Tumor Necrosis Factor-α Promotes Malignant Pleural Effusion

Stathopoulos, Georgios T.; Kollintza, Androniki; Moschos, Charalampos; Psallidas, Ioannis; Sherrill, Taylor P.; Pitsinos, Emmanuel N.; Vassiliou, Spyridoula; Karatza, Marilena; Papiris, Spyros; Graf, Daniel; Orphanidou, Dora; Light, Richard W.; Roussos, Charis; Blackwell, Timothy S.; Kalomenidis, Ioannis

doi:10.1158/0008-5472.can-07-1064

Cited by 96 publications

(122 citation statements)

References 44 publications

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“…4) in relation to elevated NF-κB activation (Fig. 3B) agrees with that NF-κB activation leading to TNF-α production in tumor cells (31,32). NF-κB is a key regulator of MMP-2 and MMP-9 expression (33,34), even in SAS cells (35) Figure 5.…”

Section: Discussionsupporting

confidence: 81%

“…These results indicated elevation of the signaling pathway to NF-κB and resultant increase of NF-κB activation in the highly metastatic oral SCC cells. NF-κB activation leads to TNF-α production in cancer cells (31,32), thus, TNF-α secretion from the cancer cells was measured. In agreement with increased TNF-α mRNA expression ( Fig.…”

Section: Elevation Of Tnf-r1-nf-κb Pathway and Tnf-α Secretion In Gsamentioning

confidence: 99%

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Enhancement of active MMP release and invasive activity of lymph node metastatic tongue cancer cells by elevated signaling via the TNF-α-TNFR1-NF-κB pathway and a possible involvement of angiopoietin-like 4 in lung metastasis

Tanaka

Imamura

Yoneda

et al. 2016

International Journal of Oncology

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Abstract.To study the role of TNF-α in tongue cancer metastasis, we made highly metastatic cells from a human oral squamous cell carcinoma cell line (SAS) by repeating the passage in which the cells were injected into a nude mouse tongue and harvested from metastasized cervical lymph nodes. Cancer cells after 5 passages (GSAS/N5) increased invasive activity 7-fold in a TNF-α receptor 1 (TNFR1)-dependent manner and enhanced mRNA expression of TNF-α and TNFR1. In the highly metastatic cells, NF-κB activation was upregulated via elevated phosphorylation of Akt and Ikkα/β in the signaling pathway and secretion of TNF-α, active MMP-2 and MMP-9 increased. Suppression of increase of TNF-α mRNA expression and MMP secretion by NF-κB inhibitor NBD peptide suggested a positive feedback loop in GSAS/N5 cells; TNF-α activates NF-κB and activated NF-κB induces further TNF-α secretion, leading to increase of active MMP release and promotion of invasion and metastasis of the cells. GSAS/N5 cells that had been injected into the nude mouse tongue and harvested from metastasized lungs multiplied angiopoietin-like 4 (Angptl4) expression with enhanced migration activity, which indicated a possible involvement of Angptl4 in lung metastasis of the cells. These results suggest that TNF-α and Angptl4 promote metastasis of the oral cancer cells, thus, these molecules may be therapeutic targets for patients with tongue cancer. IntroductionThe American Cancer Society estimated 45,780 new cases of oral cavity and pharyngeal cancer, and 8,650 deaths from these tumors, in 2015 in the United States (1). By advances in surgery and radiation therapy, the 5-year survival rate for oropharyngeal cancer has increased to 66%, but the rate is still unsatisfactory in comparison with some other site cancers including prostate, thyroid and breast; the rates of these types of cancer are >90% (1). A primary cause for the unfavorable prognosis is patient death from the cancer metastasized at regional and distant sites (2-5). Squamous cell carcinoma (SCC) accounts for approximately 90% of oral and oropharyngeal malignancies in the United States and tongue is a common site of the malignant diseases (6,7). The rate of nodal metastasis is higher in tongue cancer patients than oral cavity cancer patients whose rate is 30% on their initial evaluation (8,9). Several studies have shown a high rate of occult nodal metastasis (20-40%) in tongue SCC patients with no evidence of regional spread on clinical or radiographic evaluation (8,10-15). There is a tendency that tongue cancer increases in young females in recent 2-3 decades (16-18). Thus, metastasis suppression is a main and urgent subject in the treatments of patients with tongue SCC.The process of metastasis is complex and involves tumor growth, the extra-cellular matrix breakdown, invasion to the vessels, escape from immune surveillance, transport to other sites with adhesion to the vessel, subsequent invasion into an organ where tumor cells proliferate, grow and spread. Various molecules participate in the pr...

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Section: Discussionsupporting

confidence: 81%

Section: Elevation Of Tnf-r1-nf-κb Pathway and Tnf-α Secretion In Gsamentioning

confidence: 99%

Enhancement of active MMP release and invasive activity of lymph node metastatic tongue cancer cells by elevated signaling via the TNF-α-TNFR1-NF-κB pathway and a possible involvement of angiopoietin-like 4 in lung metastasis

Tanaka

Imamura

Yoneda

et al. 2016

International Journal of Oncology

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“…To aid in elucidating MPE pathobiology, we have developed an immunocompetent model of MPE using syngeneic mice (13)(14)(15). Immunocompetent models are vital, because recent evidence has linked inflammation with enhanced formation, growth, and metastasis of tumors (16)(17)(18)(19).…”

mentioning

confidence: 99%

Host-derived Interleukin-5 Promotes Adenocarcinoma-induced Malignant Pleural Effusion

Stathopoulos¹,

Sherrill²,

Karabela³

et al. 2010

Am J Respir Crit Care Med

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Rationale: IL-5 is a T helper 2 cytokine important in the trafficking and survival of eosinophils. Because eosinophils can be found in malignant pleural effusions (MPE) from mice and humans, we asked whether IL-5 is involved in the pathogenesis of MPE. Objectives: To determine the role of IL-5 in MPE formation. Methods: The effects of IL-5 on experimental MPE induced in C57BL/6 mice by intrapleural injection of syngeneic lung (Lewis lung cancer [LLC]) or colon (MC38) adenocarcinoma cells were determined using wild-type (il5 1/1 ) and IL-5-deficient (il5 2/2 ) mice, exogenous administration of recombinant mouse (rm) IL-5, and in vivo antibody-mediated neutralization of endogenous IL-5. The direct effects of rmIL-5 on LLC cell proliferation and gene expression in vitro were determined by substrate reduction and microarray. Measurements and Main Results: Eosinophils and IL-5 were present in human and mouse MPE, but the cytokine was not detected in mouse (LLC) or human (A549) lung and mouse colon (MC38) adenocarcinoma-conditioned medium, suggesting production by host cells in MPE. Compared with il5 1/1 mice, il5 2/2 mice showed markedly diminished MPE formation in response to both LLC and MC38 cells. Exogenous IL-5 promoted MPE formation in il5 1/1 and il5 2/2 mice, whereas anti-IL-5 antibody treatment limited experimental MPE in il5 1/1 mice. Exogenous IL-5 had no effects on LLC cell proliferation and gene expression; however, IL-5 was found to be responsible for recruitment of eosinophils and tumor-promoting myeloid suppressor cells to MPE in vivo. Conclusions: Host-derived IL-5 promotes experimental MPE and may be involved in the pathogenesis of human MPE.

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“…Inflammation is a balance between pro-and anti-inflammatory mediators and appears to play a large role in tumour behavior and physiological responses to surgery. Lung cancer tumour cells, as with other malignant tumours, have higher baseline levels of TNF-α, IL-1 and IL-6 prior to surgery compared to nonmalignant controls, indicating that inflammatory changes are innate to the malignant process (22,23). Inflammation has also been significantly linked to physiological surgical stress in lung surgery, and an increased risk of post-surgical complications (24,25).…”

Section: Discussionmentioning

confidence: 99%

“…Inflammation has also been significantly linked to physiological surgical stress in lung surgery, and an increased risk of post-surgical complications (24,25). An increase in TNF-α levels was found to increase pleural vascular permeability in a murine model, a key factor in the accumulation of fluid in the pleura (22). Takenaka et al found that patients undergoing thoracic surgery who developed symptoms of systemic inflammatory response syndrome (with associated elevation of IL-6 concentrations) were admitted 4 days longer with increased pleural drainage volumes (7).…”

Section: Discussionmentioning

confidence: 99%

Does the usage of digital chest drainage systems reduce pleural inflammation and volume of pleural effusion following oncologic pulmonary resection?—A prospective randomized trial

Waele¹,

Agzarian²,

Hanna³

et al. 2017

J. Thorac. Dis.

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Background: Prolonged air leak and high-volume pleural drainage are the most common causes for delays in chest tube removal following lung resection. While digital pleural drainage systems have been successfully used in the management of post-operative air leak, their effect on pleural drainage and inflammation has not been studied before. We hypothesized that digital drainage systems (as compared to traditional analog continuous suction), using intermittent balanced suction, are associated with decreased pleural inflammation and postoperative drainage volumes, thus leading to earlier chest tube removal. Methods: One hundred and three [103] patients were enrolled and randomized to either analog (n=50) or digital (n=53) drainage systems following oncologic lung resection. Chest tubes were removed according to standardized, pre-defined protocol. Inflammatory mediators [interleukin-1B (IL-1B), 6, 8, tumour necrosis factor-alpha (TNF-α)] in pleural fluid and serum were measured and analysed. The primary outcome of interest was the difference in total volume of postoperative fluid drainage. Secondary outcome measures included duration of chest tube in-situ, prolonged air-leak incidence, length of hospital stay and the correlation between pleural effusion formation, degree of inflammation and type of drainage system used.Results: There was no significant difference in total amount of fluid drained or length of hospital stay between the two groups. A trend for shorter chest tube duration was found with the digital system when compared to the analog (P=0.055). Comparison of inflammatory mediator levels revealed no significant differences between digital and analog drainage systems. The incidence of prolonged post-operative air leak was significantly higher when using the analog system (9 versus 2 patients; P=0.025). Lobectomy was associated with longer chest tube duration (P=0.001) and increased fluid drainage when compared to sublobar resection (P<0.001), regardless of drainage system. Conclusions: Use of post-lung resection digital drainage does not appear to decrease pleural fluid formation, but is associated with decreased prolonged air leaks. Total pleural effusion volumes did not differ with the type of drainage system used. These findings support previously established benefits of the digital system in decreasing prolonged air leaks, but the advantages do not appear to extend to decreased pleural fluid formation.

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Tumor Necrosis Factor-α Promotes Malignant Pleural Effusion

Cited by 96 publications

References 44 publications

Enhancement of active MMP release and invasive activity of lymph node metastatic tongue cancer cells by elevated signaling via the TNF-α-TNFR1-NF-κB pathway and a possible involvement of angiopoietin-like 4 in lung metastasis

Enhancement of active MMP release and invasive activity of lymph node metastatic tongue cancer cells by elevated signaling via the TNF-α-TNFR1-NF-κB pathway and a possible involvement of angiopoietin-like 4 in lung metastasis

Host-derived Interleukin-5 Promotes Adenocarcinoma-induced Malignant Pleural Effusion

Does the usage of digital chest drainage systems reduce pleural inflammation and volume of pleural effusion following oncologic pulmonary resection?—A prospective randomized trial

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