Fusion between cancer cells and macrophages occurs in a murine model of spontaneous neu+ breast cancer without increasing its metastatic potential

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.

Cell fusion potentiates tumor heterogeneity and reveals circulating hybrid cells that correlate with stage and survival

“…Cell fusion between immune and neoplastic cells initiating tumorigenesis and affecting progression is an untested, century-old hypothesis ( 9 , 10 ) that has been only circumstantially examined ( 10 , 12 , 17 , 31 , 33 – 37 ). Reports of cells located in tumors containing components of both immune and neoplastic cells are increasingly frequent ( 1 , 10 – 13 , 16 , 17 , 19 , 35 , 38 – 44 ), although without strong evidence of etiologic mechanism or physiologic relevance. Early in vitro studies revealed that cell fusion hybrids displayed reduced cell doubling times relative to their genetic burden ( 45 ).…”

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

“…Although CD163 is primarily expressed on monocytes and macrophages it has been detected on tumor cells with high malignant potential. However, tumor cell lines do not express CD163, even after stimulation with macrophage activating cytokines, so it has been hypothesized that tumor cells fuse with macrophages becoming more genetically unstable and aggressive (110). Assessment of patient tissues with CD163-positive tumor cells correlated with higher tumor grade, invasiveness, radioresistance and poor progression free-and overall survival in melanoma (111), breast (54,112,113), CRC (113), renal cell (114), and gastric (115) carcinomas.…”

Cell Fusion in Human Cancer: The Dark Matter Hypothesis

“…In fact, there have been a plethora of in vitro and in vivo studies in the past decades demonstrating that tumor cells do fuse with normal cells, such as macrophages, fibroblasts, stromal cells or stem cells, thereby giving rise to viable proliferating TN-hybrid cells with properties that are linked with tumor progression including enhanced tumorigenic and metastatic capacity or enhanced drug resistance [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31]. Likewise, several studies have reported putative TN-hybrid cells in human cancers, in some cases comprising up to 40% of tumors [7,13,20,25,32,33,34,35,36,37,38,39,40,41,42].…”