Abstract
BackgroundFusion of breast cancer cells with tumor-associated populations of the microenvironment including mesenchymal stroma/stem-like cells (MSC) represents a rare event in cell communication whereby the metastatic capacity of those hybrid cells remains unclear.MethodsFunctional changes were investigated in vitro and in vivo following spontaneous fusion and hybrid cell formation between primary human MSC and human MDA-MB-231 breast cancer cells. Thus, lentiviral eGFP-labeled MSC and breast cancer cells labeled with mcherry resulted in dual-fluorescing hybrid cells after co-culture.ResultsDouble FACS sorting and single cell cloning revealed two different aneuploid male hybrid populations (MDA-hyb1 and MDA-hyb2) with different STR profiles, pronounced telomerase activities, and enhanced proliferative capacities as compared to the parental cells. Microarray-based mRNA profiling demonstrated marked regulation of genes involved in epithelial-mesenchymal transition and increased expression of metastasis-associated genes including S100A4. In vivo studies following subcutaneous injection of the breast cancer and the two hybrid populations substantiated the in vitro findings by a significantly elevated tumor growth of the hybrid cells. Moreover, both hybrid populations developed various distant organ metastases in a much shorter period of time than the parental breast cancer cells.ConclusionTogether, these data demonstrate spontaneous development of new tumor cell populations exhibiting different parental properties after close interaction and subsequent fusion of MSC with breast cancer cells. This formation of tumor hybrids contributes to continuously increasing tumor heterogeneity and elevated metastatic capacities.
Highlights
Fusion of breast cancer cells with tumor-associated populations of the microenvironment including mesenchymal stroma/stem-like cells (MSC) represents a rare event in cell communication whereby the metastatic capacity of those hybrid cells remains unclear
Co-culture of different human MSCGFP with mcherrylabeled breast cancer cells was accompanied by formation of hybrid cells via spontaneous cell fusions
A significantly elevated hybrid cell population was observed with a 10-fold enhanced proliferation for MDA-hyb1 and a 4-fold increased cell growth for MDA-hyb2 as compared to their wildtype MDA-MB-231 tumor counterpart (Fig.1a)
Summary
Fusion of breast cancer cells with tumor-associated populations of the microenvironment including mesenchymal stroma/stem-like cells (MSC) represents a rare event in cell communication whereby the metastatic capacity of those hybrid cells remains unclear. Previous work has demonstrated that different breast and ovarian cancer cells at least transiently acquire new functional properties following interaction with MSC via gap junctional intercellular communication or notch signaling in vitro and in vivo [8, 9]. Receptor interactions such as the intercellular adhesion molecule ICAM-1 expressed on MSC can directly associate with the transmembrane heterodimeric glycoprotein MUC-1 (CD227, DF3, CA15–3) on the cell surface of breast cancer cells to promote an actin-based cell invasive motility in the tumor cells [10–12]. Such changes of cancer cell properties and function by transient stimulation and interaction with MSC can be induced permanently e.g. by fusion processes and the generation of new cancer cell hybrid populations
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