Abstract
Current strategies to determine tumor × normal (TN)-hybrid cells among human cancer cells include the detection of hematopoietic markers and other mesodermal markers on tumor cells or the presence of donor DNA in cancer samples from patients who had previously received an allogenic bone marrow transplant. By doing so, several studies have demonstrated that TN-hybrid cells could be found in human cancers. However, a prerequisite of this cell fusion search strategy is that such markers are stably expressed by TN-hybrid cells over time. However, cell fusion is a potent inducer of genomic instability, and TN-hybrid cells may lose these cell fusion markers, thereby becoming indistinguishable from nonfused tumor cells. In addition, hybrid cells can evolve from homotypic fusion events between tumor cells or from heterotypic fusion events between tumor cells and normal cells possessing similar markers, which would also be indistinguishable from nonfused tumor cells. Such indistinguishable or invisible hybrid cells will be referred to as dark matter hybrids, which cannot as yet be detected and quantified, but which contribute to tumor growth and progression.
Highlights
It is well known that cell–cell fusion and hybridization play a crucial role in several physiological processes, such as fertilization, placentation, myogenesis, osteogenesis, wound healing, and tissue regeneration
Its impact on cancer initiation and progression is as yet unclear. This applies to the question of whether cell fusion events do truly occur in human cancers and if the evolving tumor cell × normal cell hybrids and their progenies do truly contribute to disease progression, as was proposed by the German physician Otto Aichel in 1911 [6]
There have been a plethora of in vitro and in vivo studies in the past decades demonstrating that tumor cells do fuse with normal cells, such as macrophages, fibroblasts, stromal cells or stem cells, thereby giving rise to viable proliferating tumor × normal (TN)-hybrid cells with properties that are linked with tumor progression including enhanced tumorigenic and metastatic capacity or enhanced drug resistance [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31]
Summary
It is well known that cell–cell fusion and hybridization play a crucial role in several physiological processes, such as fertilization, placentation, myogenesis, osteogenesis, wound healing, and tissue regeneration. EpCAM, whereas macrophages and tumor cells are single positive for CD45 or EpCAM, respectively While these studies show that putative TN-hybrid cells can be identified in human cancer patients based on the coexpression of hematopoietic markers and tumor-specific markers [20,29,41,42], a degree of uncertainty remains whether hematopoietic lineage markers are legitimate fusion markers, even though these findings are supported by appropriate animal studies [12,20,29]. Lazova et al and LaBerge et al were able to demonstrate an overlay of various donor and recipient alleles in microdissected tumor cells of male melanoma patients who received a BMT from their brothers [33,39] To date, this is the most reliable proof that cell fusion events truly occur in human cancers. What if TN-hybrid cells originate that do not express these specific markers or have lost them? This brings us to the section
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