Cancer, it is known, may arise from any of a trio of well-known causes—inherited defects, exposure to environmental insults, and infection with oncogenic viruses. Still, the origin of most common cancers remains unclear. Perhaps cancer’s causes, scientists have speculated, actually form a quartet.
A possible fourth cause of cancer—cell fusion—has been the subject of many investigations, without success. Yet a new study suggests that even one cell fusion event can both initiate malignancy and fuel tumor evolution. This study, undertaken by investigators at the University of Michigan and the Mayo Clinic, indicates that the fusion of one normal cell with another can trigger multiple catastrophic genetic changes that ultimately transform normal cells into cancerous cells.
The results of the study appeared online June 8 in the American Journal of Pathology (AJP), in an article entitled, “Cell Fusion Connects Oncogenesis with Tumor Evolution.” The article describes how scientists induced cell fusion events by subjecting cultured cells to chemical stimulation. (In vivo, cells may fuse because of cell injury, inflammation, or viral infection.) The article also reports that when the scientists injected fused cells into immunodeficient mice, tumor formation commenced.
“We report that a fusion event involving normal, nontransformed, cytogenetically stable epithelial cells can initiate chromosomal instability, DNA damage, cell transformation, and malignancy,” the authors of the AJP article wrote. “Chromosomal instability” in this context refers to changes in the number and appearance of chromosomes in a species.
“Clonal analysis of fused cells reveals that the karyotypic and phenotypic potential of tumors formed by cell fusion is established immediately or within a few cell divisions after the fusion event,” the authors continued, “without further ongoing genetic and phenotypic plasticity, and that subsequent evolution of such tumors reflects selection from the initial diverse population rather than ongoing plasticity of the progeny.”
The scientists studied rat IEC-6 intestinal epithelial cells, chosen because they maintain a stable diploid genomic structure (two sets of chromosomes), lack the cellular characteristics of cancer cells, and replicate normally. They also do not form tumors when monitored over many generations. IEC-6 cells were labeled with either red or green fluorescent dyes. The cells were then exposed to 50% polyethylene glycol to encourage cell fusion. The fused cells were identified by the presence of both red and green dyes within one cell, whereas non-fused cells displayed only one color. Fused cells were also larger than non-fused cells.
The fused cells, the scientists observed, could replicate, with 19% of fused IEC-6 cells establishing clones. With replication, the chromosomes from the two cells intermixed. The scientists also observed that 41% of the clones had abnormal numbers of chromosomes (aneuploidy), 56% were near-diploid (40 to 44 chromosomes), and 4% were tetraploid (84 chromosomes), whereas the large majority (86 percent) of non-fused cells were diploid.
Because aneuploidy and chromosomal abnormalities are commonly observed in cancer, the researchers looked for evidence of DNA damage in the fused clones. The double-strand DNA break marker phosphorylated H2AX revealed breaks in significantly more fusion-derived clones than in non-fused clones (35-42% versus 4-9%). This finding suggests that after cells fuse, chromosomal instability might lead to DNA damage and hence to genetic changes that underlie cancer. Consistent with that possibility, fused cells often exhibited the same abnormal growth characteristics as cancer cells.
“Although fusion of normal cells in vitro and in vivo may be a rare event, this study shows that cell fusion between normal cells can have pathological consequences,” commented noted authority and cancer specialist William B. Coleman, Ph.D., of the Department of Pathology and Laboratory Medicine, Program in Translational Medicine at the University of North Carolina Comprehensive Cancer Center (Chapel Hill). “The results provide evidence for another molecular mechanism driving neoplastic transformation—genomic catastrophe.”
Perhaps the most exciting observation occurred when fused IEC-6 cells were transplanted into immunodeficient mice. “We believe one cell fusion event can both initiate malignancy and fuel evolution of the tumor that ensues,' noted the AJP study’s lead author Xiaofeng Zhou, Ph.D., a researcher at the University of Michigan (Ann Arbor).
According to Dr. Coleman, most cases of spontaneous cancers in humans are thought to derive from cells that sustained random DNA damage or random errors during DNA replication: “Zhou et al. provide evidence for a different mechanism of spontaneous neoplastic transformation. The observations suggest strongly that genomic catastrophe can produce the required and necessary molecular alterations for neoplastic transformation and tumorigenesis in normal founder cells in the absence of selective pressures or ongoing genomic evolution.”
Dr. Coleman added that further research is needed to determine whether cell fusion events between normal human cell types result in genomic catastrophe and neoplastic transformation.