Neutrophil extracellular traps modulate chemotherapy efficacy and its adverse side effects.

Neutrophils, major regulator of innate immunity have recently emerged as key components of the tumor microenvironment. The role of neutrophils in cancer has been linked to their ability to form neutrophil extracellular traps (NETs), structures composed of decondensed DNA decorated with enzymes that are released into the extracellular space. Here, we discuss the pivotal roles of NETs, in influencing responses to chemotherapy and its severe adverse effect. Highlighting recent insights, we discuss the dual nature of NETs in the context of chemotherapy treatment, examining their potential to either counteract or enhance treatment outcomes. Strategic targeting of NETs emerges as a promising avenue for determining combination therapies that could help counteracting resistance or enhancing chemotherapy efficacy as well as limiting complications due to this type of treatment.

NETscape or NEThance: tailoring anti-cancer therapy.

Neutrophils, major regulators of innate immunity, have recently emerged as key components of the tumor microenvironment. The role of neutrophils in cancer has been linked to their ability to form neutrophil extracellular traps (NETs), structures composed of decondensed DNA decorated with enzymes that are released into the extracellular space. Here, we discuss the pivotal roles of NETs in influencing responses to anticancer therapies such as chemotherapy, radiotherapy, immunotherapy, and targeted therapy. Highlighting recent insights, we delve into the dual nature of NETs in the context of anticancer treatments, examining their potential to either counteract or enhance treatment outcomes. Strategic targeting of NETs may be a promising avenue for crafting combination therapies to counteract resistance or enhance anticancer treatments' efficacy.

NETs unleashed: neutrophil extracellular traps boost chemotherapy against colorectal cancer.

Chemotherapy, which primarily acts on cancer cells, can influence the tumor microenvironment and the recruitment and behavior of stromal cells. In this issue of the JCI, Li et al. explored the potent anticancer effect of the combination of a glutaminase inhibitor (CB-839) and 5-FU against PIK3CA-mutant colorectal cancer tumors. This chemotherapy treatment strongly induced the recruitment of neutrophils that formed neutrophil extracellular traps in cancer, which actively killed cancer cells by inducing apoptosis. This study substantially advances our understanding of the multifaceted role of neutrophils and NETs in the outcome of anticancer treatment.

Neutrophil extracellular traps formed during chemotherapy confer treatment resistance via TGF-ß activation.

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.

TGF-ß mediated drug resistance in solid cancer.

Transforming growth factor ß (TGF-ß) is an important signaling molecule which is expressed in three different isoforms in mammals (i.e. TGF-ß1, -ß2, and -ß3). The interaction between TGF-ß and its receptor triggers several pathways, which are classified into SMAD-dependent (canonical) and SMAD-independent (non-canonical) signaling, whose activation/transduction is finely regulated by several mechanisms. TGF-ß is involved in many physiological and pathological processes, assuming a dualistic role in cancer progression depending on tumor stage. Indeed, TGF-ß inhibits cell proliferation in early-stage tumor cells, while it promotes cancer progression and invasion in advanced tumors, where high levels of TGF-ß have been reported in both tumor and stromal cells. In particular, TGF-ß signaling has been found to be strongly activated in cancers after treatment with chemotherapeutic agents and radiotherapy, resulting in the onset of drug resistance conditions. In this review we provide an up-to-date description of several mechanisms involved in TGF-ß-mediated drug resistance, and we report different strategies that are currently under development in order to target TGF-ß pathway and increase tumor sensitivity to therapy.