Abstract
Cell fusion between neoplastic and normal cells has been suggested to play a role in the acquisition of a malignant phenotype. Several studies have pointed to the macrophage as the normal partner in this fusion, suggesting that the fused cells could acquire new invasive properties and become able to disseminate to distant organs. However, this conclusion is mainly based on studies with transplantable cell lines. We tested the occurrence of cell fusion in the MMTV-neu model of mouse mammary carcinoma. In the first approach, we generated aggregation chimeras between GFP/neu and RFP/neu embryos. Tumor cells would display both fluorescent proteins only if cell fusion with normal cells occurred. In addition, if cell fusion conferred a growth/dissemination advantage, cells with both markers should be detectable in lung metastases at increased frequency. We confirmed that fused cells are present at low but consistent levels in primary neoplasms and that the macrophage is the normal partner in the fusion events. Similar results were obtained using a second approach in which bone marrow from mice carrying the Cre transgene was transplanted into MMTV-neu/LoxP-tdTomato transgenic animals, in which the Tomato gene is activated only in the presence of CRE recombinase. However, no fused cells were detected in lung metastases in either model. We conclude that fusion between macrophages and tumor cells does not confer a selective advantage in our spontaneous model of breast cancer, although these data do not rule out a possible role in models in which an inflammation environment is prominent.
Highlights
Neoplastic transformation is a multistep process [1] there could be many roads to the acquisition of the full spectrum of malignancy
In addition to challenging genome integrity, cell fusion with normal cells could provide the neoplastic cells with a full spectrum of gene expression programs which could be the target of selection by the environment, leading to the acquisition of a full malignancy status, including the ability to metastatize
The approach initially used in our work is based on embryonic chimera production between a MMTV-neu mouse carrying a reporter gene and a normal mouse carrying a second reporter gene
Summary
Neoplastic transformation is a multistep process [1] there could be many roads to the acquisition of the full spectrum of malignancy. A distinct event which could potentially contribute to the acquisition of additional properties of the malignant cell is cell fusion. One mechanism by which cell fusion could increase the malignant potential is polyploidy, which can predispose of its own to aneuploidy, since an abnormal content of DNA is unstable [3] (and references therein). In addition to challenging genome integrity, cell fusion with normal cells could provide the neoplastic cells with a full spectrum of gene expression programs which could be the target of selection by the environment, leading to the acquisition of a full malignancy status, including the ability to metastatize
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