Macrophage traits in cancer cells are induced by macrophage-cancer cell fusion and cannot be explained by cellular interaction

Abstract

BackgroundCell fusion is a natural process in normal development and tissue regeneration. Fusion between cancer cells and macrophages generates metastatic hybrids with genetic and phenotypic characteristics from both maternal cells. However, there are no clinical markers for detecting cell fusion in clinical context. Macrophage-specific antigen CD163 expression in tumor cells is reported in breast and colorectal cancers and proposed being caused by macrophages-cancer cell fusion in tumor stroma. The purpose of this study is to examine the cell fusion process as a biological explanation for macrophage phenotype in breast.MethodsMonocytes, harvested from male blood donor, were activated to M2 macrophages and co-cultured in ThinCert transwell system with GFP-labeled MCF-7 cancer cells. MCF7/macrophage hybrids were generated by spontaneous cell fusion, isolated by fluorescence-activated cell sorting and confirmed by fluorescence microscopy, short tandem repeats analysis and flow cytometry. CD163 expression was evaluated in breast tumor samples material from 127 women by immunohistochemistry.ResultsMCF-7/macrophage hybrids were generated spontaneously at average rate of 2 % and showed phenotypic and genetic traits from both maternal cells. CD163 expression in MCF-7 cells could not be induced by paracrine interaction with M2-activated macrophages. CD163 positive cancer cells in tumor sections grew in clonal collection and a cutoff point >25 % of positive cancer cells was significantly correlated to disease free and overall survival.ConclusionsIn conclusion, macrophage traits in breast cancer might be caused by cell fusion rather than explained by paracrine cellular interaction. These data provide new insights into the role of cell fusion in breast cancer and contributes to the development of clinical markers to identify cell fusion.

Tumor cell expression of CD163 is associated to postoperative radiotherapy and poor prognosis in patients with breast cancer treated with breast-conserving surgery

“…This phenomenon is a more efficient mechanism of DNA-exchange and cellular reprogramming than the accumulation of mutations in single cells (Bastida-Ruiz et al 2016; Dittmar et al 2013; Duelli and Lazebnik 2003). Growing in vitro (Busund et al 2002, 2003; Shabo et al 2015; Wei et al 2014), in vivo (Powell et al 2011; Silk et al 2013), and clinical (LaBerge et al 2017; Lazova et al 2013; Yilmaz et al 2005) data indicate that this process occurs in solid tumors and may play a significant role in clinical tumor progression. Moreover, this process generates malignant cell clones (hybrids) with reduced susceptibility to oncological treatments (Carloni et al 2013; Nagler et al 2011; Wang et al 2012; Yang et al 2010).…”

“…In a recent study, we showed that macrophage:MCF-7 hybrids can be generated spontaneously at an average rate of 2% (Shabo et al 2015). One gram of tumor mass is assumed to contain approximately 1 × 10 8 tumor cells (Del Monte 2009), suggesting theoretically that each gram of breast cancer tissue may potentially generate approximately 2 million hybrid cells.…”

Immune Selection Pressure Contributes to Pancreatic Cancer Immune Evasion

“…The myeloid mimicry phenomenon in cancer cells has been reported previously in several cancer entities, including breast cancer, colorectal cancer and pancreatic cancer, and it is associated with advanced disease and worse outcomes (21)(22)(23). Some studies determined that the expression of myeloid markers by cancer cells was a result of cancer cell-immune cell fusion, and thus created hybrids that express characteristics of both cellular origins (24)(25)(26). In our study, we determined that FACS-sorted malignant epithelial cells and murine KPC cell lines express chemokine (C-C motif) ligand 9 (CCL9), arginase 1 (ARG1), and cluster of differentiation 68 (CD68), but do not express CD45, the transmembrane protein expressed by all hematopoietic cells, suggesting that the myeloid mimicry phenomenon we reported here is not a consequence of cell fusion.…”

Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer

“…Cell fusion is a natural biological process in normal development and tissue regeneration (207,208). Fusion between cancer cells and macrophages results in hybrids that acquire genetic and phenotypic characteristics from both maternal cells (129,139,209). 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 (133,134,138,139,210,211).…”

“…Based on the cell fusion theory, it has been suggested that macrophage phenotype in cancer cells might be caused by fusion between tumor-associated macrophages (TAM) and cancer cells (129,138,139).…”