Intrinsic signalling factors associated with cancer cell-cell fusion

Abstract

Cellular fusion e.g. between cancer cells and normal cells represents a stepwise process that is tightly regulated. During a pre-hybrid preparation program somatic cells and/or cancer cells are promoted to a pro-fusogenic state as a prerequisite to prepare a fusion process. A pro-fusogenic state requires significant changes including restructure of the cytoskeleton, e.g., by the formation of F-actin. Moreover, distinct plasma membrane lipids such as phosphatidylserine play an important role during cell fusion. In addition, the expression of distinct fusogenic factors such as syncytins and corresponding receptors are of fundamental importance to enable cellular mergers. Subsequent hybrid formation and fusion are followed by a post-hybrid selection process. Fusion among normal cells is important and often required during organismal development. Cancer cells fusion appears more rarely and is associated with the generation of new cancer hybrid cell populations. These cancer hybrid cells contribute to an elevated tumour plasticity by altered metastatic behaviour, changes in therapeutic and apoptotic responses, and even in the formation of cancer stem/ initiating cells. While many parts within this multi-step cascade are still poorly understood, this review article predominantly focusses on the intracellular necessities for fusion among cancer cells or with other cell populations of the tumour microenvironment. Video Abstract.

Keywords: Cancer cell fusion; Fusogens; Phosphatidylserine (PS); Post-hybrid selection process (PHSP); Pre-hybrid preparation program (PHPP); Pro-fusogenic state.

Fig. 1

Schematic scheme of decisive steps in membrane fusion. Fusogens ultimately catalyse the merger two phospholipid double membranes that should actually repel each other due to their negative charge

Fig. 2

Homotypic and heterotypic cell-cell fusion. Physiological homotypic cell-cell fusion is characterised by a highly efficient fusion frequency and the generation of multiple syncytia, which is most likely attributed to a high number of cells in a pro-fusogenic state (A). However, it is also possible that pro-fusogenic cells fuse with non-fusogenic cells in a homotypic manner. Heterotypic cell-cell fusion is different since it remains unclear, which cells provide fusogens and exhibit further fusion relevant properties (B). A pro-fusogenic cell fuses with a cell in a non-fusogenic state, which only expresses cognate receptors and phosphatidylserine (PS) (adapted from [166])

Fig. 3

In this model it is assumed that cancer cells fuse with other cells suggesting that all cells have entered a pre-hybrid preparation program (PHPP) by acquisition of a pro-fusogenic state (A). Alternatively, it cannot be ruled out that other cells in a pro-fusogenic state, such as macrophages, MSC, or stem cells could fuse with cancer cells in a non-fusogenic state (B). Similarly, both a cancer cell and a normal cell must have acquired a pro-fusogenic state for fusion (C). The resulting cancer hybrid populations from all of these alternatives have to undergo a post-hybrid selection process (PHSP) for re-organization of the chromosomal ploidy and corresponding metabolic adaptation to ensure survival

Fig. 4

Cancer cell-cell fusion model which is focused predominantly on the expression of the fusogen syncytin-1 and includes some basal similarities to physiological fusion events. In this model it is assumed that a cancer cell with a re-organised actin cytoskeleton expresses syncytin-1 and a PS-binding receptor, which recognises ASCT2 and PS, respectively. A basal syncytin-1 expression could be attributed to promotor mutation and/or hypomethylation (TF = transcription factor). The majority of expressed syncytin-1 will remain in the cytosol. In some cells, syncytin-1 may translocate to the plasma membrane, which may be facilitated by altered cytoskeletal structures. The corresponding cell exhibits Ca²⁺-PLS activity, which is engaged by Ca²⁺ to shuttle PS and subsequently enable plasma membrane merger and cell fusion (modified according to [166])