Oncotarget

Research Papers:

Fusion between M2-macrophages and cancer cells results in a subpopulation of radioresistant cells with enhanced DNA-repair capacity

Annelie Lindström, Kristine Midtbö, Lars-Gunnar Arnesson, Stina Garvin and Ivan Shabo _

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Oncotarget. 2017; 8:51370-51386. https://doi.org/10.18632/oncotarget.17986

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Abstract

Annelie Lindström1, Kristine Midtbö1, Lars-Gunnar Arnesson3, Stina Garvin2 and Ivan Shabo3,4,5

1Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, SE 581 85, Linköping, Sweden

2Department of Clinical Pathology, Department of Clinical and Experimental Medicine, Linköping University, SE 581 85, Linköping, Sweden

3Division of Surgery, Department of Clinical and Experimental Medicine, Linköping University, SE 581 85, Linköping, Sweden

4Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, SE 171 77, Stockholm, Sweden

5Department of Breast and Endocrine Surgery, Karolinska University Hospital, SE 171 76, Stockholm, Sweden

Correspondence to:

Ivan Shabo, email: Ivan.Shabo@ki.se

Keywords: cell fusion, M2-macrophage, radiotherapy, breast cancer, radioresistance

Received: March 06, 2017     Accepted: May 07, 2017     Published: May 18, 2017

ABSTRACT

Cell fusion is a natural biological process in normal development and tissue regeneration. Fusion between cancer cells and macrophages results in hybrids that acquire genetic and phenotypic characteristics from both maternal cells. There is a growing body of in vitro and in vivo data indicating that this process also occurs in solid tumors and may play a significant role in tumor progression. However, investigations of the response of macrophage:cancer cell hybrids to radiotherapy have been lacking. In this study, macrophage:MCF-7 hybrids were generated by spontaneous in vitro cell fusion. After irradiation, both hybrids and their maternal MCF-7 cells were treated with 0 Gy, 2.5 Gy and 5 Gy γ-radiation and examined by clonogenic survival and comet assays at three time points (0 h, 24 h, and 48 h). Compared to maternal MCF-7 cells, the hybrids showed increased survival fraction and plating efficiency (colony formation ability) after radiation. The hybrids developed less DNA-damage, expressed significantly lower residual DNA-damage, and after higher radiation dose showed less heterogeneity in DNA-damage compared to their maternal MCF-7 cells. To our knowledge this is the first study that demonstrates that macrophage:cancer cell fusion generates a subpopulation of radioresistant cells with enhanced DNA-repair capacity. These findings provide new insight into how the cell fusion process may contribute to clonal expansion and tumor heterogeneity. Furthermore, our results provide support for cell fusion as a mechanism behind the development of radioresistance and tumor recurrence.


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