Abstract
Cellular communication within the tumor microenvironment enables important interactions between cancer cells and recruited adjacent populations including mesenchymal stroma/stem-like cells (MSC). These interactions were monitored in vivo following co-injection of GFP-labeled human MSC together with mcherry-labeled MDA-MB-231 breast cancer cells in NODscid mice. Within 14 days of tumor development the number of initially co-injected MSC had significantly declined and spontaneous formation of breast cancer/MSC hybrid cells was observed by the appearance of double fluorescing cells. This in vivo fusion displayed a rare event and occurred in less than 0.5% of the tumor cell population. Similar findings were observed in a parallel in vitro co-culture. Characterization of the new cell fusion products obtained after two consecutive flow cytometry cell sorting and single cell cloning revealed two populations, termed MDA-hyb3 and MDA-hyb4. The breast cancer fusion cells expressed both, GFP and mcherry and displayed more characteristics of the MDA-MB-231 cells than of the parental MSC. While little if any differences were determined in the proliferative capacity, a significant delay of MDA-hyb3 cells in tumor formation was observed when compared to the parental MDA-MB-231 cells. Moreover, MDA-hyb3 cells developed an altered pattern of distant organ metastases. These findings demonstrated dynamic tumor changes by in vivo and in vitro fusion with the development of new breast cancer hybrid cells carrying altered tumorigenic properties. Consequently, cancer cell fusion contributes to progressively increasing tumor heterogeneity which complicates a therapeutic regimen.
Highlights
Cell fusion in general represents a rare biological process which requires close proximity between fusogenic cell partners and is tightly regulated by multiple pathways which, are not yet fully understood [1]
Distant organ metastases in liver, heart, lung, spleen, or brain remained undetectable whereas metastasized mcherry-positive fluorescing cancer cells exclusively appeared in kidney sections of the two mice after 45 and 51 days post injection (Figure 1C). These metastases demonstrated only mcherry fluorescence without any traceable greenfluorescent fluorescent protein protein (GFP) fluorescence. This is supported by fluorescence microscopy demonstrating that in parallel to the increasing tumor development, the amount of detectable MSCGFP decreased over time (Figure 1D)
The amount of cherry fluorescence continuously increased over time. These in vivo observations were substantiated by 2D in vitro co-cultures with decreasing numbers of GFP-expressing mesenchymal stroma/stem-like cells (MSC) (Figure 1D upper panel)
Summary
Cell fusion in general represents a rare biological process which requires close proximity between fusogenic cell partners and is tightly regulated by multiple pathways which, are not yet fully understood [1]. This process of hybrid cell formation besides entosis or cell cannibalism is associated with a proper alignment of certain glycoproteins and a permissive lipid composition of the involved parts of the cell membranes to facilitate the initiation of a fusion event. Observed cell fusions include the generation of muscle fibers by a continuous homo- or autofusion of myoblasts to form multi-nucleated myocytes.
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