Cell–Cell Fusion and the Roads to Novel Properties of Tumor Hybrid Cells

Abstract

The phenomenon of cancer cell–cell fusion is commonly associated with the origin of more malignant tumor cells exhibiting novel properties, such as increased drug resistance or an enhanced metastatic capacity. However, the whole process of cell–cell fusion is still not well understood and seems to be rather inefficient since only a certain number of (cancer) cells are capable of fusing and only a rather small population of fused tumor hybrids will survive at all. The low survivability of tumor hybrids is attributed to post-fusion processes, which are characterized by the random segregation of mixed parental chromosomes, the induction of aneuploidy and further random chromosomal aberrations and genetic/epigenetic alterations in daughter cells. As post-fusion processes also run in a unique manner in surviving tumor hybrids, the occurrence of novel properties could thus also be a random event, whereby it might be speculated that the tumor microenvironment and its spatial habitats could direct evolving tumor hybrids towards a specific phenotype.

Cell-Cell Fusion Mediated by Viruses and HERV-Derived Fusogens in Cancer Initiation and Progression

“…Albeit syncytin-1 was reported to improve the prognosis of breast cancer patients [65], most data from other carcinoma types rather indicated a relationship between syncyctin-1 and tumor progression [59,61,64,66]. These findings also suggested that fusion of cancer cells in general develops a more malignant phenotype with progression of metastatic lesions [16,20,22,99,167,169,170,172]. Further involvement of syncytin-1 in the fusion of two non-transformed cells undergoing a malignant conversion has not yet been reported and, hence, remains ambiguous.…”

“…Fusion also includes infection of host cells with enveloped viruses [19] and tumor development [20,21]. Even though the process of cell fusion appears phenomenologically simple, like two merging soap bubbles, it is tightly regulated whereby various molecular processes remain to be elucidated [22].…”

“…In parallel to the induction of a fusogenic state, hybrid cells must adopt a non-fusogenic state (or post-fusion state) to prevent additional hybridization events, which, i.e., is accompanied by rearrangements of the mixing cytoskeleton and cytoplasms [3,5,19]. Likewise, hybrid cells could either remain in a bi-or multinucleated state, such as osteoclasts and syncytiotrophoblasts [3,8,27], or could undergo heterokaryonto-synkaryon transition (HST)/ploidy reduction (PR) (HST/PR) [22,[28][29][30][31].…”

“…Hybrid cells contain additional copies of centrosomes (one centrosome per parental cell) and both the localization of the centrosomes and attachment of spindle fibers to chromosomes during metaphase and anaphase have an impact whether randomly mixed chromosomes will be equally segregated in a bipolar manner or missegregated due to tri-and multipolar divisions and lagging chromosomes to daughter cells (Figure 2, Videos S1 and S2). In particular, chromosome missegregation has been associated with an overall increased genomic/chromosomal instability (GCIN) due to induction of aneuploidy, multinucleation, micronuclei formation and chromothripsis [22,[28][29][30][31][33][34][35][36]. In contrast, virus-infected cells have already reached a post-fusion state directly after virus-host cell membrane fusion that is commonly accompanied by virus replication and cell death.…”

Cell fusion as a link between the SARS-CoV-2 spike protein, COVID-19 complications, and vaccine side effects

“…Another potential concern comes from a longstanding model that cell fusion, particularly fusion induced by viruses, contributes to cancer development, progression, metastasis, recurrence, dormancy, and acquired drug resistance (reviewed in: [39,[63][64][65]). This model has been supported by recent reports of cell hybrids in human cancers, [58,66] by multiple observations in animal models (reviewed in: [39,65,67,68]), by findings that human cells can be made cancerous through cell fusion, [59,69,70] and by comparing the evolution of tumors and cell hybrids [71]. However, whether any neoplastic hybrids found in humans [58] are made by viral fusogens, as has been suggested [72][73][74], is yet to be determined.…”