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Tumor necrosis factor in lung cancer: Complex roles in biology and resistance to treatment.

ABSTRACT: Tumor necrosis factor (TNF) and its receptors are widely expressed in non-small cell lung cancer (NSCLC). TNF has an established role in inflammation and also plays a key role in inflammation-induced cancer. TNF can induce cell death in cancer cells and has been used as a treatment in certain types of cancer. However, TNF is likely to play an oncogenic role in multiple types of cancer, including NSCLC. TNF is a key activator of the transcription factor NF-?B. NF-?B, in turn, is a key effector of TNF in inflammation-induced cancer. Data from The Cancer Genome Atlas database suggest that TNF could be a biomarker in NSCLC and indicate a complex role for TNF and its receptors in NSCLC. Recent studies have reported that TNF is rapidly upregulated in NSCLC in response to targeted treatment with epidermal growth factor receptor (EGFR) inhibition, and this upregulation leads to NF-?B activation. The TNF upregulation and consequent NF-?B activation play a key role in mediating both primary and secondary resistance to EGFR inhibition in NSCLC, and a combined inhibition of EGFR and TNF can overcome therapeutic resistance in experimental models. TNF may mediate the toxic side effects of immunotherapy and may also modulate resistance to immune checkpoint inhibitors. Drugs inhibiting TNF are widely used for the treatment of various inflammatory and rheumatologic diseases and could be quite useful in combination with targeted therapy of NSCLC and other cancers.

SUBMITTER: Gong K

PROVIDER: S-EPMC7773536 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Tumor necrosis factor in lung cancer: Complex roles in biology and resistance to treatment.

Gong Ke K Guo Gao G Beckley Nicole N Zhang Yue Y Yang Xiaoyao X Sharma Mishu M Habib Amyn A AA

Neoplasia (New York, N.Y.) 20201226 2

Tumor necrosis factor (TNF) and its receptors are widely expressed in non-small cell lung cancer (NSCLC). TNF has an established role in inflammation and also plays a key role in inflammation-induced cancer. TNF can induce cell death in cancer cells and has been used as a treatment in certain types of cancer. However, TNF is likely to play an oncogenic role in multiple types of cancer, including NSCLC. TNF is a key activator of the transcription factor NF-κB. NF-κB, in turn, is a key effector of ...[more]

PMID: 33373873

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Project description:Background and aimAnti-tumor necrosis factor-α (anti-TNF-α) agents have been used for inflammatory bowel disease; however, it has up to 30% nonresponse rate. Identifying molecular pathways and finding reliable diagnostic biomarkers for patient response to anti-TNF-α treatment are needed.MethodsPublicly available transcriptomic data from inflammatory bowel disease patients receiving anti-TNF-α therapy were systemically collected and integrated. In silico flow cytometry approaches and Metascape were applied to evaluate immune cell populations and to perform gene enrichment analysis, respectively. Genes identified within enrichment pathways validated in neutrophils were tracked in an anti-TNF-α-treated animal model (with lipopolysaccharide-induced inflammation). The receiver operating characteristic curve was applied to all genes to identify the best prediction biomarkers.ResultsA total of 449 samples were retrieved from control, baseline, and after primary anti-TNF-α therapy or placebo. No statistically significant differences were observed between anti-TNF-α treatment responders and nonresponders at baseline in immune microenvironment scores. Neutrophil, endothelial cell, and B-cell populations were higher in baseline nonresponders, and chemotaxis pathways may contribute to the treatment resistance. Genes related to chemotaxis pathways were significantly upregulated in lipopolysaccharide-induced neutrophils, but no statistically significant changes were observed in neutrophils treated with anti-TNF-α. Interleukin 13 receptor subunit alpha 2 (IL13RA2) is the best predictor (receiver operating characteristic curve: 80.7%, 95% confidence interval: 73.8-87.5%), with a sensitivity of 68.13% and specificity of 84.93%, and significantly higher in nonresponders compared with responders (P < 0.0001).ConclusionsHyperactive neutrophil chemotaxis influences responses to anti-TNF-α treatment, and IL13RA2 is a potential biomarker to predict anti-TNF-α treatment response.

Project description:PurposeThis meta-analysis was performed to clarify the association between tumor necrosis factor alpha (TNF-α) gene polymorphisms and open angle glaucoma (OAG) risks, and the association between the TNF-α level in aqueous humor (AH) and the risks of glaucoma.MethodsA computerized literature search was performed for the relevant available studies from three databases including PubMed, ISI Web of Science, and Embase. The fixed or random effect model was selected based on the heterogeneity test using the Q test and the I(2) statistic. The associations between TNF-α gene polymorphisms and OAG risks were estimated by calculating pooled odds ratios (ORs) and the 95% confidence interval (CI), while a pooled standardized mean difference with 95% CI was used for the comparison of TNF-α levels in AH between patients with OAG and controls. Publication bias was estimated using Begg's funnel plots and Egger's regression test.ResultsA total of 14 (1,182 cases and 3,003 controls), five (808 cases and 1,039 controls), three (645 cases and 666 controls), and three studies (404 cases and 625 controls) were finally included in the analyses for the associations between TNF-α -308G/A, -857C/T, -863C/A, and -238G/A polymorphisms and the risks of OAG, respectively. The combined results showed that the TNF-α -308G/A gene polymorphism was significantly associated with risks of high-tension glaucoma (A versus G: OR=1.660, 95% CI=1.033-2.667; AA/AG versus GG: OR=1.713, 95% CI=1.10-2.651), but not with normal tension glaucoma or exfoliation glaucoma. Ethnicity-stratified analysis revealed that a significant association also existed in Asians (A versus G: OR=1.947, 95% CI=1.097-3.456; AA/AG versus GG: OR=1.949, 95% CI=1.140-3.332). None of the other polymorphisms was significantly associated with OAG risks. Furthermore, the pooled results of six studies showed that the TNF-α levels in the AH of patients with OAG was higher than that of the control subjects (standardized mean difference=0.517, 95% CI=0.207-0.826, p=0.001). Probability of publication bias was low across all comparisons illustrated by the funnel plots and Egger's test.ConclusionsThis meta-analysis suggests that patients with OAG may have higher TNF-α levels compared with the control subjects, and the TNF-α -308G/A polymorphism is significantly associated with the risks of high-tension glaucoma. Since potential confounders could not be ruled out completely, further studies are needed to confirm these results.

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Tumor necrosis factor in lung cancer: Complex roles in biology and resistance to treatment.

Publications

Tumor necrosis factor in lung cancer: Complex roles in biology and resistance to treatment.

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