Abstract
There is a long history of literature suggesting parallels between wound healing and cancer growth, and similarly, much anecdotal evidence that tissue damage may impact on the growth and progression of cancers. In our recent studies we have investigated the association between wound-induced inflammation, as might be triggered post biopsy or surgery, and the subsequent proliferation and migratory tumour cell characteristics in zebrafish and human ulcerated melanoma. The translucent zebrafish allowed us to live visualise the behaviour of inflammatory cells around a wound, which we made in the vicinity of clones of early pre-neoplastic cells. These studies showed that neutrophils and macrophages are sequentially recruited to sites of tissue wounding, and subsequently distracted from the wound by competing attractants from the nearby pre-neoplastic cells. The interaction between inflammatory cells, largely neutrophils, and pre-neoplastic cells directly led to increased proliferation of the pre-neoplastic cells, through release of trophic/growth factors including prostaglandin (PGE2). Complementary clinical data showed that the density of infiltrating neutrophils correlates with increasing size of wound, in this instance extent of ulceration, and with tumour-cell proliferation in human melanoma, whilst there was no correlation between infiltrating macrophages and proliferation or prognosis. In addition to the demonstrated inflammation induced tumour-cell proliferation we showed an independent prognostic link between neutrophil influx and melanoma specific survival, supporting the hypothesis that wound-induced inflammation may be detrimental to patient survival. Reactivation of developmental and migratory cell behaviours of melanocytes may be an essential link between inflammation and tumour progression, equivalent to what is conventionally described as epithelial to mesenchymal transition (EMT) in epithelial-derived tumours. In what has been found from zebrafish studies, both melanoblasts and mature melanocytes migrate towards sites of tissue wounding, under the influence of innate immune cells. In ulcerated melanomas, the infiltration of neutrophils in ulcerated areas is associated with migratory tumour cell characteristics such as spindle shaped morphology and loss of e-cadherin expression and extravascular migratory metastasis (angiotropism), linking inflammation to a pro-migratory microenvironment.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Martin P, Leibovich SJ (2005) Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol 15(11):599–607
Wilgus TA, Roy S, McDaniel JC (2013) Neutrophils and wound repair: positive actions and negative reactions. Adv Wound Care (New Rochelle) 2(7):379–388
Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315(26):1650–1659
Ceol CJ, Houvras Y, White RM, Zon LI (2008) Melanoma biology and the promise of zebrafish. Zebrafish 5(4):247–255
Martin P, Feng Y (2009) Inflammation: wound healing in zebrafish. Nature 459(7249):921–923
White R, Rose K, Zon L (2013) Zebrafish cancer: the state of the art and the path forward. Nat Rev Cancer 13(9):624–636
Feng Y, Santoriello C, Mione M, Hurlstone A, Martin P (2010) Live imaging of innate immune cell sensing of transformed cells in zebrafish larvae: parallels between tumor initiation and wound inflammation. PLoS Biol 8(12):e1000562
Feng Y, Renshaw S, Martin P (2012) Live imaging of tumor initiation in zebrafish larvae reveals a trophic role for leukocyte-derived PGE(2). Curr Biol 22(13):1253–1259
Jensen TO, Schmidt H, Moller HJ, Hoyer M, Maniecki MB, Sjoegren P et al (2009) Macrophage markers in serum and tumor have prognostic impact in American Joint Committee on Cancer stage I/II melanoma. J Clin Oncol 27(20):3330–3337
Jensen TO, Schmidt H, Moller HJ, Donskov F, Hoyer M, Sjoegren P et al (2012) Intratumoral neutrophils and plasmacytoid dendritic cells indicate poor prognosis and are associated with pSTAT3 expression in AJCC stage I/II melanoma. Cancer 118(9):2476–2485
Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66(2):605–612
Bonnelykke-Behrndtz ML, Schmidt H, Christensen IJ, Damsgaard TE, Moller HJ, Bastholt L et al (2014) Prognostic stratification of ulcerated melanoma: not only the extent matters. Am J Clin Pathol 142(6):845–856
Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119(6):1420–1428
Kalluri R (2009) EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 119(6):1417–1419
Nunan R, Campbell J, Mori R, Pitulescu ME, Jiang WG, Harding KG et al (2015) Ephrin-Bs Drive Junctional Downregulation and actin stress fiber disassembly to enable wound re-epithelialization. Cell Rep 13(7):1380–1395
Lopez-Novoa JM, Nieto MA (2009) Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med 1(6–7):303–314
Levesque M, Feng Y, Jones RA, Martin P (2013) Inflammation drives wound hyperpigmentation in zebrafish by recruiting pigment cells to sites of tissue damage. Dis Model Mech 6(2):508–515
Bønnelykke-Behrndtz ML et al (2017) Loss of E-cadherin as part of a migratory phenotype in melanoma is associated with ulceration. Am J Dermatopathol. doi:10.1097/DAD.0000000000000750
Bonde AK, Tischler V, Kumar S, Soltermann A, Schwendener RA (2012) Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors. BMC Cancer 12:35, 2407-12-35
Grosse-Steffen T, Giese T, Giese N, Longerich T, Schirmacher P, Hansch GM et al (2012) Epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma and pancreatic tumor cell lines: the role of neutrophils and neutrophil-derived elastase. Clin Dev Immunol 2012:720768
Gaida MM, Steffen TG, Gunther F, Tschaharganeh DF, Felix K, Bergmann F et al (2012) Polymorphonuclear neutrophils promote dyshesion of tumor cells and elastase-mediated degradation of E-cadherin in pancreatic tumors. Eur J Immunol 42(12):3369–3380
Freisinger CM, Huttenlocher A (2014) Live imaging and gene expression analysis in zebrafish identifies a link between neutrophils and epithelial to mesenchymal transition. PLoS One 9(11):e112183
Ardi VC, Van den Steen PE, Opdenakker G, Schweighofer B, Deryugina EI, Quigley JP (2009) Neutrophil MMP-9 proenzyme, unencumbered by TIMP-1, undergoes efficient activation in vivo and catalytically induces angiogenesis via a basic fibroblast growth factor (FGF-2)/FGFR-2 pathway. J Biol Chem 284(38):25854–25866
Bekes EM, Schweighofer B, Kupriyanova TA, Zajac E, Ardi VC, Quigley JP et al (2011) Tumor-recruited neutrophils and neutrophil TIMP-free MMP-9 regulate coordinately the levels of tumor angiogenesis and efficiency of malignant cell intravasation. Am J Pathol 179(3):1455–1470
Ardi VC, Kupriyanova TA, Deryugina EI, Quigley JP (2007) Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc Natl Acad Sci U S A 104(51):20262–20267
Pla P, Moore R, Morali OG, Grille S, Martinozzi S, Delmas V et al (2001) Cadherins in neural crest cell development and transformation. J Cell Physiol 189(2):121–132
Lugassy C, Wadehra M, Li X, Corselli M, Akhavan D, Binder SW et al (2013) Pilot study on “pericytic mimicry” and potential embryonic/stem cell properties of angiotropic melanoma cells interacting with the abluminal vascular surface. Cancer Microenviron 6(1):19–29
Lugassy C, Vernon SE, Busam K, Engbring JA, Welch DR, Poulos EG et al (2006) Angiotropism of human melanoma: studies involving in transit and other cutaneous metastases and the chicken chorioallantoic membrane: implications for extravascular melanoma invasion and metastasis. Am J Dermatopathol 28(3):187–193
Barnhill R, Dy K, Lugassy C (2002) Angiotropism in cutaneous melanoma: a prognostic factor strongly predicting risk for metastasis. J Invest Dermatol 119(3):705–706
Bald T, Quast T, Landsberg J, Rogava M, Glodde N, Lopez-Ramos D et al (2014) Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507(7490):109–113
Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545
Blaisdell A, Crequer A, Columbus D, Daikoku T, Mittal K, Dey SK et al (2015) Neutrophils oppose uterine epithelial carcinogenesis via debridement of hypoxic tumor cells. Cancer Cell 28(6):785–799
Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R (2011) Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20(3):300–314
Hoption Cann SA, van Netten JP, van Netten C, Glover DW (2002) Spontaneous regression: a hidden treasure buried in time. Med Hypotheses 58(2):115–119
Porcheray F, Viaud S, Rimaniol AC, Leone C, Samah B, Dereuddre-Bosquet N et al (2005) Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol 142(3):481–489
Slaton JW, Karashima T, Perrotte P, Inoue K, Kim SJ, Izawa J et al (2001) Treatment with low-dose interferon-alpha restores the balance between matrix metalloproteinase-9 and E-cadherin expression in human transitional cell carcinoma of the bladder. Clin Cancer Res 7(9):2840–2853
Ceelen W, Pattyn P, Mareel M (2014) Surgery, wound healing, and metastasis: recent insights and clinical implications. Crit Rev Oncol Hematol 89(1):16–26
Lee JW, Shahzad MM, Lin YG, Armaiz-Pena G, Mangala LS, Han HD et al (2009) Surgical stress promotes tumor growth in ovarian carcinoma. Clin Cancer Res 15(8):2695–2702
Kasper M, Jaks V, Are A, Bergstrom A, Schwager A, Svard J et al (2011) Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes. Proc Natl Acad Sci U S A 108(10):4099–4104
Senet P, Combemale P, Debure C, Baudot N, Machet L, Aout M et al (2012) Malignancy and chronic leg ulcers: the value of systematic wound biopsies: a prospective, multicenter, cross-sectional study. Arch Dermatol 148(6):704–708
Hofer SO, Shrayer D, Reichner JS, Hoekstra HJ, Wanebo HJ (1998) Wound-induced tumor progression: a probable role in recurrence after tumor resection. Arch Surg 133(4):383–389
Bogden AE, Moreau JP, Eden PA (1997) Proliferative response of human and animal tumours to surgical wounding of normal tissues: onset, duration and inhibition. Br J Cancer 75(7):1021–1027
Kuraishy A, Karin M, Grivennikov SI (2011) Tumor promotion via injury- and death-induced inflammation. Immunity 35(4):467–477
Neil JR, Johnson KM, Nemenoff RA, Schiemann WP (2008) Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-beta through a PGE2-dependent mechanisms. Carcinogenesis 29(11):2227–2235
Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW (2011) Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377(9759):31–41
Muinonen-Martin AJ, Susanto O, Zhang Q, Smethurst E, Faller WJ, Veltman DM et al (2014) Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal. PLoS Biol 12(10):e1001966
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this chapter
Cite this chapter
Bønnelykke-Behrndtz, M.L., Schmidt, H., Feng, Y., Martin, P. (2017). The Impact of Wound Inflammation on Cancer Progression: Studies in Fish and Patients. In: Retsky, M., Demicheli, R. (eds) Perioperative Inflammation as Triggering Origin of Metastasis Development. Springer, Cham. https://doi.org/10.1007/978-3-319-57943-6_8
Download citation
DOI: https://doi.org/10.1007/978-3-319-57943-6_8
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-57942-9
Online ISBN: 978-3-319-57943-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)