Abstract
Simple SummaryCell fusion as a fundamental biological process is required for various physiological processes, including fertilization, placentation, myogenesis, osteoclastogenesis, and wound healing/tissue regeneration. However, cell fusion is also observed during pathophysiological processes like tumor development. Mesenchymal stroma/stem-like cells (MSC) which play an important role within the tumor microenvironment like other cell types such as macrophages can closely interact and hybridize with cancer cells. The formation of cancer hybrid cells can involve various different mechanisms whereby the genomic parts of the hybrid cells require rearrangement to form a new functional hybrid cell. The fusion of cancer cells with neighboring cell types may represent an important mechanism during tumor development since cancer hybrid cells are detectable in various tumor tissues. During this rare event with resulting genomic instability the cancer hybrid cells undergo a post-hybrid selection process (PHSP) to reorganize chromosomes of the two parental nuclei whereby the majority of the hybrid population undergoes cell death. The remaining cancer hybrid cells survive by displaying altered properties within the tumor tissue.The generation of cancer hybrid cells by intra-tumoral cell fusion opens new avenues for tumor plasticity to develop cancer stem cells with altered properties, to escape from immune surveillance, to change metastatic behavior, and to broaden drug responsiveness/resistance. Genomic instability and chromosomal rearrangements in bi- or multinucleated aneuploid cancer hybrid cells contribute to these new functions. However, the significance of cell fusion in tumorigenesis is controversial with respect to the low frequency of cancer cell fusion events and a clonal advantage of surviving cancer hybrid cells following a post-hybrid selection process. This review highlights alternative processes of cancer hybrid cell development such as entosis, emperipolesis, cannibalism, therapy-induced polyploidization/endoreduplication, horizontal or lateral gene transfer, and focusses on the predominant mechanisms of cell fusion. Based upon new properties of cancer hybrid cells the arising clinical consequences of the subsequent tumor heterogeneity after cancer cell fusion represent a major therapeutic challenge.
Highlights
Cell fusion is a fundamental biological mechanism that describes the plasma membrane merging of two or more cells, thereby giving rise to one new hybrid cell displaying altered functionalities
The complexity of heterokaryon-to-synkaryon transition” (HST)/ploidy reductions” (PR) is displayed by the transition of a cellular state carrying two discrete diploid nuclei from different parental cells to merge to a new functional nuclear unit with initially a tetraploid chromosomal phenotype
Since CCL21 has been associated with lymph node metastases in breast cancer [207], these findings likely indicate that the fusion of CCL21-insensitive cancer cells could give rise to CCL21-sensitive cancer hybrid cells
Summary
Cell fusion is a fundamental biological mechanism that describes the plasma membrane merging of two or more cells, thereby giving rise to one new hybrid cell displaying altered functionalities. Several physiological processes, such as fertilization, placentation, myogenesis, osteoclastogenesis, and wound healing/repair activities require the fusion of distinct somatic cells (for review see: [1,2,3,4,5,6,7,8,9]). The complexity of HST/PR is displayed by the transition of a cellular state carrying two discrete diploid nuclei from different parental cells to merge to a new functional nuclear unit with initially a tetraploid chromosomal phenotype. Different mechanisms exist, such as entosis, emperipolesis, cannibalism, therapy-induced polyploidization/endoreduplication, and horizontal gene transfer/lateral gene transfer (HGT/LGT), which could give rise to cell fusion like-derived cells
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