Abstract
Simple SummaryEven though it is known that (cancer) cells can fuse, it is still less understood how (cancer) cells merge their plasma membranes, thereby giving rise to bi- and multinucleated hybrid cells. Cell-cell fusion is an energy-dependent process and so-called fusogens are a crucial type of membrane-bound proteins, which are mandatory for overcoming plasma membrane hybridization with associated energetic barriers. Viruses and fusogens of human endogenous retroviral elements are a natural reservoir of fusogenic particles and proteins that could cause bi- and multinucleation of cancer cells. Likewise, multinucleated giant cancer cells have been found in several cancers caused by oncogenic viruses suggesting a possible correlation between viruses and fusogens of human endogenous retroviral origin in cancer cell fusion.Cell fusion is a well-known, but still scarcely understood biological phenomenon, which might play a role in cancer initiation, progression and formation of metastases. Although the merging of two (cancer) cells appears simple, the entire process is highly complex, energy-dependent and tightly regulated. Among cell fusion-inducing and -regulating factors, so-called fusogens have been identified as a specific type of proteins that are indispensable for overcoming fusion-associated energetic barriers and final merging of plasma membranes. About 8% of the human genome is of retroviral origin and some well-known fusogens, such as syncytin-1, are expressed by human (cancer) cells. Likewise, enveloped viruses can enable and facilitate cell fusion due to evolutionarily optimized fusogens, and are also capable to induce bi- and multinucleation underlining their fusion capacity. Moreover, multinucleated giant cancer cells have been found in tumors derived from oncogenic viruses. Accordingly, a potential correlation between viruses and fusogens of human endogenous retroviral origin in cancer cell fusion will be summarized in this review.
Highlights
Cell fusion represents a fundamental biological mechanism, which is mandatory for physiological processes such as fertilization, placentation, myogenesis, osteoclastogenesis and wound healing/tissue repair [1,2,3,4,5,6,7]
The actual process of cell fusion by the merging of the plasma membranes is facilitated by so-called fusogens, which are mandatory for overcoming certain energetic barriers and steric formation of distinct (iii) lipid intermediates named “the hallmarks of cell-cell fusion” [5]
The impact of human endogenous retroviruses (HERVs) elements in cancer progression is much more complex than “transduction” of oncogenes and “insertional mutagenesis” by HERV long terminal repeat (LTR), which has been previously suggested as the major retroviral tumorigenic mechanisms [138]. While these findings clearly indicate an involvement of HERV elements in cancer initiation and progression, the role of HERV env elements in cancer cell-cell fusion still remains unclear
Summary
Cell fusion represents a fundamental biological mechanism, which is mandatory for physiological processes such as fertilization, placentation, myogenesis, osteoclastogenesis and wound healing/tissue repair [1,2,3,4,5,6,7]. The actual process of cell fusion by the merging of the plasma membranes is facilitated by so-called fusogens, which are mandatory for overcoming certain energetic barriers and steric formation of distinct (iii) lipid intermediates named “the hallmarks of cell-cell fusion” [5]. These are (a) dehydration of contacting membranes, whereby phospholipid heads are brought to distances of close to. Besides the action of fusogens, some physico-chemical conditions and membrane properties necessitate further prerequisites of cell fusion Among these requirements is the close proximity of plasma membranes between the fusion partners accompanied by the extension of local lamellipodia-containing membrane protrusions [85]. A viral infection usually results in the death of the host cells either by the virus itself, induction of apoptosis or by the immune system, which applies to virus-induced syncytia formation in oncolytic immunotherapy [114,115,116]
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