Abstract
This perspective article highlights the leukocyte-cancer cell hybrid theory as a mechanism for cancer metastasis. Beginning from the first proposal of the theory more than a century ago and continuing today with the first proof for this theory in a human cancer, the hybrid theory offers a unifying explanation for metastasis. In this scenario, leukocyte fusion with a cancer cell is a secondary disease superimposed upon the early tumor, giving birth to a new, malignant cell with a leukocyte-cancer cell hybrid epigenome.
Highlights
Background and Research ResultsThe cancer cell fusion theoryIn 1911, Prof
Hybrid clones with the highest rate of metastasis expressed high levels of melanin production[8] and autophagy[10]. Underlying this phenotype was the expression of a macrophage-like glycosylation pattern, most notably an increase in oligosaccharide chains conjugated with β1,6-branched oligosaccharides and the responsible glucosyltransferase, β1,6N-acetylglucosaminyltransferase (GNT-V; E.C.2.4.1.155)[10,11]
In other systems, when fluorescently labeled mouse bone marrow–derived cells were introduced into mice, macrophagecancer cell hybrids exhibiting gene expression patterns that are
Summary
At the time of Aichel’s proposal, there was no knowledge of DNA-based genetics and no experimental model to test, and for decades the literature was silent. Our first step was to experimentally fuse normal mouse or human macrophages with mouse Cloudman S91 melanoma cells that are only weakly metastatic[8] The majority of these hybrid clones showed markedly enhanced chemotactic motility toward a variety of attractants in two-chambered culture systems, a hallmark of metastatic cells[9]. Hybrid clones with the highest rate of metastasis expressed high levels of melanin production (see the darker bars in Figure 2)[8] and autophagy[10] Underlying this phenotype was the expression of a macrophage-like glycosylation pattern, most notably an increase in oligosaccharide chains conjugated with β1,6-branched oligosaccharides and the responsible glucosyltransferase, β1,6N-acetylglucosaminyltransferase (GNT-V; E.C.2.4.1.155)[10,11]. In other systems, when fluorescently labeled mouse bone marrow–derived cells were introduced into mice, macrophagecancer cell hybrids exhibiting gene expression patterns that are
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