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The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer.

Antonio N, Bønnelykke-Behrndtz ML, Ward LC, Collin J, Christensen IJ, Steiniche T, Schmidt H, Feng Y, Martin P - EMBO J. (2015)

Bottom Line: There is a long-standing association between wound healing and cancer, with cancer often described as a "wound that does not heal".In an adult model of chronic wounding in zebrafish, we show that repeated wounding with subsequent inflammation leads to a greater incidence of local melanoma formation.We find a strong correlation between neutrophil presence at sites of melanoma ulceration and cell proliferation at these sites, which is associated with poor prognostic outcome.

View Article: PubMed Central - PubMed

Affiliation: School of Biochemistry, University of Bristol, Bristol, UK.

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Ulcerated human melanomas show a correlation between level of neutrophil influx, tumour cell proliferation and prognostic outcomeA–C’’ Typical non-ulcerated, moderate and excessively ulcerated melanomas, respectively, all immunostained for pan-cytokeratin to illustrate epidermal wound margins. (A’, B’ and C’) High magnification details from (A, B and C) (highlighted by red boxes) co-stained for CD66b to illustrate neutrophil accumulation. (A’’, B’’ and C’’) Parallel sections from the same patient blocks, but stained for MelanA and Ki67 to determine proliferating melanoma cells.D Graph illustrating the extent of correlation between neutrophil influx and tumour cell proliferation (P = 0.002; R2 = 0.17). Solid dots are from non-ulcerated lesions and show a good correlation, whereas circles represent ulcerated melanomas.E Graph showing considerably less correlation between macrophage influx and tumour cell proliferation (P = 0.56; R2 = 0.10).F A series of Kaplan–Meier curves illustrating the link between neutrophil influx (total absence, moderate infiltration (<75 percentile)) and excessive infiltration (>75 percentile) and prognostic outcome in patients with non-ulcerated and ulcerated melanomas, respectively.Data information: Scale bars represent 3 mm (A), 6 mm (B), 10 mm (C) and 200 μm (all other panels).
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fig06: Ulcerated human melanomas show a correlation between level of neutrophil influx, tumour cell proliferation and prognostic outcomeA–C’’ Typical non-ulcerated, moderate and excessively ulcerated melanomas, respectively, all immunostained for pan-cytokeratin to illustrate epidermal wound margins. (A’, B’ and C’) High magnification details from (A, B and C) (highlighted by red boxes) co-stained for CD66b to illustrate neutrophil accumulation. (A’’, B’’ and C’’) Parallel sections from the same patient blocks, but stained for MelanA and Ki67 to determine proliferating melanoma cells.D Graph illustrating the extent of correlation between neutrophil influx and tumour cell proliferation (P = 0.002; R2 = 0.17). Solid dots are from non-ulcerated lesions and show a good correlation, whereas circles represent ulcerated melanomas.E Graph showing considerably less correlation between macrophage influx and tumour cell proliferation (P = 0.56; R2 = 0.10).F A series of Kaplan–Meier curves illustrating the link between neutrophil influx (total absence, moderate infiltration (<75 percentile)) and excessive infiltration (>75 percentile) and prognostic outcome in patients with non-ulcerated and ulcerated melanomas, respectively.Data information: Scale bars represent 3 mm (A), 6 mm (B), 10 mm (C) and 200 μm (all other panels).

Mentions: While there is considerable anecdotal evidence for wound-exacerbated cancer progression (Hofer et al, 1998), our zebrafish studies prompted us to investigate whether this association was linked to innate immune cell influx at the wound site. It is already established that ulceration of melanoma is a bad prognostic indicator (Balch et al, 2011), and so we examined whether this might be due to wound inflammation. Haematoxylin and eosin staining of sections allows us to delineate the extent of the epidermal wound and to categorise melanomas as having no ulceration, minimal/moderate ulceration (<70% of total tumour length) or excessive ulceration (>70% of tumour length) (In ‘t Hout et al, 2012) (Fig5). Our co-staining for CD66b+ neutrophils and CD163+ macrophages and automated software for quantification of leucocyte numbers reveal a 15 times increase in neutrophils from non-ulcerated to minimal/moderate ulcerated lesions and 100 times increase from non-ulcerated to excessively ulcerated lesions (Fig5A–C and G), whereas there is no such correlation with macrophage numbers and ulceration (Fig5D–F and H, Supplementary Table S1). We observe that recruited neutrophils can be located throughout the melanoma, but are often associated with the superficial wound site in ulcerated lesions (Fig5B and C). We see also a significant correlation between tumour cell proliferation [as assessed by Ki67/MelanA double staining (Nielsen et al, 2013)] and extent of neutrophil influx (Fig6A’, B’, C’ and D). This association appears strongest only up to minimal/moderate ulcers, suggesting that melanoma may reach a proliferation plateau soon after initial ulceration when they first become infiltrated by neutrophils, although we have no means to determine at which time point this might have occurred relative to our biopsies. We see no significant correlation between macrophage numbers and tumour cell proliferation (Fig6E and Supplementary Table S2).


The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer.

Antonio N, Bønnelykke-Behrndtz ML, Ward LC, Collin J, Christensen IJ, Steiniche T, Schmidt H, Feng Y, Martin P - EMBO J. (2015)

Ulcerated human melanomas show a correlation between level of neutrophil influx, tumour cell proliferation and prognostic outcomeA–C’’ Typical non-ulcerated, moderate and excessively ulcerated melanomas, respectively, all immunostained for pan-cytokeratin to illustrate epidermal wound margins. (A’, B’ and C’) High magnification details from (A, B and C) (highlighted by red boxes) co-stained for CD66b to illustrate neutrophil accumulation. (A’’, B’’ and C’’) Parallel sections from the same patient blocks, but stained for MelanA and Ki67 to determine proliferating melanoma cells.D Graph illustrating the extent of correlation between neutrophil influx and tumour cell proliferation (P = 0.002; R2 = 0.17). Solid dots are from non-ulcerated lesions and show a good correlation, whereas circles represent ulcerated melanomas.E Graph showing considerably less correlation between macrophage influx and tumour cell proliferation (P = 0.56; R2 = 0.10).F A series of Kaplan–Meier curves illustrating the link between neutrophil influx (total absence, moderate infiltration (<75 percentile)) and excessive infiltration (>75 percentile) and prognostic outcome in patients with non-ulcerated and ulcerated melanomas, respectively.Data information: Scale bars represent 3 mm (A), 6 mm (B), 10 mm (C) and 200 μm (all other panels).
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fig06: Ulcerated human melanomas show a correlation between level of neutrophil influx, tumour cell proliferation and prognostic outcomeA–C’’ Typical non-ulcerated, moderate and excessively ulcerated melanomas, respectively, all immunostained for pan-cytokeratin to illustrate epidermal wound margins. (A’, B’ and C’) High magnification details from (A, B and C) (highlighted by red boxes) co-stained for CD66b to illustrate neutrophil accumulation. (A’’, B’’ and C’’) Parallel sections from the same patient blocks, but stained for MelanA and Ki67 to determine proliferating melanoma cells.D Graph illustrating the extent of correlation between neutrophil influx and tumour cell proliferation (P = 0.002; R2 = 0.17). Solid dots are from non-ulcerated lesions and show a good correlation, whereas circles represent ulcerated melanomas.E Graph showing considerably less correlation between macrophage influx and tumour cell proliferation (P = 0.56; R2 = 0.10).F A series of Kaplan–Meier curves illustrating the link between neutrophil influx (total absence, moderate infiltration (<75 percentile)) and excessive infiltration (>75 percentile) and prognostic outcome in patients with non-ulcerated and ulcerated melanomas, respectively.Data information: Scale bars represent 3 mm (A), 6 mm (B), 10 mm (C) and 200 μm (all other panels).
Mentions: While there is considerable anecdotal evidence for wound-exacerbated cancer progression (Hofer et al, 1998), our zebrafish studies prompted us to investigate whether this association was linked to innate immune cell influx at the wound site. It is already established that ulceration of melanoma is a bad prognostic indicator (Balch et al, 2011), and so we examined whether this might be due to wound inflammation. Haematoxylin and eosin staining of sections allows us to delineate the extent of the epidermal wound and to categorise melanomas as having no ulceration, minimal/moderate ulceration (<70% of total tumour length) or excessive ulceration (>70% of tumour length) (In ‘t Hout et al, 2012) (Fig5). Our co-staining for CD66b+ neutrophils and CD163+ macrophages and automated software for quantification of leucocyte numbers reveal a 15 times increase in neutrophils from non-ulcerated to minimal/moderate ulcerated lesions and 100 times increase from non-ulcerated to excessively ulcerated lesions (Fig5A–C and G), whereas there is no such correlation with macrophage numbers and ulceration (Fig5D–F and H, Supplementary Table S1). We observe that recruited neutrophils can be located throughout the melanoma, but are often associated with the superficial wound site in ulcerated lesions (Fig5B and C). We see also a significant correlation between tumour cell proliferation [as assessed by Ki67/MelanA double staining (Nielsen et al, 2013)] and extent of neutrophil influx (Fig6A’, B’, C’ and D). This association appears strongest only up to minimal/moderate ulcers, suggesting that melanoma may reach a proliferation plateau soon after initial ulceration when they first become infiltrated by neutrophils, although we have no means to determine at which time point this might have occurred relative to our biopsies. We see no significant correlation between macrophage numbers and tumour cell proliferation (Fig6E and Supplementary Table S2).

Bottom Line: There is a long-standing association between wound healing and cancer, with cancer often described as a "wound that does not heal".In an adult model of chronic wounding in zebrafish, we show that repeated wounding with subsequent inflammation leads to a greater incidence of local melanoma formation.We find a strong correlation between neutrophil presence at sites of melanoma ulceration and cell proliferation at these sites, which is associated with poor prognostic outcome.

View Article: PubMed Central - PubMed

Affiliation: School of Biochemistry, University of Bristol, Bristol, UK.

Show MeSH
Related in: MedlinePlus