NLRP3 Inflammasome From Bench to Bedside: New Perspectives for Triple Negative Breast Cancer

Sonnessa, Margherita; Cioffi, Antonella; Brunetti, Oronzo; Silvestris, Nicola; Zito, Francesco Alfredo; Saponaro, Concetta; Mangia, A.

doi:10.3389/fonc.2020.01587

Cited by 23 publications

(17 citation statements)

References 109 publications

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“…Abnormal activation of TLRs can induce immune reaction in tumor cells and thereby modulate the TME ( 42 ). NOD-like receptors (NLRs) are reported to be capable of activating innate immune responses ( 43 ). NLRs play crucial roles in immune functions, metastasis and tumorigenesis ( 44 , 45 ).…”

Section: Discussionmentioning

confidence: 99%

Significance of CD47 and Its Association With Tumor Immune Microenvironment Heterogeneity in Ovarian Cancer

et al. 2021

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BackgroundIt was reported that tumor heterogeneity and the surrounding tumor microenvironment (TME) in ovarian cancer affects immunotherapy efficacy and patient outcomes. And the TME of ovarian cancer is intrinsically heterogeneous. CD47 plays vital roles in cell functional behavior and immune homeostasis relating to cancer prognosis. But how it affects TME and its contribution to heterogeneity in ovarian cancer has not been fully illustrated. Therefore, we aimed to identify a prognostic biomarker which may help explain tumor immune microenvironment heterogeneity of ovarian cancer.MethodsCancer single-cell state atlas (CancerSEA) was used to evaluate functional role of CD47. Several bioinformatics database including Oncomine, Gene Expression Profiling Interaction Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), The Human Protein Atlas (HPA), Ualcan and Kaplan-Meier plotter (KM plotter) were applied to illustrate correlation of CD47 with ovarian cancer prognosis and immune infiltration. Tumor Immune Single-cell Hub (TISCH) single cell database was employed to evaluate correlation of CD47 with tumor microenvironment. GeneMANIA was implemented to identify regulation networks of CD47. Differentially expressed genes (DEGs) between CD47 high and low expression groups were analyzed with R package DESeq2. Kyoto encyclopedia of genes and genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) were utilized to explore how CD47 affect the immune related cell signaling pathway.ResultsCD47 expression was upregulated and connected to worse OS and PFS in ovarian cancer. Close relation was found between CD47 expression level and immune infiltration in ovarian cancer, especially with Treg cells, Monocytes, Macrophages and T cell exhaustion (P<0.05). The CD47 expression level was relatively low in plasma cells, dendritic cells and Mono/Macro cells of OV_GSE115007, in myofibroblasts, fibroblasts and endothelial cells of OV_GSE118828, compared to malignant cells of OV_GSE118828 dataset. The cell components and distribution in primary and metastatic ovarian cancer are quite distinct, which may lead to TME heterogeneity of ovarian cancer.ConclusionOur results indicated that CD47 is closely correlated to ovarian cancer immune microenvironment and might induce ovarian cancer heterogeneity. Therefore, CD47 may be used as a candidate prognostic biomarker and provide us with new insights into potential immunotherapy in ovarian cancer patients.

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Section: Discussionmentioning

confidence: 99%

Significance of CD47 and Its Association With Tumor Immune Microenvironment Heterogeneity in Ovarian Cancer

et al. 2021

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“…The primary function of the NLRP3 inflammasome is to inducing cell pyroptosis via cleaving Gasdermin D (GSDMD) and to enhancing inflammation by releasing interleukin 1β (IL1β) and interleukin 18 (IL18) [ 7 , 10 ]. It has been demonstrated in the previous studies that the NLRP3 inflammasome and its downstream products are involved in the carcinogenesis of many cancers, including colitis-associated cancer, lung cancer, breast cancer, and melanoma [ 7 , 11 , 12 ]. In terms of CRC, it has been reported that increased susceptibility of dextran sulfate sodium (DSS)-induced colitis and colitis-associated tumorigenesis in NLRP3 −/− and IL18 −/− mice, respectively [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Low NLRP3 expression predicts a better prognosis of colorectal cancer

et al. 2021

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Background: NOD-like receptor pyrin domain-3 (NLRP3) inflammasome activation is a double-edged sword in tumorigenesis. Whether NLRP3 is involved in the progression and prognosis of colorectal cancer (CRC) remains elucidated and is the focus of this study. Methods: Immunohistochemistry (IHC) was applied on tissue microarray to determine the expression of NLRP3 in CRC patients. All 100 patients were divided into the low NLRP3 group and the high NLRP3 group according to their NLRP3 IHC scoring. Additionally, CRC xenografts were established by injecting HCT116 or RKO cells subcutaneously into nude mice. Cell proliferation and apoptosis were determined in HCT116 cells after treatment with NLRP3 inhibitor MCC950. Results: NLRP3 expression was up-regulated in colon adenocarcinoma tissues compared with that in paracancerous tissues in CRC patients, HCT116 xenograft, and RKO xenograft. High NLRP3 level correlated with the advanced TNM classification of malignant tumors, the occurrence of distant metastasis, vascular invasion, and positive lymph nodes. Furthermore, Kaplan-Meier survival analysis revealed that a high NLRP3 level was associated with a low 5-year survival rate and even a low 10-year survival rate. Moreover, the multivariable Cox proportional hazards regression model implied that NLRP3 expression level was an independent risk factor for CRC prognosis. Inhibition of NLRP3 by MCC950 suppressed cell proliferation, induced cell apoptosis, and decreased mRNA levels of interleukin 1β and interleukin 18 in HCT116 cells. Conclusions: High level of NLRP3 predicts poor survival in CRC patients. NLRP3 is a putative prognostic biomarker and a potential therapeutic target in CRC treatments.

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“…The tumor microenvironment (TME) is the result of a multistep process characterized by reprogramming across cellular components. Different critical oncogenic processes contribute to changing the TME, such as angiogenesis, invasion/metastasis, drug resistance and chronic inflammation ( 1 ). Uncontrolled chronic inflammation has been shown to play a pivotal role in the onset and development of cancer via the up-regulation of growth factors, free radicals, prostaglandins and pro-inflammatory cytokines [interleukin (IL)-1β and IL-18] ( 2 , 3 ).…”

Section: Introductionmentioning

confidence: 99%

Prognostic Value of NLRP3 Inflammasome and TLR4 Expression in Breast Cancer Patients

et al. 2021

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Inflammasome complexes play a pivotal role in different cancer types. NOD-like receptor protein 3 (NLRP3) inflammasome is one of the most well-studied inflammasomes. Activation of the NLRP3 inflammasome induces abnormal secretion of soluble cytokines, generating advantageous inflammatory surroundings that support tumor growth. The expression levels of the NLRP3, PYCARD and TLR4 were determined by immunohistochemistry in a cohort of primary invasive breast carcinomas (BCs). We observed different NLRP3 and PYCARD expressions in non-tumor vs tumor areas (p<0.0001). All the proteins were associated to more aggressive clinicopathological characteristics (tumor size, grade, tumor proliferative activity etc.). Univariate analyses were carried out and related Kaplan-Meier curves plotted for NLRP3, PYCARD and TLR4 expression. Patients with higher NLRP3 and TLR4 expression had worse 5-year disease-free survival (DFS) compared to patients with lower NLRP3 and TLR4 expression (p =0.021 and p = 0.009, respectively). In multivariate analysis, TLR4 was confirmed as independent prognostic factors for DFS (HR = 2.03, 95% CI 1.16–3.57, p = 0.014), and high NLRP3 expression showed a slight association with DFS (HR = 1.75, 95% CI 0.98–3.15, p = 0.06). In conclusion, we showed TLR4 expression as independent prognostic factors and we highlighted for the first time that high expression of NLRP3 is linked to a poor prognosis in BC patients. These results suggest that NLRP3 and TLR4 could be two new good prognostic factor for BC patients.

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NLRP3 Inflammasome From Bench to Bedside: New Perspectives for Triple Negative Breast Cancer

Cited by 23 publications

References 109 publications

Significance of CD47 and Its Association With Tumor Immune Microenvironment Heterogeneity in Ovarian Cancer

Significance of CD47 and Its Association With Tumor Immune Microenvironment Heterogeneity in Ovarian Cancer

Low NLRP3 expression predicts a better prognosis of colorectal cancer

Prognostic Value of NLRP3 Inflammasome and TLR4 Expression in Breast Cancer Patients

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