Trends in Cell Biology
Macrophage fusion: are somatic and cancer cells possible partners?
Section snippets
Macrophages initial interactions and fusion
The molecular mechanisms used by macrophages to fuse with each other, unlike those used by viruses to infect cells, remain uncharacterized. We know that fusing macrophages initially develop abundant interdigitations in their adjacent plasma membranes. These interdigitations might favor the concentration of the fusogenic molecules in specific domains of the plasma membrane (Figure 2a,b) 5, 6, 7. Macrophages in tissue culture fuse by an internalization process (Figure 2c,d) 5, 7, 8, 9, 10, 11, 12
The putative macrophage-fusion machinery
Components of the putative machinery that mediates the fusion of macrophage were identified initially using monoclonal antibodies that recognized cell-surface determinants and altered fusion in tissue culture. The first protein identified in this way by antibodies that blocked fusion was designated the macrophage fusion receptor (MFR) 9, 10, reported simultaneously as SIRPα, SHPS-1, BIT, p84 and MyD-1 13, 14, 15, 16, 17. We chose the name MFR because of its structural resemblance to CD4, the
Macrophages recognize each other as ‘self’ in order to fuse
As one of the main functions of macrophages is internalization of apoptotic cells, pathogens and foreign bodies and their subsequent routing towards lysosomes for degradation, macrophages must use an alternative pathway for cellocytosis leading to fusion. This is because cellocytosed cells survive and become integrated into the new cell. Indeed, mechanisms used by macrophages to internalize apoptotic cells, as compared with pathogens, involve pathways mediated by different cell-surface
Do macrophages fuse with somatic cells to repair tissues and organs?
The observation made by Vassilopoulos and colleagues [27] and Wang and colleagues [28] that hematopoietic stem cells repair damaged liver tissue in mice through cell fusion with hepatocytes challenged the old concept that adult stem cells reside in tissues and are the progenitors that renew somatic cells 29, 30. In a different study, for the first time, macrophages derived from hematopoietic stem cells were associated with fusion to acquire a new identity, thus increasing perceptions of their
Do macrophages fuse with tumor cells to trigger metastasis?
Tumor cells share with stem cells the capacity to self-renew and to migrate. When tumor cells leave their primary tissue to invade another one, they have become metastatic. Metastasis is the most devastating attribute of cancer, being the spread of tumor cells to distant organs in which they proliferate. Metastasis is associated with enhanced motility of cancer cells and with the capacity of these cells to evade the immune system. Thus, metastatic cells appear to have at least one of the
Conclusion and future directions
Macrophages have developed a sophisticated fusion machinery that endows them with potent destructive ability as multinucleate osteoclasts or giant cells. They appear to use this fusion machinery to control the fate of other cells, becoming potentially both lifesavers and killers. Macrophages might exploit the MFR–CD47 axis to recognize each other as ‘self’, as well as to recognize somatic and tumor cells. They might also use the MFR–CD47 axis to bring plasma membranes closer together and fuse.
Acknowledgements
The author is deeply grateful to Drs Dominik Duelli and George Vassilopoulos, who shared their thoughts about the fusion of myeloid cells with tumor cells and with somatic cells, respectively, at the meeting of the Cell–Cell subgroup of the American Society for Cell Biology in 2003. The author also thanks Drs Cristina Pelizon and Ann Körner for their careful editing of this manuscript. The author is grateful to her collaborators and colleagues at Yale University for their support and to the
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