No abstract

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.

The composition of the oral milieu reflects oral health. Saliva provides an environment for multiple microorganisms, and contains soluble factors and immune cells. Neutrophils, which rapidly react on the changes in the microenvironment, are a major immune cell population in saliva and thus may serve as a biomarker for oral pathologies. This review focuses on salivary neutrophils in the oral cavity, their phenotype changes in physiological and pathological conditions, as well as on factors regulating oral neutrophil amount, activation and functionality, with special emphasis on oral cancer and its risk factors.

Angiogenesis plays an important role during tumor growth and metastasis. We could previously show that Type I interferon (IFN)‐deficient tumor‐associated neutrophils (TANs) show strong pro‐angiogenic activity, and stimulate tumor angiogenesis and growth. However, the exact mechanism responsible for their pro‐angiogenic shift is not clear. Here, we set out to delineate the molecular mechanism and factors regulating pro‐angiogenic properties of neutrophils in the context of Type I IFN availability. We demonstrate that neutrophils from IFN‐deficient (Ifnar1−/−) mice efficiently release pro‐angiogenic factors, such as VEGF, MMP9 or BV8, and thus significantly support the vascular normalization of tumors by increasing the maturation of perivascular cells. Mechanistically, we could show here that the expression of pro‐angiogenic factors in neutrophils is controlled by the transcription factor forkhead box protein O3a (FOXO3a), which activity depends on its post‐translational modifications, such as deacetylation or phosphorylation. In TANs isolated from Ifnar1−/− mice, we observe significantly elevated SIRT1, resulting in SIRT1‐mediated deacetylation of FOXO3a, its nuclear retention and activation. Activated FOXO3a supports in turn the transcription of pro‐angiogenic genes in TANs. In the absence of SIRT1, or after its inhibition in neutrophils, elevated kinase MEK/ERK and PI3K/AKT activity is observed, leading to FOXO3a phosphorylation, cytoplasmic transfer and inactivation. In summary, we have found that FOXO3a is a key transcription factor controlling the angiogenic switch of neutrophils. Post‐translational FOXO3a modifications regulate its transcriptional activity and, as a result, the expression of pro‐angiogenic factors supporting development of vascular network in growing tumors. Therefore, targeting FOXO3a activity could provide a novel strategy of antiangiogenic targeted therapy for cancer.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by mucocutaneous telangiectases and visceral vascular malformations. Individuals suffering from HHT have a significantly increased risk of bacterial infections, but the mechanisms involved in this are not clear. White blood cell subpopulations were estimated with flow cytometry in 79 patients with HHT and 45 healthy individuals, and association with clinicopathological status was assessed. A prominent decrease in absolute numbers of T cells in HHT was revealed (0.7 (0.5–1.1) vs. 1.3 (0.8–1.6), 106/mL, p < 0.05), and in multivariate regression analysis, hemoglobin level was associated with lymphopenia (OR = 0.625, 95% CI: 0.417–0.937, p < 0.05). Although no changes in absolute numbers of neutrophils and monocytes were observed, we revealed a significant impairment of neutrophil antibacterial functions in HHT (n = 9), compared to healthy individuals (n = 7), in vitro. The release of neutrophil extracellular traps (NETs) against Pseudomonas aeruginosa MOI10 was significantly suppressed in HHT (mean area per cell, mm2: 76 (70–92) vs. 121 (97–128), p < 0.05), due to impaired filamentous actin organization (% of positive cells: 69 (59–77) vs. 92 (88–94), p < 0.05). To conclude, this study reveals the categories of patients with HHT that are prone to immunosuppression and require careful monitoring, and suggests a potential therapeutic strategy based on the functional activation of neutrophils.