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A primate virus generates transformed human cells by fusion.

Duelli DM, Hearn S, Myers MP, Lazebnik Y - J. Cell Biol. (2005)

Bottom Line: Amodel that explains both the origin and sporadic nature of cancer argues that cancer cells are a chance result of events that cause genomic and epigenetic variability.We also show that this virus can produce viable oncogenically transformed cells by fusing cells that are otherwise destined to die.Therefore, we argue that viruses can contribute to carcinogenesis by fusing cells.

View Article: PubMed Central - PubMed

Affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

ABSTRACT
Amodel that explains both the origin and sporadic nature of cancer argues that cancer cells are a chance result of events that cause genomic and epigenetic variability. The prevailing view is that these events are mutations that affect chromosome segregation or stability. However, genomic and epigenetic variability is also triggered by cell fusion, which is often caused by viruses. Yet, cells fused by viruses are considered harmless because they die. We provide evidence that a primate virus uses both viral and exosomal proteins involved in cell fusion to produce transformed proliferating human cells. Although normal cells indeed fail to proliferate after fusion, expression of an oncogene or a mutated tumor suppressor p53 in just one of the fusion partners is sufficient to produce heterogeneous progeny. We also show that this virus can produce viable oncogenically transformed cells by fusing cells that are otherwise destined to die. Therefore, we argue that viruses can contribute to carcinogenesis by fusing cells.

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Spontaneous fusion produces proliferating hybrids. (A) IMR90 cells (I0) resistant to puromycin (I0P) or I0 cells transformed with E1A and resistant to hygromycin (IEH) were cultured as indicated and stained with crystal violet to visualize the cells. (B) Co-culture of I0P and IEH cells results in cells resistant to both drugs. Cells were plated together, treated with PEG or left untreated, cultured for 20 d, and visualized as in A. (C and D) IEH cells fuse to each other but not to themselves. I0P and IEH cells were dyed and cultured as indicated for 16 h and visualized by fluorescence microscopy. Heterokaryons (indicated by arrows in C and scored in D) contained both green and blue dyes and at least one green and one blue nucleus. (E) Tissue culture medium from IEH cells induces cell fusion. Tissue culture medium conditioned by either I0P or IEH cells for 16 h was tested in the fusion assay (see Materials and methods). All experiments were performed at least three times. The data in D and E are from three independent experiments, and the error bars indicate SD.
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fig1: Spontaneous fusion produces proliferating hybrids. (A) IMR90 cells (I0) resistant to puromycin (I0P) or I0 cells transformed with E1A and resistant to hygromycin (IEH) were cultured as indicated and stained with crystal violet to visualize the cells. (B) Co-culture of I0P and IEH cells results in cells resistant to both drugs. Cells were plated together, treated with PEG or left untreated, cultured for 20 d, and visualized as in A. (C and D) IEH cells fuse to each other but not to themselves. I0P and IEH cells were dyed and cultured as indicated for 16 h and visualized by fluorescence microscopy. Heterokaryons (indicated by arrows in C and scored in D) contained both green and blue dyes and at least one green and one blue nucleus. (E) Tissue culture medium from IEH cells induces cell fusion. Tissue culture medium conditioned by either I0P or IEH cells for 16 h was tested in the fusion assay (see Materials and methods). All experiments were performed at least three times. The data in D and E are from three independent experiments, and the error bars indicate SD.

Mentions: This study resulted from using cell fusion as a tool to investigate how expression of the oncogenes Myc or adenoviral E1A sensitizes cells to chemotherapy-induced apoptosis (Duelli and Lazebnik, 2000). In one of the experiments, we needed to monitor cells produced by fusion of normal and E1A-expressing cells. We used PEG to fuse normal human fibroblasts that expressed a puromycin-resistance gene (I0P cells) with fibroblasts that expressed both a hygromycin-resistance gene and E1A (IEH cells). As expected, I0P cells were killed by hygromycin and IEH cells by puromycin (Fig. 1 A). Therefore, we expected only hybrids produced by PEG to proliferate in the presence of both drugs. To our surprise, we found that the number of proliferating cells did not depend on the PEG treatment (Fig. 1 B). One possible explanation was that cells fused spontaneously. We were intrigued by this possibility because of the link between fusion and carcinogenesis, the numerous reports that cancer cell lines are inexplicably fusogenic (for review see Duelli and Lazebnik, 2003), our finding that transformed cells acquire resistance to anticancer agents through fusion to normal cells (Duelli and Lazebnik, 2000), and the observation that cells recovered from individual colonies vary widely in their properties (unpublished data).


A primate virus generates transformed human cells by fusion.

Duelli DM, Hearn S, Myers MP, Lazebnik Y - J. Cell Biol. (2005)

Spontaneous fusion produces proliferating hybrids. (A) IMR90 cells (I0) resistant to puromycin (I0P) or I0 cells transformed with E1A and resistant to hygromycin (IEH) were cultured as indicated and stained with crystal violet to visualize the cells. (B) Co-culture of I0P and IEH cells results in cells resistant to both drugs. Cells were plated together, treated with PEG or left untreated, cultured for 20 d, and visualized as in A. (C and D) IEH cells fuse to each other but not to themselves. I0P and IEH cells were dyed and cultured as indicated for 16 h and visualized by fluorescence microscopy. Heterokaryons (indicated by arrows in C and scored in D) contained both green and blue dyes and at least one green and one blue nucleus. (E) Tissue culture medium from IEH cells induces cell fusion. Tissue culture medium conditioned by either I0P or IEH cells for 16 h was tested in the fusion assay (see Materials and methods). All experiments were performed at least three times. The data in D and E are from three independent experiments, and the error bars indicate SD.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171256&req=5

fig1: Spontaneous fusion produces proliferating hybrids. (A) IMR90 cells (I0) resistant to puromycin (I0P) or I0 cells transformed with E1A and resistant to hygromycin (IEH) were cultured as indicated and stained with crystal violet to visualize the cells. (B) Co-culture of I0P and IEH cells results in cells resistant to both drugs. Cells were plated together, treated with PEG or left untreated, cultured for 20 d, and visualized as in A. (C and D) IEH cells fuse to each other but not to themselves. I0P and IEH cells were dyed and cultured as indicated for 16 h and visualized by fluorescence microscopy. Heterokaryons (indicated by arrows in C and scored in D) contained both green and blue dyes and at least one green and one blue nucleus. (E) Tissue culture medium from IEH cells induces cell fusion. Tissue culture medium conditioned by either I0P or IEH cells for 16 h was tested in the fusion assay (see Materials and methods). All experiments were performed at least three times. The data in D and E are from three independent experiments, and the error bars indicate SD.
Mentions: This study resulted from using cell fusion as a tool to investigate how expression of the oncogenes Myc or adenoviral E1A sensitizes cells to chemotherapy-induced apoptosis (Duelli and Lazebnik, 2000). In one of the experiments, we needed to monitor cells produced by fusion of normal and E1A-expressing cells. We used PEG to fuse normal human fibroblasts that expressed a puromycin-resistance gene (I0P cells) with fibroblasts that expressed both a hygromycin-resistance gene and E1A (IEH cells). As expected, I0P cells were killed by hygromycin and IEH cells by puromycin (Fig. 1 A). Therefore, we expected only hybrids produced by PEG to proliferate in the presence of both drugs. To our surprise, we found that the number of proliferating cells did not depend on the PEG treatment (Fig. 1 B). One possible explanation was that cells fused spontaneously. We were intrigued by this possibility because of the link between fusion and carcinogenesis, the numerous reports that cancer cell lines are inexplicably fusogenic (for review see Duelli and Lazebnik, 2003), our finding that transformed cells acquire resistance to anticancer agents through fusion to normal cells (Duelli and Lazebnik, 2000), and the observation that cells recovered from individual colonies vary widely in their properties (unpublished data).

Bottom Line: Amodel that explains both the origin and sporadic nature of cancer argues that cancer cells are a chance result of events that cause genomic and epigenetic variability.We also show that this virus can produce viable oncogenically transformed cells by fusing cells that are otherwise destined to die.Therefore, we argue that viruses can contribute to carcinogenesis by fusing cells.

View Article: PubMed Central - PubMed

Affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

ABSTRACT
Amodel that explains both the origin and sporadic nature of cancer argues that cancer cells are a chance result of events that cause genomic and epigenetic variability. The prevailing view is that these events are mutations that affect chromosome segregation or stability. However, genomic and epigenetic variability is also triggered by cell fusion, which is often caused by viruses. Yet, cells fused by viruses are considered harmless because they die. We provide evidence that a primate virus uses both viral and exosomal proteins involved in cell fusion to produce transformed proliferating human cells. Although normal cells indeed fail to proliferate after fusion, expression of an oncogene or a mutated tumor suppressor p53 in just one of the fusion partners is sufficient to produce heterogeneous progeny. We also show that this virus can produce viable oncogenically transformed cells by fusing cells that are otherwise destined to die. Therefore, we argue that viruses can contribute to carcinogenesis by fusing cells.

Show MeSH
Related in: MedlinePlus