differential RAF-AKT crosstalk

et al. 2012

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“…In particular, cancer cells can fuse with different cell types, including stromal, epithelial and endothelial cells generating genetically instable hybrids202122. Additionally, it was shown that macrophages or bone marrow-derived cells behave as fusion partners in several types of tumours2324252627.…”

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confidence: 99%

Mesenchymal stem cells generate distinct functional hybrids in vitro via cell fusion or entosis

Sottile

Aulicino

Theka

et al. 2016

Sci Rep

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Homotypic and heterotypic cell-to-cell fusion are key processes during development and tissue regeneration. Nevertheless, aberrant cell fusion can contribute to tumour initiation and metastasis. Additionally, a form of cell-in-cell structure called entosis has been observed in several human tumours. Here we investigate cell-to-cell interaction between mouse mesenchymal stem cells (MSCs) and embryonic stem cells (ESCs). MSCs represent an important source of adult stem cells since they have great potential for regenerative medicine, even though they are also involved in cancer progression. We report that MSCs can either fuse forming heterokaryons, or be invaded by ESCs through entosis. While entosis-derived hybrids never share their genomes and induce degradation of the target cell, fusion-derived hybrids can convert into synkaryons. Importantly we show that hetero-to-synkaryon transition occurs through cell division and not by nuclear membrane fusion. Additionally, we also observe that the ROCK-actin/myosin pathway is required for both fusion and entosis in ESCs but only for entosis in MSCs. Overall, we show that MSCs can undergo fusion or entosis in culture by generating distinct functional cellular entities. These two processes are profoundly different and their outcomes should be considered given the beneficial or possible detrimental effects of MSC-based therapeutic applications.

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Fusion with mesenchymal stem cells differentially affects tumorigenic and metastatic abilities of lung cancer cells

Zhang

Kong

Zhao

et al. 2018

Journal Cellular Physiology

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Cell fusion plays a crucial role in cancer progression and leads to massive aberrant changes in chromosome and gene expression involved in tumor metastasis. Cancer cells can fuse with many cell types, including stromal cells, epithelial cells, macrophages, and endothelial cells. Mesenchymal stem cells (MSCs) have been reported to migrate and incorporate into tumor sites during cancer progression. However, the underlying mechanism of stem cell fusion in tumor metastasis has not been fully deciphered. In this research, we established a cell fusion model between lung cancer cells and MSCs in vitro. We found that the hybrid cells showed enhanced metastatic capacity with increased expression of MMP-2 and MMP-9, whereas the proliferation ability was inhibited and cell cycle was blocked in the G 0 /G 1 phase with elevated expression of p21, p27, and p53. Moreover, the hybrid cells lost epithelial morphology and exhibited an epithelial-mesenchymal transition (EMT) change with downregulation of E-cadherin and upregulation of N-cadherin, Vimentin, α-SMA and Fibronectin1. Meanwhile, the expressions of EMT transcription factors, including Snail1, Slug, Twist1, Zeb1, and Zeb2, were also increased in hybrid cells. More important, the fusion hybrids acquired stem cell-like properties, which exhibited increased expression stem cell transcription factors Oct4, Sox2, Nanog, Kif4 as well as Bmi1. Taken together, our results suggested that cell fusion between lung cancer cells and MSCs offered enhanced metastatic capacity and characteristics of cancer stem cell by undergoing EMT. This study will contribute to explaning the origin of lung cancer stem cells and to elucidate the role of cell fusion in cancer metastasis. K E Y W O R D S cancer stem cells (CSCs), cell fusion, epithelial-mesenchymal transition (EMT), lung cancer, mesenchymal stem cells (MSCs)

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Characterization of hybrid cells derived from spontaneous fusion events between breast epithelial cells exhibiting stem-like characteristics and breast cancer cells

Cited by 62 publications

References 49 publications

Hybrid cells derived from breast epithelial cell/breast cancer cell fusion events show a differential RAF-AKT crosstalk

Hybrid cells derived from breast epithelial cell/breast cancer cell fusion events show a differential RAF-AKT crosstalk

Mesenchymal stem cells generate distinct functional hybrids in vitro via cell fusion or entosis

Fusion with mesenchymal stem cells differentially affects tumorigenic and metastatic abilities of lung cancer cells

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