Pituitary Adenoma and the Chemokine Network: A Systemic View

Grizzi, Fabio; Borroni, Elena Monica; Vacchini, Alessandro; Qehajaj, Dorina; Liguori, Manuela; Štifter, Sanja; Chiriva‐Internati, Maurizio; Ieva, Antonio Di

doi:10.3389/fendo.2015.00141

Cited by 16 publications

(9 citation statements)

References 59 publications

(56 reference statements)

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“…The tumour microenvironment (TME) consists of neoplastic, immune and stromal cells together with enzymes, growth factors and cytokines within the extracellular matrix [5–7, 11, 24]. Chemokines produced by the neoplastic cells contribute to trafficking and modulation of immune cells, angiogenesis and tumour invasion [5, 89].…”

Section: Introductionmentioning

confidence: 99%

Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours

Marques

Barry

Carlsen³

et al. 2019

acta neuropathol commun

105

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Non-tumoural cells within the tumour microenvironment (TME) influence tumour proliferation, invasiveness and angiogenesis. Little is known about TME in pituitary neuroendocrine tumours (PitNETs). We aimed to characterise the role of TME in the aggressive behaviour of PitNETs, focusing on immune cells and cytokines. The cytokine secretome of 16 clinically non-functioning PitNETs (NF-PitNETs) and 8 somatotropinomas was assessed in primary culture using an immunoassay panel with 42 cytokines. This was correlated with macrophage (CD68, HLA-DR, CD163), T-lymphocyte (CD8, CD4, FOXP3), B-lymphocyte (CD20), neutrophil (neutrophil elastase) and endothelial cells (CD31) content, compared to normal pituitaries (NPs, n = 5). In vitro tumour–macrophage interactions were assessed by conditioned medium (CM) of GH3 (pituitary tumour) and RAW264.7 (macrophage) cell lines on morphology, migration/invasion, epithelial-to-mesenchymal transition and cytokine secretion. IL-8, CCL2, CCL3, CCL4, CXCL10, CCL22 and CXCL1 are the main PitNET-derived cytokines. PitNETs with increased macrophage and neutrophil content had higher IL-8, CCL2, CCL3, CCL4 and CXCL1 levels. CD8+ T-lymphocytes were associated to higher CCL2, CCL4 and VEGF-A levels. PitNETs had more macrophages than NPs (p < 0.001), with a 3-fold increased CD163:HLA-DR macrophage ratio. PitNETs contained more CD4+ T-lymphocytes (p = 0.005), but fewer neutrophils (p = 0.047) with a 2-fold decreased CD8:CD4 ratio. NF-PitNETs secreted more cytokines and had 9 times more neutrophils than somatotropinomas (p = 0.002). PitNETs with higher Ki-67 had more FOXP3+ T cells, as well as lower CD68:FOXP3, CD8:CD4 and CD8:FOXP3 ratios. PitNETs with “deleterious immune phenotype” (CD68hiCD4hiFOXP3hiCD20hi) had a Ki-67 ≥ 3%. CD163:HLA-DR macrophage ratio was positively correlated with microvessel density (p = 0.015) and area (p < 0.001). GH3 cell-CM increased macrophage chemotaxis, while macrophage-CM changed morphology, invasion, epithelial-to-mesenchymal transition and secreted cytokines of GH3 cells. PitNETs are characterised by increased CD163:HLA-DR macrophage and reduced CD8:CD4 and CD8:FOXP3 T cell ratios. PitNET-derived chemokines facilitate macrophage, neutrophil and T cell recruitment into the tumours which can determine aggressive behaviour.

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Section: Introductionmentioning

confidence: 99%

Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours

Marques

Barry

Carlsen³

et al. 2019

acta neuropathol commun

105

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“…Over expression of microtubule associated protein TPX2 stimulates the cell cycle in cancer [61] , but this gene might be activates cell cycle in pituitary prolactinoma. Genes such as FGFR2 [62] , SOX2 [63] , POMC (proopiomelanocortin) [64] , FSHB (follicle stimulating hormone beta subunit) [65] , EFEMP1 [66] , SFRP2 [67] , CSH2 [68] , IHH (indian hedgehog) [69] , GH1 [70] , PTTG2 [71] , CCNB2 [72] , RACGAP1 [73] , CXCR2 [74] , CXCR3 [75] , FOXL2 [76] , RUNX2 [77] , TF (transferrin) [78] , CCK (cholecystokinin) [79] , DPPA4 [80] , RUNX1 [81] and BDNF (brain derived neurotrophic factor) [82] are associated with progression of pituitary prolactinoma.…”

Section: Discussionmentioning

confidence: 99%

Identification of potential and novel target genes in pituitary prolactinoma by bioinformatics analysis

Ghatnatti

Vastrad²,

Patil

et al. 2021

AIMS Neuroscience

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Pituitary prolactinoma is one of the most complicated and fatally pathogenic pituitary adenomas. Therefore, there is an urgent need to improve our understanding of the underlying molecular mechanism that drives the initiation, progression, and metastasis of pituitary prolactinoma. The aim of the present study was to identify the key genes and signaling pathways associated with pituitary prolactinoma using bioinformatics analysis. Transcriptome microarray dataset GSE119063 was downloaded from Gene Expression Omnibus (GEO) database. Limma package in R software was used to screen DEGs. Pathway and Gene ontology (GO) enrichment analysis were conducted to identify the biological role of DEGs. A protein-protein interaction (PPI) network was constructed and analyzed by using HIPPIE database and Cytoscape software. Module analyses was performed. In addition, a target gene-miRNA regulatory network and target gene-TF regulatory network were constructed by using NetworkAnalyst and Cytoscape software. Finally, validation of hub genes by receiver operating characteristic (ROC) curve analysis. A total of 989 DEGs were identified, including 461 up regulated genes and 528 down regulated genes. Pathway enrichment analysis showed that the DEGs were significantly enriched in the retinoate biosynthesis II, signaling pathways regulating pluripotency of stem cells, ALK2 signaling events, vitamin D3 biosynthesis, cell cycle and aurora B signaling. Gene Ontology (GO) enrichment analysis showed that the DEGs were significantly enriched in the sensory organ morphogenesis, extracellular matrix, hormone activity, nuclear division, condensed chromosome and microtubule binding. In the PPI network and modules, SOX2, PRSS45, CLTC, PLK1, B4GALT6, RUNX1 and GTSE1 were considered as hub genes. In the target gene-miRNA regulatory network and target gene-TF regulatory network, LINC00598, SOX4, IRX1 and UNC13A were considered as hub genes. Using integrated bioinformatics analysis, we identified candidate genes in pituitary prolactinoma, which might improve our understanding of the molecular mechanisms of pituitary prolactinoma.

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“…Pituitary tumors are common tumors of the anterior pituitary gland that can appear in up to a fifth of the general population [1,2]. Based on the sole clinically relevant anterior pituitary tumors, their prevalence is 80–100 cases/100,000 people.…”

Section: Introductionmentioning

confidence: 99%

The Microenvironment of Pituitary Tumors—Biological and Therapeutic Implications

Ilie

Vasiljevic

Raverot

et al. 2019

Cancers

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The tumor microenvironment (TME) includes resident and infiltrative non-tumor cells, as well as blood and lymph vessels, extracellular matrix molecules, and numerous soluble factors, such as cytokines and chemokines. While the TME is now considered to be a prognostic tool and a therapeutic target for many cancers, little is known about its composition in pituitary tumors. This review summarizes our current knowledge of the TME within pituitary tumors and the strong interest in TME as a therapeutic target. While we cover the importance of angiogenesis and immune infiltrating cells, we also address the role of the elusive folliculostellate cells, the emerging literature on pituitary tumor-associated fibroblasts, and the contribution of extracellular matrix components in these tumors. The cases of human pituitary tumors treated with TME-targeting therapies are reviewed and emerging concepts of vascular normalization and combined therapies are presented. Together, this snapshot overview of the current literature pinpoints not only the underestimated role of TME components in pituitary tumor biology, but also the major promise it may offer for both prognosis and targeted therapeutics.

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Pituitary Adenoma and the Chemokine Network: A Systemic View

Cited by 16 publications

References 59 publications

Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours

Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours

Identification of potential and novel target genes in pituitary prolactinoma by bioinformatics analysis

The Microenvironment of Pituitary Tumors—Biological and Therapeutic Implications

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