ABSTRACT
Metastasis is the major cause of cancer death, and the development of therapy resistance is common. The tumor microenvironment can confer chemotherapy resistance (chemoresistance), but little is known about how specific host cells influence therapy outcome. We show that chemotherapy induces neutrophil recruitment and neutrophil extracellular trap (NET) formation, which reduces therapy response in mouse models of breast cancer lung metastasis. We reveal that chemotherapy-treated cancer cells secrete IL-1ß, which in turn triggers NET formation. Two NET-associated proteins are required to induce chemoresistance: integrin-αvß1, which traps latent TGF-ß, and matrix metalloproteinase 9, which cleaves and activates the trapped latent TGF-ß. TGF-ß activation causes cancer cells to undergo epithelial-to-mesenchymal transition and correlates with chemoresistance. Our work demonstrates that NETs regulate the activities of neighboring cells by trapping and activating cytokines and suggests that chemoresistance in the metastatic setting can be reduced or prevented by targeting the IL-1ß-NET-TGF-ß axis.
Subject(s)
Breast Neoplasms , Drug Resistance, Neoplasm , Extracellular Traps , Lung Neoplasms , Neutrophils , Tumor Microenvironment , Neutrophils/metabolism , Neutrophils/pathology , Humans , Animals , Mice , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Neoplasm Metastasis , Extracellular Traps/metabolism , Inflammation/pathologyABSTRACT
INTRODUCTION: Sleeve gastrectomy (SG) is the most performed bariatric surgery but gastric leaks following SG occur in up to 2% of cases. Regenerative medicine is emerging as a promising field offering multiple possibilities in wound healing. We studied the efficiency of locally administered mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) on leak closure following SG in rats. METHODS: The amount of PRP and MSCs extracted from one rat was analyzed and a model of gastric leak was developed in 10-week-old male Zucker rats. Twenty-four rats underwent SG fashioned with a leak. After 24 h, a second surgery was performed. The control group was treated by peritoneal lavage and drainage only while the experimental group received an additional treatment of locally administered MSCs and PRP at the leak orifice. Analysis of the leak healing process was done by an anatomopathological examination of the stomach 1, 2, 3, and 4 weeks after SG. RESULTS: The extraction of MSCs and PRP from one rat was necessary for three recipients. Anatomopathological examination suggests that the closure of the leak orifice was faster in the experimental group. Statistical analysis revealed a significantly increased mucosae renewal and fibrosis score at the leak orifice after treatment with MSCs and PRP (p < 0.001). CONCLUSION: These results suggest that PRP and MSCs may accelerate the closure of leaks following SG in rats and may become a new tool in the treatment of human gastric leaks but more research on this topic is needed to confirm these findings.
