Abstract
Simple SummaryTumor angiogenesis is one of the most critical steps in the progression of cancer. Owing to its fundamental role in tumor growth and metastasis, tumor angiogenesis is accepted to be a limiting factor and considered a powerful therapeutic target. Neutrophils contribute to the tumor progression via multiple mechanisms, ranging from the direct support of tumor cell survival to the immunosuppression. A strong body of evidence suggests that neutrophils also play a prominent role in tumor angiogenesis. In this manuscript, we provide an up do date review of the pro-angiogenic functions of neutrophils, in the context of cancer, and discuss the possibility of therapeutically targeting the pro-angiogenic capacity of these cells in cancer patients. Angiogenesis, the formation of new blood vessels from already existing vasculature, is tightly regulated by pro- and anti-angiogenic stimuli and occurs under both physiological and pathological conditions. Tumor angiogenesis is central for tumor development, and an “angiogenic switch” could be initiated by multiple immune cells, such as neutrophils. Tumor-associated neutrophils promote tumor angiogenesis by the release of both conventional and non-conventional pro-angiogenic factors. Therefore, neutrophil-mediated tumor angiogenesis should be taken into consideration in the design of novel anti-cancer therapy. This review recapitulates the complex role of neutrophils in tumor angiogenesis and summarizes neutrophil-derived pro-angiogenic factors and mechanisms regulating angiogenic activity of tumor-associated neutrophils. Moreover, it provides up-to-date information about neutrophil-targeting therapy, complementary to anti-angiogenic treatment.
Highlights
The functional vascular system, in complex a multicellular organism, is a very vital asset for survival
The balance between pro- and anti-angiogenic factors is crucial for normal, functional vessel formation; its deregulation results in pathology and contributes to the progression of diseases, such as cancer
VEGF production by neutrophils might promote the further recruitment of neutrophils, in a positive feedback loop, to establish pro-angiogenic signaling inside the tumor and support tumor angiogenesis
Summary
The functional vascular system, in complex a multicellular organism, is a very vital asset for survival. Endothelial cells are non-proliferating and quiescent, and their activation is strongly coordinated by pro-angiogenic signals [6]. The balance between pro- and anti-angiogenic factors is crucial for normal, functional vessel formation; its deregulation results in pathology and contributes to the progression of diseases, such as cancer. Opposite to physiological angiogenesis, where the activity of ECs is tightly controlled, tumor angiogenesis is strongly accelerated through the constant pro-angiogenic signaling and results in the formation of disordered, partly non-functional vasculature. The expression of pro-inflammatory molecules is upregulated in TECs [43], leading to the recruitment and activation of inflammatory cells, such as macrophages and neutrophils, that contribute to the tumor angiogenesis
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