Mast cells mediate malignant pleural effusion formation

Giannou, Anastasios D.; Marazioti, Antonia; Spella, Magda; Kanellakis, Nikolaos I.; Apostolopoulou, Hara; Psallidas, Ioannis; Prijovich, Zeljko M.; Vreka, Malamati; Zazara, Dimitra E.; Lilis, Ioannis; Papaleonidopoulos, Vassilios; Kairi, Chrysoula A.; Patmanidi, Alexandra L.; Giopanou, Ioanna; Spiropoulou, Nikolitsa; Harokopos, Vaggelis; Aidinis, Vassilis; Spyratos, Dionisios; Teliousi, Stamatia; Papadaki, Helen; Taraviras, Stavros; Snyder, Linda A.; Eickelberg, Oliver; Kardamakis, Dimitrios; Iwakura, Yoichiro; Feyerabend, Thorsten B.; Rodewald, Hans Reimer; Kalomenidis, Ioannis; Blackwell, Timothy S.; Agalioti, Theodora; Stathopoulos, Georgios T.

doi:10.1172/jci79840

Cited by 97 publications

(174 citation statements)

References 58 publications

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“…Autocrine tumour necrosis factor (TNF), interleukin (IL)-6 and osteopontin (OPN) participate in positive feedback loops regulating tumour NF-κB/STAT3 activation to promote MPE [29][30][31]. In addition, tumour-derived mediators, including vascular endothelial growth factor (VEGF), C-C-motif chemokine ligand (CCL) 2 and TNF, directly stimulate inflammatory cell influx and/or vascular changes [31][32][33][34]. Finally, host mediators perpetuate this malicious interplay by amplifying inflammatory and angiogenic signalling loops.…”

Section: Formation Of Mpe: General Aspectsmentioning

confidence: 99%

“…In addition, tumour-expressed OPN protects tumour cells from pro-apoptotic stimuli and host-secreted OPN promotes pleural inflammation and angiogenesis, while the cytokine from both origins provokes vascular leakage [30]. Recently, it has been proved that mast cells are required for MPE formation and by releasing tryptase AB1 and IL-1β they induce pleural vasculature leakiness and trigger NF-κB activation thereby fostering fluid accumation and tumour growth [34]. This novel concept on MPE pathogenesis was exploited in preclinical studies that demonstrated that a variety of pharmacological agents including VEGF, sulindac derivative, TNF and angiopoietin inhibitors, zolendronic acid, a dual VEGF receptor/sTie2 antagonist, bortezomib and endostatin curtail experimental MPE, and may now warrant clinical testing [33,[36][37][38][39][40].…”

Section: Formation Of Mpe: General Aspectsmentioning

confidence: 99%

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Malignant pleural effusion: from bench to bedside

et al. 2016

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Malignant pleural effusion (MPE) is a common but serious condition that is related with poor quality of life, morbidity and mortality. Its incidence and associated healthcare costs are rising and its management remains palliative, with median survival ranging from 3 to 12 months. During the last decade there has been significant progress in unravelling the pathophysiology of MPE, as well as its diagnostics, imaging, and management. Nowadays, formerly bed-ridden patients are genotyped, phenotyped, and treated on an ambulatory basis. This article attempts to provide a comprehensive overview of current advances in MPE from bench to bedside. In addition, it highlights unanswered questions in current clinical practice and suggests future directions for basic and clinical research in the field. @ERSpublications This review provides up to date knowledge for malignant pleural effusion covering aspects from bench to bedside http://ow.ly/10w7vN

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Section: Formation Of Mpe: General Aspectsmentioning

confidence: 99%

Section: Formation Of Mpe: General Aspectsmentioning

confidence: 99%

Malignant pleural effusion: from bench to bedside

et al. 2016

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“…For this, treatments commenced at day 4–14 post-mouse tumour cell injections and at day 14 post-human tumour cell injections to allow initial tumour implantation in the pleural space67. At day 13 after pleural injection of MC38 cells ( Kras G13R ), deltarasin-treated C57BL/6 mice developed fewer and smaller MPEs, retarded pleural tumour dissemination and decreased pleural CD11b+Gr1+ accumulation compared with controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mutant KRAS promotes malignant pleural effusion formation

et al. 2017

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Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition.

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“…Myeloid cells play important roles in both innate immunity and tumorigenesis (Giannou et al, 2015; Stathopoulos et al, 2010; Zaynagetdinov et al, 2011). It is now well-accepted that macrophages and neutrophils can act as pro- or anti-tumorigenic cells during tumorigenesis depending on signals that they receive from the tumor and the tumor stroma (Fridlender and Albelda, 2012; Rajnavolgyi et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Neutrophil-Derived IL-1β Impairs the Efficacy of NF-κB Inhibitors against Lung Cancer

et al. 2016

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SUMMARY While epithelial NF-κB signaling is important for lung carcinogenesis, NF-κB inhibitors are ineffective for cancer treatment. To explain this paradox, we studied mice with genetic deletion of IKKβ in myeloid cells and found enhanced tumorigenesis in KrasG12D and urethane models of lung cancer. Myeloid-specific inhibition of NF-κB augmented pro-IL-1β processing by cathepsin G in neutrophils, leading to increased IL-1β and enhanced epithelial cell proliferation. Combined treatment with bortezomib, a proteasome inhibitor that blocks NF-κB activation, and IL-1 receptor antagonist reduced tumor formation and growth in vivo. In lung cancer patients, plasma IL-1β levels correlated with poor prognosis and IL-1β increased following bortezomib treatment. Together, our studies elucidate an important role for neutrophils and IL-1β in lung carcinogenesis and resistance to NF-κB inhibitors.

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Mast cells mediate malignant pleural effusion formation

Cited by 97 publications

References 58 publications

Malignant pleural effusion: from bench to bedside

Malignant pleural effusion: from bench to bedside

Mutant KRAS promotes malignant pleural effusion formation

Neutrophil-Derived IL-1β Impairs the Efficacy of NF-κB Inhibitors against Lung Cancer

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