Tumor-Cell-Macrophage Fusion Cells as Liquid Biomarkers and Tumor Enhancers in Cancer

Abstract

Although molecular mechanisms driving tumor progression have been extensively studied, the biological nature of the various populations of circulating tumor cells (CTCs) within the blood is still not well understood. Tumor cell fusion with immune cells is a longstanding hypothesis that has caught more attention in recent times. Specifically, fusion of tumor cells with macrophages might lead to the development of metastasis by acquiring features such as genetic and epigenetic heterogeneity, chemotherapeutic resistance, and immune tolerance. In addition to the traditional FDA-approved definition of a CTC (CD45-, EpCAM+, cytokeratins 8+, 18+ or 19+, with a DAPI+ nucleus), an additional circulating cell population has been identified as being potential fusions cells, characterized by distinct, large, polymorphonuclear cancer-associated cells with a dual epithelial and macrophage/myeloid phenotype. Artificial fusion of tumor cells with macrophages leads to migratory, invasive, and metastatic phenotypes. Further studies might investigate whether these have a potential impact on the immune response towards the cancer. In this review, the background, evidence, and potential relevance of tumor cell fusions with macrophages is discussed, along with the potential role of intercellular connections in their formation. Such fusion cells could be a key component in cancer metastasis, and therefore, evolve as a diagnostic and therapeutic target in cancer precision medicine.

Keywords: cancer; circulating tumor cells; fusion cells; liquid biomarkers.

Figure 1

Concepts of fusion between tumor cells and macrophages. It is hypothesized that tumor-associated M2-polarized macrophages (TAMs) fuse their membranes with tumor cells, forming a tumor–macrophage hybrid cell. These fusion cells are large, mononuclear/polynuclear, and express both epithelial and myeloid markers. Importantly, fusion cells exert pro-tumorigenic and pro-metastatic effects through the outlined mechanisms.

Figure 2

Illustration of partial cell fusion via tunneling nanotubes (TNTs) and permanent cell fusion. (up-arrow: increased capacity).

Figure 3

Fusion of tumor cells with macrophages might impact the immune response (Abbreviations: MDSC—myeloid-derived suppressor cell; NK—natural killer cell; Treg—regulatory T cell).