Abstract
Recent imaging studies in genetically tractable and translucent zebrafish and Drosophila melanogaster models have opened a window on the earliest stages of tumorigenesis, when pre-neoplastic cells first arise in tissues before they progress into full-blown cancers. Innate immune cells often find these cells soon after they develop, but this efficient surveillance is not always good for the host because although immune cells have phagocytic capacity, they can also nurture the growing clones of pre-neoplastic cells. We describe these newly observed early interactions between immune cells and cancer cells and speculate on their potential clinical implications.
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Acknowledgements
The authors thank members of their laboratories for advice and thoughts during the writing of this article, and M. Vidal for the image of a Drosophila melanogaster imaginal disc. The laboratory of Y.F. is funded by a Wellcome Trust Sir Henry Dale Fellowship; the laboratory of P.M. is funded by a Wellcome Trust Investigator award, and project grants from Cancer Research UK programme and the Biotechnology and Biological Sciences Research Council (BBSRC).
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Supplementary information
Supplementary information S1 (movie)
A neutrophil (red) glides beneath a pre-neoplastic goblet cell (green) as it undergoes division. (MOV 2316 kb)
Supplementary information S2 (movie)
A neutrophil (red) captured as it takes up several patches of membrane from the surface of a pre-neoplastic cell (green) – similar to a movie published in the below reference (reference 4 in main text). Feng, Y., Santoriello, C., Mione, M., Hurlstone, A. & Martin, P. Live imaging of innate immune cell sensing of transformed cells in zebrafish larvae: parallels between tumor initiation and wound inflammation. PLoS Biol 8, e1000562 (2010). (MOV 7002 kb)
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Glossary
- Adaptive immune cells
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T cells and B cells that promote cell-mediated immunity (T cells) and humoral antibody-mediated immunity (B cells). Adaptive immunity is an antigen-specific response.
- Damage-associated molecular pattern molecules
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(DAMPs). Molecules that are released at sites of cell damage, and can be full proteins, such as high mobility group box 1 (HMGB1), cleaved extracellular matrix components, DNA or RNA, or even small molecules, including ATP.
- Dual oxidase
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(DUOX). A member of the family of reactive oxygen species (ROS)-generating NADPH oxidases. In humans, DUOX1 and DUOX2 are largely expressed by wet epithelia. Zebrafish has only one DUOX homologue and it is mainly localized to wet epithelia.
- Granulation tissue
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Formed during the tissue repair process; composed of mixed cell and tissue types, including new blood vessels, fibroblasts, newly deposited extracellular matrix, and immune cells.
- Innate immune cells
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Primarily neutrophils and macrophages that contribute to the inflammatory response.
- Matrix metalloproteinase 1
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(MMP1). One of the members of the MMP family, which are key players in matrix remodelling — for example, during wound healing — and operate by clipping various extracellular matrix and other molecules at key motifs.
- Neutrophil and macrophage phenotypic switching
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Neutrophils and macrophages are two leukocyte lineages known to switch from a pro-inflammatory (N1 or M1) phenotype to a pro-healing/tumorigenic (N2 or M2) phenotype, according to the signals that they receive.
- Wet epithelium
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Epithelial tissues that contain mucus-secreting cells, which provide a mucus layer that retains water; wet epithelial tissues include lung epithelium and gut epithelium, and in zebrafish, the skin as well.
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Feng, Y., Martin, P. Imaging innate immune responses at tumour initiation: new insights from fish and flies. Nat Rev Cancer 15, 556–562 (2015). https://doi.org/10.1038/nrc3979
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DOI: https://doi.org/10.1038/nrc3979
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