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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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Related in: MedlinePlus

PGE2 is one component of the trophic signal driving wound-inflammation-triggered pre-neoplastic cell proliferationA–B’ Images of Ras+ larval flanks from control fish bathed in Danieau’s solution or with 10 μM NS398 to block Cox-2 enzyme activity, and left unwounded (A, B) or laser-wounded (A’, B’) at 3 dpf before subsequent fixation at 5 dpf.C Graph showing quantification of pre-neoplastic cell numbers at 5 dpf from (A–B’) (n = 15–20 larvae in each group).D, D’ Unwounded control Ras+ larvae (D) versus sibling larvae that have been laser-wounded at 2 dpf (D’).E–F’ Unwounded versus wounded larvae after injection with PU-1 and GCSF morpholinos (E and E’), and addition of 20 μM dmPGE2 (F and F’).G Graph showing pre-neoplastic cell numbers from (D–F’).Data information: All scale bars represent 50 μm. Graphs display mean ± SEM.
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fig04: PGE2 is one component of the trophic signal driving wound-inflammation-triggered pre-neoplastic cell proliferationA–B’ Images of Ras+ larval flanks from control fish bathed in Danieau’s solution or with 10 μM NS398 to block Cox-2 enzyme activity, and left unwounded (A, B) or laser-wounded (A’, B’) at 3 dpf before subsequent fixation at 5 dpf.C Graph showing quantification of pre-neoplastic cell numbers at 5 dpf from (A–B’) (n = 15–20 larvae in each group).D, D’ Unwounded control Ras+ larvae (D) versus sibling larvae that have been laser-wounded at 2 dpf (D’).E–F’ Unwounded versus wounded larvae after injection with PU-1 and GCSF morpholinos (E and E’), and addition of 20 μM dmPGE2 (F and F’).G Graph showing pre-neoplastic cell numbers from (D–F’).Data information: All scale bars represent 50 μm. Graphs display mean ± SEM.

Mentions: Since we have previously shown that PGE2 is released by neutrophils and macrophages when recruited to pre-neoplastic cells in unwounded larvae (Feng et al, 2012), we wondered whether this factor might also be, in part, responsible for the wound-inflammation-triggered local proliferation of these cells. To test this, larvae were immersed in either 0.5% DMSO or 10 μM Cox-2 inhibitor NS398 with 0.5% DMSO and the number of pre-neoplastic cells was analysed 2 days post-laser wounding (Fig4A–C). Although the addition of NS398 does not completely block the increase in pre-neoplastic cell number post-wounding, we now see a significant reduction in numbers, such that there is no significant difference between the unwounded DMSO-treated larvae and the wounded NS398-treated larvae, suggesting that the addition of a Cox-2 inhibitor could partially negate the trophic impact of a cancer surgery (Fig4C). 20 μM of synthetic prostaglandin E2 (dmPGE2) was added at the point of wounding and largely rescued the proliferative response in immune-depleted zebrafish larvae (Figs3L and 4G), suggesting that PGE2 derived from immune cells is one contributor towards the trophic factors responsible for the wound-induced increase in proliferation.


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)

PGE2 is one component of the trophic signal driving wound-inflammation-triggered pre-neoplastic cell proliferationA–B’ Images of Ras+ larval flanks from control fish bathed in Danieau’s solution or with 10 μM NS398 to block Cox-2 enzyme activity, and left unwounded (A, B) or laser-wounded (A’, B’) at 3 dpf before subsequent fixation at 5 dpf.C Graph showing quantification of pre-neoplastic cell numbers at 5 dpf from (A–B’) (n = 15–20 larvae in each group).D, D’ Unwounded control Ras+ larvae (D) versus sibling larvae that have been laser-wounded at 2 dpf (D’).E–F’ Unwounded versus wounded larvae after injection with PU-1 and GCSF morpholinos (E and E’), and addition of 20 μM dmPGE2 (F and F’).G Graph showing pre-neoplastic cell numbers from (D–F’).Data information: All scale bars represent 50 μm. Graphs display mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4585460&req=5

fig04: PGE2 is one component of the trophic signal driving wound-inflammation-triggered pre-neoplastic cell proliferationA–B’ Images of Ras+ larval flanks from control fish bathed in Danieau’s solution or with 10 μM NS398 to block Cox-2 enzyme activity, and left unwounded (A, B) or laser-wounded (A’, B’) at 3 dpf before subsequent fixation at 5 dpf.C Graph showing quantification of pre-neoplastic cell numbers at 5 dpf from (A–B’) (n = 15–20 larvae in each group).D, D’ Unwounded control Ras+ larvae (D) versus sibling larvae that have been laser-wounded at 2 dpf (D’).E–F’ Unwounded versus wounded larvae after injection with PU-1 and GCSF morpholinos (E and E’), and addition of 20 μM dmPGE2 (F and F’).G Graph showing pre-neoplastic cell numbers from (D–F’).Data information: All scale bars represent 50 μm. Graphs display mean ± SEM.
Mentions: Since we have previously shown that PGE2 is released by neutrophils and macrophages when recruited to pre-neoplastic cells in unwounded larvae (Feng et al, 2012), we wondered whether this factor might also be, in part, responsible for the wound-inflammation-triggered local proliferation of these cells. To test this, larvae were immersed in either 0.5% DMSO or 10 μM Cox-2 inhibitor NS398 with 0.5% DMSO and the number of pre-neoplastic cells was analysed 2 days post-laser wounding (Fig4A–C). Although the addition of NS398 does not completely block the increase in pre-neoplastic cell number post-wounding, we now see a significant reduction in numbers, such that there is no significant difference between the unwounded DMSO-treated larvae and the wounded NS398-treated larvae, suggesting that the addition of a Cox-2 inhibitor could partially negate the trophic impact of a cancer surgery (Fig4C). 20 μM of synthetic prostaglandin E2 (dmPGE2) was added at the point of wounding and largely rescued the proliferative response in immune-depleted zebrafish larvae (Figs3L and 4G), suggesting that PGE2 derived from immune cells is one contributor towards the trophic factors responsible for the wound-induced increase in proliferation.

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