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.
Highlights
Cancer progression and metastasis are highly complex processes consisting of significant molecular changes [1]
Circulating tumor cells (CTCs) are cancer cells that are shed from a primary tumor into the vasculature, circulate throughout the body, have the potential to settle in distant organs and develop into solid organ tumor metastases that are responsible for most cancer-associated deaths [2]
Recent reports on circulating cancer-associated cells with dual epithelial and macrophage/myeloid phenotypes, combined with genetic analyses, have supported the idea that fusion events between tumor cells and macrophages might have a critical role in tumor progression, development of metastatic disease, and poor outcome for cancer patients [12,15,16,17,18,19,20,21,22]
Summary
Cancer progression and metastasis are highly complex processes consisting of significant molecular changes [1]. In addition to potential complexity, high cost, and single time-point limitations of the typical tissue biopsy, treatment responses, and monitoring are exclusively based on costly and indirect image interpretation that includes radiation exposure to the patient To address these risks and limitations, liquid biomarkers such as CTCs detected via peripheral blood draws are a unique opportunity to characterize tumor biology and personalize clinical treatment decisions by analyzing whole tumor cells in real-time. A CTC has been defined as having a well-defined 4 ,6-diamidino-2-phenylindole (DAPI)+ nucleus that expresses cytokeratin (CK) 8/18 and/or 19 and EpCAM (epithelial cell markers), but distinctively lacks the expression of CD45 (a pan-leukocyte marker) [3] This rather broad definition has been shown to be incomplete as potentially highly relevant circulating cancer-associated cells might lack EpCAM, or even co-express CD45 and other macrophage/myeloid or stem-cell markers [4,5,6,7,8] (Table 1). EpCAM+/CK+, CD45-, DAPI,
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