The Good, the Bad, and the Ugly: Neutrophils, Angiogenesis, and Cancer

Ozel, Irem; Duerig, Inga; Domnich, Maksim; Lang, Stephan; Pylaeva, Ekaterina; Jabłońska, Jadwiga

doi:10.3390/cancers14030536

Cited by 35 publications

(34 citation statements)

References 182 publications

(278 reference statements)

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“…This analysis enriches the knowledge on PCa progression by providing a list of proteins and their relative abundance across the disease grades. TCA cycle and overall metabolic reprogramming is a prominent feature represented by the observed protein changes along the progression of PCa in our analysis (shown in Table S2 ), which is also reflected in the literature [ 49 , 50 , 51 , 52 ]. Apart from the metabolic reprogramming, processes related to angiogenesis (neutrophil and platelet degranulation, VEGFA-VEGFR2 signaling pathway) [ 50 , 51 ], apoptosis [ 52 ], Rho GTPases [ 53 ], and reactive oxygen species signaling [ 54 ] are shown to be altered among the grade groups and have been previously linked to PCa and disease progression, which further supports the validity of our findings.…”

Section: Discussionsupporting

confidence: 78%

Proteomic Analysis of Prostate Cancer FFPE Samples Reveals Markers of Disease Progression and Aggressiveness

Lygirou

Fasoulakis

Stroggilos

et al. 2022

Cancers

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Prostate cancer (PCa) is the second most common cancer in men. Diagnosis and risk assessment are widely based on serum Prostate Specific Antigen (PSA) and biopsy, which might not represent the exact degree of PCa risk. Towards the discovery of biomarkers for better patient stratification, we performed proteomic analysis of Formalin Fixed Paraffin Embedded (FFPE) prostate tissue specimens using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Comparative analysis of 86 PCa samples among grade groups 1–5 identified 301 significantly altered proteins. Additional analysis based on biochemical recurrence (BCR; BCR+ n = 14, BCR- n = 51) revealed 197 significantly altered proteins that indicate disease persistence. Filtering the overlapping proteins of these analyses, seven proteins (NPM1, UQCRH, HSPA9, MRPL3, VCAN, SERBP1, HSPE1) had increased expression in advanced grades and in BCR+/BCR- and may play a critical role in PCa aggressiveness. Notably, all seven proteins were significantly associated with progression in Prostate Cancer Transcriptome Atles (PCTA) and NPM1NPM1, UQCRH, and VCAN were further validated in The Cancer Genome Atlas (TCGA), where they were upregulated in BCR+/BCR-. UQCRH levels were also associated with poorer 5-year survival. Our study provides valuable insights into the key regulators of PCa progression and aggressiveness. The seven selected proteins could be used for the development of risk assessment tools.

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Section: Discussionsupporting

confidence: 78%

Proteomic Analysis of Prostate Cancer FFPE Samples Reveals Markers of Disease Progression and Aggressiveness

Lygirou

Fasoulakis

Stroggilos

et al. 2022

Cancers

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“…Their behavior is determined by signals from tumor cells and the tumor microenvironment (1)(2)(3). In many cancer entities, including head and neck cancer (HNC), high intra-tumoral neutrophil counts have been shown to be associated with a worse patient prognosis (4)(5)(6). Several responsible mechanisms have been identified, including the support of angiogenesis (7,8), the promotion of metastatic spread (9)(10)(11)(12), the regulation of B cell activation (13,14), as well as the regulation of T-cell responses in tumor tissue (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes

et al. 2022

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Tumor-draining lymph nodes (TDLNs) are the first organs where the metastatic spread of different types of cancer, including head and neck cancer (HNC), occurs and have therefore high prognostic relevance. Moreover, first anti-cancer immune responses have been shown to be initiated in such LNs via tumor-educated myeloid cells. Among myeloid cells present in TDLNs, neutrophils represent a valuable population and considerably participate in the activation of effector lymphocytes there. Tumor-supportive or tumor-inhibiting activity of neutrophils strongly depends on the surrounding microenvironment. Thus, type I interferon (IFN) availability has been shown to prime anti-tumor activity of these cells. In accordance, mice deficient in type I IFNs show elevated tumor growth and metastatic spread, accompanied by the pro-tumoral neutrophil bias. To reveal the mechanism responsible for this phenomenon, we have studied here the influence of defective type I IFN signaling on the immunoregulatory activity of neutrophils in TDLNs. Live imaging of such LNs was performed using two-photon microscopy in a transplantable murine HNC model. CatchupIVM-red and Ifnar1-/- (type I IFN receptor- deficient) CatchupIVM-red mice were used to visualize neutrophils and to assess their interaction with T-cells in vivo. We have evaluated spatiotemporal patterns of neutrophil/T-cell interactions in LNs in the context of type I interferon receptor (IFNAR1) availability in tumor-free and tumor-bearing animals. Moreover, phenotypic and functional analyses were performed to further characterize the mechanisms regulating neutrophil immunoregulatory capacity. We demonstrated that inactive IFNAR1 leads to elevated accumulation of neutrophils in TDLNs. However, these neutrophils show significantly impaired capacity to interact with and to stimulate T-cells. As a result, a significant reduction of contacts between neutrophils and T lymphocytes is observed, with further impairment of T-cell proliferation and activation. This possibly contributes to the enhanced tumor growth in Ifnar1-/- mice. In agreement with this, IFNAR1-independent activation of downstream IFN signaling using IFN-λ improved the immunostimulatory capacity of neutrophils in TDLNs and contributed to the suppression of tumor growth. Our results suggest that functional type I IFN signaling is essential for neutrophil immunostimulatory capacity and that stimulation of this signaling may provide a therapeutic opportunity in head and neck cancer patients.

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“…Even if neutrophils have a central role in the inflammatory process, they are also involved at different levels in the oncogenic process (tumor initiation, proliferation and dissemination). Neutrophils facilitate the tumor initiation through multiple mechanisms: they produce oxidative stress, can induce angiogenesis, attenuate the immune system (by the inhibition of macrophages’, DC’ and NK cells’ function), produce MMP9 and facilitate the extravasation of tumor cells [ 237 , 238 , 239 ].…”

Section: Other Immune Cells In Tumor Microenvironment and New Techniq...mentioning

confidence: 99%

“…Another line for the new therapeutic approaches in GBM can focus on the factors driving the myeloid cells activity [ 237 , 238 , 239 , 242 ].…”

Section: Cell-targeting Therapiesmentioning

confidence: 99%

Glioblastoma Microenvironment and Cellular Interactions

Crivii

Boșca

Melincovici

et al. 2022

Cancers

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The central nervous system (CNS) represents a complex network of different cells, such as neurons, glial cells, and blood vessels. In tumor pathology, glial cells result in the highest number of cancers, and glioblastoma (GB) is considered the most lethal tumor in this region. The development of GB leads to the infiltration of healthy tissue through the interaction between all the elements of the brain network. This results in a GB microenvironment, a complex peritumoral hallo composed of tumor cells and several non-tumor cells (e.g., nervous cells, stem cells, fibroblasts, vascular and immune cells), which might be the principal factor for the ineffective treatment due to the fact that the microenvironment modulates the biologic status of the tumor with the increase in its evasion capacity. Crosstalk between glioma cells and the brain microenvironment finally inhibits the beneficial action of molecular pathways, favoring the development and invasion of the tumor and its increasing resistance to treatment. A deeper understanding of cell–cell interactions in the tumor microenvironment (TME) and with the tumor cells could be the basis for a more efficient therapy.

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The Good, the Bad, and the Ugly: Neutrophils, Angiogenesis, and Cancer

Cited by 35 publications

References 182 publications

Proteomic Analysis of Prostate Cancer FFPE Samples Reveals Markers of Disease Progression and Aggressiveness

Proteomic Analysis of Prostate Cancer FFPE Samples Reveals Markers of Disease Progression and Aggressiveness

IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes

Glioblastoma Microenvironment and Cellular Interactions

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