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

TY - JOUR

T1 - The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer

AU - Antonio, Nicole

AU - Bønnelykke-Behrndtz, Marie Louise

AU - Ward, Laura Chloe

AU - Collin, John

AU - Christensen, Ib Jarle

AU - Steiniche, Torben

AU - Schmidt, Henrik

AU - Feng, Yi

AU - Martin, Paul

N1 - © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2015/9/2

Y1 - 2015/9/2

N2 - There is a long-standing association between wound healing and cancer, with cancer often described as a "wound that does not heal". However, little is known about how wounding, such as following surgery, biopsy collection or ulceration, might impact on cancer progression. Here, we use a translucent zebrafish larval model of RasG12V-driven neoplasia to image the interactions between inflammatory cells drawn to a wound, and to adjacent pre-neoplastic cells. We show that neutrophils are rapidly diverted from a wound to pre-neoplastic cells and these interactions lead to increased proliferation of the pre-neoplastic cells. One of the wound-inflammation-induced trophic signals is prostaglandin E2 (PGE2). 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. Our zebrafish studies led us to investigate the innate immune cell associations in ulcerated melanomas in human patients. 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. Synopsis This study reveals how innate immune cells, in particular neutrophils, that are initially drawn to a wound can subsequently be attracted away to nearby early- and late-stage cancer cells and drive their proliferation. Both chronic and acute wounds exacerbate cancer growth. Tissue damage in larval zebrafish, or cancer surgery in adults, draws in neutrophils and macrophages. Neutrophils are recruited from wounds to nearby pre-neoplastic cells and deliver trophic signals. Neutrophil presence correlates with tumour cell proliferative index and indicates poor prognosis in ulcerated human melanoma. Innate immune cells that are initially drawn to a wound can subsequently be attracted away to nearby cancer cells and drive their proliferation.

AB - There is a long-standing association between wound healing and cancer, with cancer often described as a "wound that does not heal". However, little is known about how wounding, such as following surgery, biopsy collection or ulceration, might impact on cancer progression. Here, we use a translucent zebrafish larval model of RasG12V-driven neoplasia to image the interactions between inflammatory cells drawn to a wound, and to adjacent pre-neoplastic cells. We show that neutrophils are rapidly diverted from a wound to pre-neoplastic cells and these interactions lead to increased proliferation of the pre-neoplastic cells. One of the wound-inflammation-induced trophic signals is prostaglandin E2 (PGE2). 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. Our zebrafish studies led us to investigate the innate immune cell associations in ulcerated melanomas in human patients. 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. Synopsis This study reveals how innate immune cells, in particular neutrophils, that are initially drawn to a wound can subsequently be attracted away to nearby early- and late-stage cancer cells and drive their proliferation. Both chronic and acute wounds exacerbate cancer growth. Tissue damage in larval zebrafish, or cancer surgery in adults, draws in neutrophils and macrophages. Neutrophils are recruited from wounds to nearby pre-neoplastic cells and deliver trophic signals. Neutrophil presence correlates with tumour cell proliferative index and indicates poor prognosis in ulcerated human melanoma. Innate immune cells that are initially drawn to a wound can subsequently be attracted away to nearby cancer cells and drive their proliferation.

KW - Animals

KW - Cell Proliferation

KW - Humans

KW - Inflammation

KW - Melanoma

KW - Mutation, Missense

KW - Neoplasms, Experimental

KW - Neutrophils

KW - Precancerous Conditions

KW - Wounds and Injuries

KW - Zebrafish

KW - Zebrafish Proteins

KW - ras Proteins

U2 - 10.15252/embj.201490147

DO - 10.15252/embj.201490147

M3 - Journal article

C2 - 26136213

SN - 0261-4189

VL - 34

SP - 2219

EP - 2236

JO - E M B O Journal

JF - E M B O Journal

IS - 17

ER -