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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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Fusion activity is associated with exosomes. (A) Fusogenic activity is enriched by sequential centrifugation. Conditioned medium from IEH cells (S0) was sequentially centrifuged at 500, 16,000, 70,000, and 110,000 g. A pellet from each centrifugation was reconstituted and used in the fusion assay with I0 cells. (B) P70 obtained as in A was treated with trypsin or buffer (see Materials and methods), and the fusogenicity of the resulting preparations was determined as in A. (C) Electron micrograph of P70 from IEH cells. (D and E) P70 was fractionated by floating in a sucrose gradient, and the fractions were analyzed for CD81 (D) and in the fusion assay with I0 cells (E). (F) Exosomes from I0 cells are not fusogenic. Indicated concentrations of exosomes from either I0 or IEH cells were tested in the fusion assay with I0 cells. The experiments in A, B, and F were performed at least three times. The data in D and E are from one of three experiments, and the data in A and B are from the same experiment. The error bars in A, B, and F indicate SDs.
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fig2: Fusion activity is associated with exosomes. (A) Fusogenic activity is enriched by sequential centrifugation. Conditioned medium from IEH cells (S0) was sequentially centrifuged at 500, 16,000, 70,000, and 110,000 g. A pellet from each centrifugation was reconstituted and used in the fusion assay with I0 cells. (B) P70 obtained as in A was treated with trypsin or buffer (see Materials and methods), and the fusogenicity of the resulting preparations was determined as in A. (C) Electron micrograph of P70 from IEH cells. (D and E) P70 was fractionated by floating in a sucrose gradient, and the fractions were analyzed for CD81 (D) and in the fusion assay with I0 cells (E). (F) Exosomes from I0 cells are not fusogenic. Indicated concentrations of exosomes from either I0 or IEH cells were tested in the fusion assay with I0 cells. The experiments in A, B, and F were performed at least three times. The data in D and E are from one of three experiments, and the data in A and B are from the same experiment. The error bars in A, B, and F indicate SDs.

Mentions: Consistent with the second possibility, tissue culture medium conditioned by IEH cells fused I0P cells and several other cell lines that we tested, whereas the medium conditioned by I0P cells did not (Fig. 1 E and not depicted). Enriching the fusogenic activity by filtration and sequential centrifugation yielded a preparation we called P70 (Fig. 2 A) and indicated that the fusogen was 100–200 nm in size. Because trypsin treatment of the P70 abolished the fusogenicity (Fig. 2 B), we identified the digested peptides by mass spectrometry. About half of the reliably identified proteins were reported as components of exosomes (Table S1, available at http://www.jcb.org/cgi/content/full/jcb.200507069/DC1).


A primate virus generates transformed human cells by fusion.

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

Fusion activity is associated with exosomes. (A) Fusogenic activity is enriched by sequential centrifugation. Conditioned medium from IEH cells (S0) was sequentially centrifuged at 500, 16,000, 70,000, and 110,000 g. A pellet from each centrifugation was reconstituted and used in the fusion assay with I0 cells. (B) P70 obtained as in A was treated with trypsin or buffer (see Materials and methods), and the fusogenicity of the resulting preparations was determined as in A. (C) Electron micrograph of P70 from IEH cells. (D and E) P70 was fractionated by floating in a sucrose gradient, and the fractions were analyzed for CD81 (D) and in the fusion assay with I0 cells (E). (F) Exosomes from I0 cells are not fusogenic. Indicated concentrations of exosomes from either I0 or IEH cells were tested in the fusion assay with I0 cells. The experiments in A, B, and F were performed at least three times. The data in D and E are from one of three experiments, and the data in A and B are from the same experiment. The error bars in A, B, and F indicate SDs.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2171256&req=5

fig2: Fusion activity is associated with exosomes. (A) Fusogenic activity is enriched by sequential centrifugation. Conditioned medium from IEH cells (S0) was sequentially centrifuged at 500, 16,000, 70,000, and 110,000 g. A pellet from each centrifugation was reconstituted and used in the fusion assay with I0 cells. (B) P70 obtained as in A was treated with trypsin or buffer (see Materials and methods), and the fusogenicity of the resulting preparations was determined as in A. (C) Electron micrograph of P70 from IEH cells. (D and E) P70 was fractionated by floating in a sucrose gradient, and the fractions were analyzed for CD81 (D) and in the fusion assay with I0 cells (E). (F) Exosomes from I0 cells are not fusogenic. Indicated concentrations of exosomes from either I0 or IEH cells were tested in the fusion assay with I0 cells. The experiments in A, B, and F were performed at least three times. The data in D and E are from one of three experiments, and the data in A and B are from the same experiment. The error bars in A, B, and F indicate SDs.
Mentions: Consistent with the second possibility, tissue culture medium conditioned by IEH cells fused I0P cells and several other cell lines that we tested, whereas the medium conditioned by I0P cells did not (Fig. 1 E and not depicted). Enriching the fusogenic activity by filtration and sequential centrifugation yielded a preparation we called P70 (Fig. 2 A) and indicated that the fusogen was 100–200 nm in size. Because trypsin treatment of the P70 abolished the fusogenicity (Fig. 2 B), we identified the digested peptides by mass spectrometry. About half of the reliably identified proteins were reported as components of exosomes (Table S1, available at http://www.jcb.org/cgi/content/full/jcb.200507069/DC1).

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