Macrophage-Tumor Cell Fusions from Peripheral Blood of Melanoma Patients

• DOI: 10.1371/journal.pone.0134320
• Publication Date: 2015-08-12T18:18:38Z
• Authors: Gary A. Clawson; Gail L. Matters; Ping Xin; Yuka Imamura-Kawa...; Zhen Du; Diane M. Thiboutot; Klaus F. Helm; Rogerio I. Neves; Thomas Abraham
• Keywords: ALCAM; Immunophenotyping; CD68

Background While the morbidity and mortality from cancer are largely attributable to its metastatic dissemination, integral features of cascade not well understood. The widely accepted hypothesis is that primary tumor microenvironment induces epithelial-to-mesenchymal transition in cells, facilitating their escape into bloodstream, possibly accompanied by stem cells. An alternative theory for metastasis involves fusion macrophages with cells (MTFs). Here we culture characterize apparent MTFs blood melanoma patients. Methods We isolated enriched CTC populations peripheral samples patients, cultured them. interrogated these characteristic BRAF mutations, used confocal microscopy immunophenotyping, motility, DNA content chromatin texture analyses, then conducted xenograft studies using nude mice. Findings Morphologically, were generally large many pseudopod extensions lamellipodia. Ultrastructurally, appeared be macrophages. They rich mitochondria lysosomes, as melanosomes. MTF all heterogeneous regard content, containing aneuploid and/or high-ploidy they typically showed sheets (and/or clumps) cytoplasmic chromatin. This was found within heterogeneously-sized autophagic vacuoles, which prominently contained micronuclei. Cultured uniformly expressed pan-macrophage markers (CD14, CD68) macrophage indicative M2 polarization (CD163, CD204, CD206). also melanocyte-specific (ALCAM, MLANA), epithelial biomarkers (KRT, EpCAM), pro-carcinogenic cytokine MIF along functionally related cell (CXCR4, CD44). cultures individual patients (5 8) melanoma-specific activating mutations. Chromatin analysis deconvoluted images condensed (DAPI-intense) regions similar focal described fusions. readily vivo human melanomas examined, often exhibiting even higher than MTFs. When transplanted subcutaneously mice, disseminated produced lesions at distant sites. Conclusions Hypothesis Apparent present cutaneous melanomas, possess ability form when hypothesize arise periphery tumors vivo, enter bloodstream invade tissues, secreting cytokines (such MIF) prepare "niches" colonization initiating