Cell Fusion in Human Cancer: The Dark Matter Hypothesis

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.

Keywords: cancer; cell fusion; dark matter; metastasis.

Figure 1

Model of how dark matter hybrids may originate. Tumor cells can either fuse with other tumor cells (homotypic fusion) or normal cells (heterotypic fusion), resulting in a heterokaryon (a hybrid cell with at least two nuclei). Hybrid cells can undergo a process known as the heterokaryon-to-synkaryon transition (HST), which is the merging of the parental chromosomes and random distribution to (at least) two daughter cells with one nucleus (synkaryon). A solid-colored nucleus represents the unchanged karyotype of a normal cell, whereas the altered karyotype of a tumor cell is presented as a gradient colored nucleus. HST is a potent inducer of genomic instability and most hybrid cells will die or will be less capable of proliferation (not shown here). (A) Homotypic tumor cell fusion results in dark matter hybrids that are indistinguishable from parental cells. (B) Heterotypic fusion of a tumor cell and a normal cell both exhibiting a similar specific marker pattern also results in dark matter hybrids that are indistinguishable from parental cells. (C) Heterotypic fusion of a tumor cell and a normal cell exhibiting a specific discrimination marker pattern. Due to genomic instability one TN-hybrid cell loses discrimination markers over time and becomes a dark matter hybrid. In contrast, the other TN-hybrid cell retains discrimination markers and becomes part of the visible matter hybrids.

Figure 2

Timeline of cell fusion events inside a tumor tissue. Cell fusion events can occur at any time inside a tumor tissue (gray), whereby the fusion frequency should increase with tumor size. Whether hybrid cells will become visible or part of the dark matter (invisible) will depend on which cell types fuse and if they retain or lose specific marker expression. A, Tumor cells could either fuse with each other (homotypic fusion) or with normal cells expressing similar markers (heterotypic fusion) resulting in invisible/dark matter hybrids. Such hybrids are indistinguishable from nonfused tumor cells (gray) but contribute to tumor heterogeneity and tumor growth (dashed and dotted lines). B, Heterotypic cell fusion between tumor cells and normal cells results in TN-hybrid cells that have lost specific marker expression over time and become part of the dark matter. A switch from red to gray indicates the loss of specific marker expression. C, Heterotypic cell fusion between tumor cells and normal cells results in TN-hybrid cells that have retained normal cell marker expression over time and can be detected in the biopsy.