Interleukin-17 promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer

Pan, Bo; Shen, Jing; Cao, Jingyan; Zhou, Yi; Shang, Lihua; Shi, Jin; Cao, Shoubo; Che, Dehai; Liu, Fang; Yu, Yan

doi:10.1038/srep16053

Cited by 143 publications

(125 citation statements)

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“…In the tumor microenvironment, inflammatory cells and molecules influence almost every aspect of cancer progression [39]. VEGF is now accepted to play a major role in the continuous growth and metastasis of tumors [24]. Here, we found that DVDMS-SDT selectively downregulated TNF-α and VEGF protein expression in H446 cells.…”

Section: Discussionsupporting

confidence: 49%

“…When VEGF is overexpressed, it can contribute to disease. Solid cancers cannot grow beyond a limited size without an adequate blood supply; cancers that express VEGF are able to grow and metastasize [24]. Tumor necrosis factor (TNF)-α is a monocyte-derived cytotoxin that has been implicated in septic shock and cachexia [25].…”

Section: Dvdms-sdt Changes Cytokine Expression In H446 Cellsmentioning

confidence: 99%

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Sinoporphyrin Sodium-Mediated Sonodynamic Therapy Inhibits RIP3 Expression and Induces Apoptosis in the H446 Small Cell Lung Cancer Cell Line

Shen

Cao

Sun

et al. 2018

Cell Physiol Biochem

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Background/Aims: Sonodynamic therapy (SDT) is expected to be a new method to solve the clinical problems caused by advanced metastasis in patients with lung cancer. The use of ultrasound has the advantage of being noninvasive, with deep-penetration properties. This study explored the anti-tumor effect of SDT with a new sonosensitizer, sinoporphyrin sodium (DVDMS), on the human small cell lung cancer H446 cell line in vitro and in vivo. Methods: Absorption of DVDMS was detected by a fluorescence spectrophotometer, and DVDMS toxicity was determined using a Cell Counting Kit-8. Mitochondrial membrane potential (MMP) was assessed using the JC-1 fluorescent probe. Cell apoptosis was measured by flow cytometry, and apoptosis-related proteins were detected by western blotting. The expression of cytokines was measured using an enzyme-linked immunosorbent assay and quantitative real-time PCR. To verify the in vitro results, we detected tumor volumes and weight changes in a xenograft nude mouse model after DVDMS-SDT. Hematoxylin and eosin staining was used to observe changes to the tumor, heart, liver, spleen, lung, and kidney of the mice, and immunohistochemistry was used to examine changes in the expression of tumor CD34 and receptor-interacting protein kinase-3 (RIP3), while terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling was used to observe apoptosis in tumor tissues. Results: DVDMS-SDT-treated H446 cells increased the rate of cellular apoptosis and the levels of reactive oxygen species (ROS), cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, and caspase-10, and decreased the levels of MMP, RIP3, B-cell lymphoma 2, vascular endothelial growth factor, and tumor necrosis factor-α. The sonotoxic effect was mediated by ROS and was reduced by a ROS scavenger (N-acetyl-L-cysteine). In the in vivo mouse xenograft model, DVDMS-SDT showed efficient anti-cancer effects with no visible side effects. Conclusion: DVDMS-SDT induced apoptosis in H446 cells, in part by targeting mitochondria through the mitochondria-mediated apoptosis signaling pathway, and the extrinsic apoptosis pathway was also shown to be involved. Both apoptosis and changes in RIP3 expression were closely related to the generation of ROS. DVDMS-SDT will be advantageous for the management of small cell lung cancer due to its noninvasive characteristics.

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Section: Discussionsupporting

confidence: 49%

Section: Dvdms-sdt Changes Cytokine Expression In H446 Cellsmentioning

confidence: 99%

Sinoporphyrin Sodium-Mediated Sonodynamic Therapy Inhibits RIP3 Expression and Induces Apoptosis in the H446 Small Cell Lung Cancer Cell Line

Shen

Cao

Sun

et al. 2018

Cell Physiol Biochem

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“…This in turn may highlight therapeutic possibilities to inhibit STAT3 signaling in NSCLC. Yu and colleagues have also recently shown that IL-17 signaling through the IL-17R in NSCLC cells promotes angiogenesis via STAT3 mediated induction of pro-angiogenic factors [58].…”

Section: The Jak/stat Pathway As a Central Pathwaymentioning

confidence: 97%

“…More recently Pan et al, have demonstrated that IL-17 utilises the STAT3/GIV pathway to promote tumor angiogenesis of NSCLC by upregulating VEGF [58], and in clinical samples the combination of intratumoral IL-17 + cells and GIV expression serves as a better prognosticator for survival than either marker alone [58]. Additionally, higher levels of IL-17A were detected in serum of patients with lung adenocarcinoma compared to healthy controls, and higher IL-17A expression was found in lung adenocarcinoma tissue compared to neighbouring healthy lung tissue [55].…”

Section: Il-17 Prognostic and Predictive Value In Lung Cancermentioning

confidence: 97%

The IL-17-Th1/Th17 pathway: an attractive target for lung cancer therapy?

Joerger

Finn

Cuffe

et al. 2016

Expert Opinion on Therapeutic Targets

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There is strong pharmaceutical development of agents targeting the IL-17-TH17 pathway for the treatment of psoriasis (Ps) and psoriatic arthritis (PsA). Lung cancer accounts for 28% of all cancer-related deaths worldwide, and roughly 80% of patients with newly-diagnosed non-small cell lung cancer (NSCLC) present with metastatic disease, with a poor prognosis of around 12 months. Therefore, there is a high unmet medical need for the development of new and potent systemic treatments in this deadly disease. The emergence of immunotherapies such as anti-PD-1 or anti-PDL1 as candidate therapies in non-small cell lung cancer (NSCLC) indicates that targeting critical immuno-modulatory cytokines including those within the IL-17-Th1/Th17 axis may have proven benefit in the treatment of lung cancer. Areas covered: In this review we describe the current evidence for aberrant IL-17-Th1/Th17 settings in cancer, particularly with regard to targeting this axis in NSCLC. We further discuss the current agents under pharmaceutical development which could potentially target this axis, and discuss the current limitations and areas of concern regarding the use of these in lung cancer. Expert opinion: Current evidence suggests that moving forward agents targeting the IL-17-Th1/Th17 pathway may have novel new oncoimmunology indications in the treatment paradigm for NSCLC.

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“…T reg s, whose activation is under control of CTLA-1 checkpoint, have the specific ability to attenuate the extent of cancer associate immuneresponse and represents a common mechanism of immuneescape for cancer cells (26)(27)(28)(29). IL-17A is able to promote A B the switch of inactive T reg s in highly suppressive subsets that, in turn, can inhibit all the attempts of immune-system and tumor-specific CTLs to counteract tumor growth and development (29)(30)(31)(32) another very active CTL subset expressing the L selectin (CD62L), a trans-membrane protein which allows the binding to the specific receptor on tumor vessels and the consequent extravasation in the tumor sites (37). In our patients, we also found a significant increase of peripheral DCs expressing CD83 and CD80, a very efficient antigen presenting cell linage able to uptake and process antigen released by tumor tissues exposed to the cytotoxic drugs (38).…”

Section: Discussionmentioning

confidence: 99%

Anti-cancer activity of dose-fractioned mPE +/− bevacizumab regimen is paralleled by immune-modulation in advanced squamous NSLC patients

Pastina¹,

Nardone²,

Croci³

et al. 2017

J. Thorac. Dis.

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Background:Results from the BEVA2007 trial, suggest that the metronomic chemotherapy regimen with dose-fractioned cisplatin and oral etoposide (mPE) +/− bevacizumab, a monoclonal antibody to the vascular endothelial growth factor (VEGF), shows anti-angiogenic and immunological effects and is a safe and active treatment for metastatic non-small cell lung cancer (mNSCLC) patients. We carried out a retrospective analysis aimed to evaluate the antitumor effects of this treatment in a subset of patients with squamous histology. Methods: Retrospective analysis was carried out in a subset of 31 patients with squamous histology enrolled in the study between September 2007 and September 2015. All of the patients received chemotherapy with cisplatin (30 mg/sqm, days 1-3q21) and oral etoposide (50 mg, days 1-15q21) (mPE) and 14 of them also received bevacizumab 5 mg/kg on the day 3q21 (mPEBev regimen). Results: This treatment showed a disease control rate of 71% with a mean progression free survival (PFS) and overall survival (OS) of 13.6 and 17 months respectively. After 4 treatment courses, 6 patients showing a remarkable tumor shrinkage, underwent to radical surgery, attaining a significant advantage in term of survival (P=0.048). Kaplan-Meier and log-rank test identified the longest survival in patients presenting low baseline levels in neutrophil-to-lymphocyte ratio (NLR) (P=0.05), interleukin (IL) 17A (P=0.036), regulatory-T-cells (T reg s) (P=0.020), and activated CD83+ dendritic cells (DCs) (P=0.03). Conclusions: These results suggest that the mPE +/− bevacizumab regimen is feasible and should be tested in comparative trials in advanced squamous-NSCLC (sqNSCLC). Moreover, its immune-biological effects strongly suggest the investigation in sequential combinations with immune check-point inhibitors.

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Interleukin-17 promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer

Cited by 143 publications

References 50 publications

Sinoporphyrin Sodium-Mediated Sonodynamic Therapy Inhibits RIP3 Expression and Induces Apoptosis in the H446 Small Cell Lung Cancer Cell Line

Sinoporphyrin Sodium-Mediated Sonodynamic Therapy Inhibits RIP3 Expression and Induces Apoptosis in the H446 Small Cell Lung Cancer Cell Line

The IL-17-Th1/Th17 pathway: an attractive target for lung cancer therapy?

Anti-cancer activity of dose-fractioned mPE +/− bevacizumab regimen is paralleled by immune-modulation in advanced squamous NSLC patients

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