Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Imaging innate immune responses at tumour initiation: new insights from fish and flies

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Translucent models of immune cell–cancer cell interactions.
Figure 2: Using zebrafish to investigate immune cell–cancer cell interactions.

Similar content being viewed by others

References

  1. Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).

    Article  CAS  Google Scholar 

  2. Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

    Article  CAS  Google Scholar 

  3. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  Google Scholar 

  4. 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).

    Article  CAS  Google Scholar 

  5. Freisinger, C. M. & Huttenlocher, A. Live imaging and gene expression analysis in zebrafish identifies a link between neutrophils and epithelial to mesenchymal transition. PLoS ONE 9, e112183 (2014).

    Article  Google Scholar 

  6. Keightley, M. C., Wang, C. H., Pazhakh, V. & Lieschke, G. J. Delineating the roles of neutrophils and macrophages in zebrafish regeneration models. Int. J. Biochem. Cell Biol. 56, 92–106 (2014).

    Article  CAS  Google Scholar 

  7. Evans, I. R. & Wood, W. Drosophila embryonic hemocytes. Curr. Biol. 21, R173–R174 (2011).

    Article  CAS  Google Scholar 

  8. Pastor-Pareja, J. C., Wu, M. & Xu, T. An innate immune response of blood cells to tumors and tissue damage in Drosophila. Dis. Model. Mech. 1, 144–154; discussion 153 (2008).

    Article  Google Scholar 

  9. Niethammer, P., Grabher, C., Look, A. T. & Mitchison, T. J. A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature 459, 996–999 (2009).

    Article  CAS  Google Scholar 

  10. Moreira, S., Stramer, B., Evans, I., Wood, W. & Martin, P. Prioritization of competing damage and developmental signals by migrating macrophages in the Drosophila embryo. Curr. Biol. 20, 464–470 (2010).

    Article  CAS  Google Scholar 

  11. Yoo, S. K., Starnes, T. W., Deng, Q. & Huttenlocher, A. Lyn is a redox sensor that mediates leukocyte wound attraction in vivo. Nature 480, 109–112 (2011).

    Article  CAS  Google Scholar 

  12. de Oliveira, S., Boudinot, P., Calado, A. & Mulero, V. Duox1-derived H2O2 modulates Cxcl8 expression and neutrophil recruitment via JNK/c-JUN/AP-1 signaling and chromatin modifications. J. Immunol. 194, 1523–1533 (2015).

    Article  CAS  Google Scholar 

  13. Razzell, W., Evans, I. R., Martin, P. & Wood, W. Calcium flashes orchestrate the wound inflammatory response through DUOX activation and hydrogen peroxide release. Curr. Biol. 23, 424–429 (2013).

    Article  CAS  Google Scholar 

  14. de Oliveira, S. et al. ATP modulates acute inflammation in vivo through dual oxidase 1-derived H2O2 production and NF-κB activation. J. Immunol. 192, 5710–5719 (2014).

    Article  CAS  Google Scholar 

  15. Enyedi, B., Kala, S., Nikolich-Zugich, T. & Niethammer, P. Tissue damage detection by osmotic surveillance. Nat. Cell Biol. 15, 1123–1130 (2013).

    Article  CAS  Google Scholar 

  16. Adachi, Y. et al. Oncogenic Ras upregulates NADPH oxidase 1 gene expression through MEK-ERK-dependent phosphorylation of GATA-6. Oncogene 27, 4921–4932 (2008).

    Article  CAS  Google Scholar 

  17. Vafa, O. et al. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol. Cell 9, 1031–1044 (2002).

    Article  CAS  Google Scholar 

  18. Myant, K. B. et al. ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell 12, 761–773 (2013).

    Article  CAS  Google Scholar 

  19. Ogrunc, M. et al. Oncogene-induced reactive oxygen species fuel hyperproliferation and DNA damage response activation. Cell Death Differ. 21, 998–1012 (2014).

    Article  CAS  Google Scholar 

  20. Gaudet, A. D. & Popovich, P. G. Extracellular matrix regulation of inflammation in the healthy and injured spinal cord. Exp. Neurol. 258, 24–34 (2014).

    Article  CAS  Google Scholar 

  21. Mollen, K. P. et al. Systemic inflammation and end organ damage following trauma involves functional TLR4 signaling in both bone marrow-derived cells and parenchymal cells. J. Leukoc. Biol. 83, 80–88 (2008).

    Article  CAS  Google Scholar 

  22. Srivastava, A., Pastor-Pareja, J. C., Igaki, T., Pagliarini, R. & Xu, T. Basement membrane remodeling is essential for Drosophila disc eversion and tumor invasion. Proc. Natl Acad. Sci. USA 104, 2721–2726 (2007).

    Article  CAS  Google Scholar 

  23. Morin, X., Daneman, R., Zavortink, M. & Chia, W. A protein trap strategy to detect GFP-tagged proteins expressed from their endogenous loci in Drosophila. Proc. Natl Acad. Sci. USA 98, 15050–15055 (2001).

    Article  CAS  Google Scholar 

  24. Cordero, J. B. et al. Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev. Cell 18, 999–1011 (2010).

    Article  CAS  Google Scholar 

  25. Bald, T. et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507, 109–113 (2014).

    Article  CAS  Google Scholar 

  26. Kuang, D. M. et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J. Hepatol. 54, 948–955 (2011).

    Article  CAS  Google Scholar 

  27. Yan, C., Huo, X., Wang, S., Feng, Y. & Gong, Z. Stimulation of hepatocarcinogenesis by neutrophils upon induction of oncogenic kras expression in transgenic zebrafish. J. Hepatol. 63, 420–428 (2015).

    Article  CAS  Google Scholar 

  28. Chauveau, A., Aucher, A., Eissmann, P., Vivier, E. & Davis, D. M. Membrane nanotubes facilitate long-distance interactions between natural killer cells and target cells. Proc. Natl Acad. Sci. USA 107, 5545–5550 (2010).

    Article  CAS  Google Scholar 

  29. Ahmed, K. A., Munegowda, M. A., Xie, Y. & Xiang, J. Intercellular trogocytosis plays an important role in modulation of immune responses. Cell. Mol. Immunol. 5, 261–269 (2008).

    Article  CAS  Google Scholar 

  30. Feng, Y., Renshaw, S. & Martin, P. Live imaging of tumor initiation in zebrafish larvae reveals a trophic role for leukocyte-derived PGE2 . Curr. Biol. 22, 1253–1259 (2012).

    Article  CAS  Google Scholar 

  31. Goessling, W. et al. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. Cell 136, 1136–1147 (2009).

    Article  CAS  Google Scholar 

  32. North, T. E. et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 447, 1007–1011 (2007).

    Article  CAS  Google Scholar 

  33. Hsueh, Y. C., Wu, J. M., Yu, C. K., Wu, K. K. & Hsieh, P. C. Prostaglandin E2 promotes post-infarction cardiomyocyte replenishment by endogenous stem cells. EMBO Mol. Med. 6, 496–503 (2014).

    Article  CAS  Google Scholar 

  34. Fan, Y. Y., Davidson, L. A., Callaway, E. S., Goldsby, J. S. & Chapkin, R. S. Differential effects of 2- and 3-series E-prostaglandins on in vitro expansion of Lgr5+ colonic stem cells. Carcinogenesis 35, 606–612 (2014).

    Article  CAS  Google Scholar 

  35. Thorat, M. A. & Cuzick, J. Role of aspirin in cancer prevention. Curr. Oncol. Rep. 15, 533–540 (2013).

    Article  CAS  Google Scholar 

  36. Kwon, O. J., Zhang, L., Ittmann, M. M. & Xin, L. Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin. Proc. Natl Acad. Sci. USA 111, E592–E600 (2014).

    Article  CAS  Google Scholar 

  37. Schafer, M. & Werner, S. Cancer as an overhealing wound: an old hypothesis revisited. Nat. Rev. Mol. Cell Biol. 9, 628–638 (2008).

    Article  CAS  Google Scholar 

  38. Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    Article  CAS  Google Scholar 

  39. Hauling, T. et al. A Drosophila immune response against Ras-induced overgrowth. Biol. Open 3, 250–260 (2014).

    Article  CAS  Google Scholar 

  40. Guo, C., Buranych, A., Sarkar, D., Fisher, P. B. & Wang, X. Y. The role of tumor-associated macrophages in tumor vascularization. Vasc. Cell 5, 20 (2013).

    Article  Google Scholar 

  41. Arwert, E. N., Hoste, E. & Watt, F. M. Epithelial stem cells, wound healing and cancer. Nat. Rev. Cancer 12, 170–180 (2012).

    Article  CAS  Google Scholar 

  42. Antonio, N. et al. The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer. EMBO J. 34, 2219–2236 (2015).

    Article  CAS  Google Scholar 

  43. Naumov, G. N., Folkman, J. & Straume, O. Tumor dormancy due to failure of angiogenesis: role of the microenvironment. Clin. Exp. Metastasis 26, 51–60 (2009).

    Article  Google Scholar 

  44. Forget, P. et al. Do intraoperative analgesics influence breast cancer recurrence after mastectomy? A retrospective analysis. Anesth. Analg. 110, 1630–1635 (2010).

    Article  CAS  Google Scholar 

  45. Maletzki, C., Klier, U., Obst, W., Kreikemeyer, B. & Linnebacher, M. Reevaluating the concept of treating experimental tumors with a mixed bacterial vaccine: Coley's toxin. Clin. Dev. Immunol. 2012, 230625 (2012).

    Article  CAS  Google Scholar 

  46. Suttmann, H. et al. Neutrophil granulocytes are required for effective Bacillus Calmette-Guerin immunotherapy of bladder cancer and orchestrate local immune responses. Cancer Res. 66, 8250–8257 (2006).

    Article  CAS  Google Scholar 

  47. Schiavone, M. et al. Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer. Dis. Model. Mech. 7, 883–894 (2014).

    Article  Google Scholar 

  48. Ramezani, T., Laux, D. W., Bravo, I. R., Tada, M. & Feng, Y. Live imaging of innate immune and preneoplastic cell interactions using an inducible Gal4/UAS expression system in larval zebrafish skin. J. Vis. Exp. http://dx.doi.org/10.3791/52107 (2015).

  49. Gil-Bernabe, A. M. et al. Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood 119, 3164–3175 (2012).

    Article  CAS  Google Scholar 

  50. Davidowitz, R. A. et al. Mesenchymal gene program-expressing ovarian cancer spheroids exhibit enhanced mesothelial clearance. J. Clin. Invest. 124, 2611–2625 (2014).

    Article  CAS  Google Scholar 

  51. Page, D. M. et al. An evolutionarily conserved program of B-cell development and activation in zebrafish. Blood 122, e1–e11 (2013).

    Article  CAS  Google Scholar 

  52. Langenau, D. M. et al. In vivo tracking of T cell development, ablation, and engraftment in transgenic zebrafish. Proc. Natl Acad. Sci. USA 101, 7369–7374 (2004).

    Article  CAS  Google Scholar 

  53. Richardson, R. et al. Adult zebrafish as a model system for cutaneous wound-healing research. J. Invest. Dermatol. 133, 1655–1665 (2013).

    Article  CAS  Google Scholar 

  54. Zhang, L. et al. An optical platform for cell tracking in adult zebrafish. Cytometry A 81, 176–182 (2012).

    Article  Google Scholar 

  55. Shan, H., Liang, Y., Wang, J. & Li, Y. Study on application of optical clearing technique in skin diseases. J. Biomed. Opt. 17, 115003 (2012).

    Article  Google Scholar 

  56. Hickman, J. A. et al. Three-dimensional models of cancer for pharmacology and cancer cell biology: capturing tumor complexity in vitro/ex vivo. Biotechnol. J. 9, 1115–1128 (2014).

    Article  CAS  Google Scholar 

  57. Boimel, P. J. et al. Contribution of CXCL12 secretion to invasion of breast cancer cells. Breast Cancer Res. 14, R23 (2012).

    Article  CAS  Google Scholar 

  58. Lohela, M. et al. Intravital imaging reveals distinct responses of depleting dynamic tumor-associated macrophage and dendritic cell subpopulations. Proc. Natl Acad. Sci. USA 111, E5086–E5095 (2014).

    Article  CAS  Google Scholar 

  59. Kajita, M. et al. Interaction with surrounding normal epithelial cells influences signalling pathways and behaviour of Src-transformed cells. J. Cell Sci. 123, 171–180 (2010).

    Article  CAS  Google Scholar 

  60. Kajita, M. et al. Filamin acts as a key regulator in epithelial defence against transformed cells. Nat. Commun. 5, 4428 (2014).

    Article  CAS  Google Scholar 

  61. Gu, Y., Forostyan, T., Sabbadini, R. & Rosenblatt, J. Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway. J. Cell Biol. 193, 667–676 (2011).

    Article  CAS  Google Scholar 

  62. Slattum, G. M. & Rosenblatt, J. Tumour cell invasion: an emerging role for basal epithelial cell extrusion. Nat. Rev. Cancer 14, 495–501 (2014).

    Article  CAS  Google Scholar 

  63. de Beco, S., Ziosi, M. & Johnston, L. A. New frontiers in cell competition. Dev. Dyn. 241, 831–841 (2012).

    Article  Google Scholar 

  64. Bondar, T. & Medzhitov, R. p53-mediated hematopoietic stem and progenitor cell competition. Cell Stem Cell 6, 309–322 (2010).

    Article  CAS  Google Scholar 

  65. Teng, Y. et al. Evaluating human cancer cell metastasis in zebrafish. BMC Cancer 13, 453 (2013).

    Article  Google Scholar 

  66. Wang, J. et al. Novel mechanism of macrophage-mediated metastasis revealed in a zebrafish model of tumor development. Cancer Res. 75, 306–315 (2015).

    Article  CAS  Google Scholar 

  67. Tang, Q. et al. Optimized cell transplantation using adult rag2 mutant zebrafish. Nat. Methods 11, 821–824 (2014).

    Article  CAS  Google Scholar 

  68. Tipping, M. & Perrimon, N. Drosophila as a model for context-dependent tumorigenesis. J. Cell. Physiol. 229, 27–33 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. White, R., Rose, K. & Zon, L. Zebrafish cancer: the state of the art and the path forward. Nat. Rev. Cancer 13, 624–636 (2013).

    Article  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Yi Feng or Paul Martin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

PowerPoint slides

Glossary

Adaptive immune cells

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

(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

(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

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

Primarily neutrophils and macrophages that contribute to the inflammatory response.

Matrix metalloproteinase 1

(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

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

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3979

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer