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1
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Xu P, Du Z, Xie X, Yang L, Zhang J. Cancer marker TNFRSF1A: From single‑cell heterogeneity of renal cell carcinoma to functional validation. Oncol Lett 2024; 28:425. [PMID: 39021735 PMCID: PMC11253100 DOI: 10.3892/ol.2024.14559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 06/06/2024] [Indexed: 07/20/2024] Open
Abstract
During the progression of renal cell carcinoma (RCC), tumor growth, metastasis and treatment response heterogeneity are regulated by both the tumor itself and the tumor microenvironment (TME). The aim of the present study was to investigate the role of the TME in RCC and construct a crosstalk network for clear cell RCC (ccRCC). An additional aim was to evaluate whether TNF receptor superfamily member 1A (TNFRSF1A) is a potential therapeutic target for ccRCC. Single-cell data analysis of RCC was performed using the GSE152938 dataset, focusing on key cellular components and their involvement in the ccRCC TME. Additionally, cell-cell communication was analyzed to elucidate the complex network of the ccRCC microenvironment. Analyses of data from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium databases were performed to further mine the key TNF receptor genes, with a particular focus on the prediction and assessment of the cancer-associated features of TNFRSF1A. In addition, following the silencing of TNFRSF1A using small interfering RNA in the 786-O ccRCC cell line, a number of in vitro experiments were conducted to further investigate the cancer-promoting characteristics of TNFRSF1A. These included 5-ethynyl-2'-deoxyuridine incorporation, Cell Counting Kit-8, colony formation, Transwell, cell cycle and apoptosis assays. The TNF signaling pathway was found to have a critical role in the development of ccRCC. Based on the specific crosstalk identified between TNF and TNFRSF1A, the communication of this signaling pathway within the TME was elucidated. The results of the cellular phenotype experiments indicated that TNFRSF1A promotes the proliferation, migration and invasion of ccRCC cells. Consequently, it is proposed that targeting TNFRSF1A may disrupt tumor progression and serve as a therapeutic strategy. In conclusion, by understanding the TME and identifying significant crosstalk within the TNF signaling pathway, the potential of TNFRSF1A as a therapeutic target is highlighted. This may facilitate an advance in precision medicine and improve the prognosis for patients with RCC.
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Affiliation(s)
- Ping Xu
- Department of Ultrasound, Ningbo Yinzhou No. 2 Hospital, Ningbo, Zhejiang 315153, P.R. China
| | - Zusheng Du
- Department of Ultrasound, Ningbo Yinzhou No. 2 Hospital, Ningbo, Zhejiang 315153, P.R. China
| | - Xiaohong Xie
- Department of Ultrasound, Ningbo Yinzhou No. 2 Hospital, Ningbo, Zhejiang 315153, P.R. China
| | - Lifei Yang
- Department of Ultrasound, Ningbo Yinzhou No. 2 Hospital, Ningbo, Zhejiang 315153, P.R. China
| | - Jingjing Zhang
- Department of Ultrasound, Ningbo Yinzhou No. 2 Hospital, Ningbo, Zhejiang 315153, P.R. China
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2
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Jeong SU, Park JM, Yoon SY, Hwang HS, Go H, Shin DM, Ju H, Sung CO, Lee JL, Jeong G, Cho YM. IFITM3-mediated activation of TRAF6/MAPK/AP-1 pathways induces acquired TKI resistance in clear cell renal cell carcinoma. Investig Clin Urol 2024; 65:84-93. [PMID: 38197755 PMCID: PMC10789540 DOI: 10.4111/icu.20230294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/19/2023] [Accepted: 11/13/2023] [Indexed: 01/11/2024] Open
Abstract
PURPOSE Vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been the standard of care for advanced and metastatic clear cell renal cell carcinoma (ccRCC). However, the therapeutic effect of TKI monotherapy remains unsatisfactory given the high rates of acquired resistance to TKI therapy despite favorable initial tumor response. MATERIALS AND METHODS To define the TKI-resistance mechanism and identify new therapeutic target for TKI-resistant ccRCC, an integrative differential gene expression analysis was performed using acquired resistant cohort and a public dataset. Sunitinib-resistant RCC cell lines were established and used to test their malignant behaviors of TKI resistance through in vitro and in vivo studies. Immunohistochemistry was conducted to compare expression between the tumor and normal kidney and verify expression of pathway-related proteins. RESULTS Integrated differential gene expression analysis revealed increased interferon-induced transmembrane protein 3 (IFITM3) expression in post-TKI samples. IFITM3 expression was increased in ccRCC compared with the normal kidney. TKI-resistant RCC cells showed high expression of IFITM3 compared with TKI-sensitive cells and displayed aggressive biologic features such as higher proliferative ability, clonogenic survival, migration, and invasion while being treated with sunitinib. These aggressive features were suppressed by the inhibition of IFITM3 expression and promoted by IFITM3 overexpression, and these findings were confirmed in a xenograft model. IFITM3-mediated TKI resistance was associated with the activation of TRAF6 and MAPK/AP-1 pathways. CONCLUSIONS These results demonstrate IFITM3-mediated activation of the TRAF6/MAPK/AP-1 pathways as a mechanism of acquired TKI resistance, and suggest IFITM3 as a new target for TKI-resistant ccRCC.
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Affiliation(s)
- Se Un Jeong
- Department of Pathology, Ewha Womans University Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, Korea
| | - Ja-Min Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sun Young Yoon
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hee Sang Hwang
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Heounjeong Go
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong-Myung Shin
- Department of Cell and Genetic Engineering, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyein Ju
- Department of Cell and Genetic Engineering, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chang Ohk Sung
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae-Lyun Lee
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gowun Jeong
- AI Recommendation, T3K, SK Telecom, Seoul, Korea
| | - Yong Mee Cho
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Chen Y, Zhou X, Xie Y, Wu J, Li T, Yu T, Pang Y, Du W. Establishment of a Seven-Gene Signature Associated with CD8 + T Cells through the Utilization of Both Single-Cell and Bulk RNA-Sequencing Techniques in Clear Cell Renal Cell Carcinoma. Int J Mol Sci 2023; 24:13729. [PMID: 37762031 PMCID: PMC10530336 DOI: 10.3390/ijms241813729] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/01/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Tumor immune microenvironment constituents, such as CD8+ T cells, have emerged as crucial focal points for cancer immunotherapy. Given the absence of reliable biomarkers for clear cell renal cell carcinoma (ccRCC), we aimed to ascertain a molecular signature that could potentially be linked to CD8+ T cells. The differentially expressed genes (DEGs) linked to CD8+ T cells were identified through an analysis of single-cell RNA sequencing (scRNA-seq) data obtained from the Gene Expression Omnibus (GEO) database. Subsequently, immune-associated genes were obtained from the InnateDB and ImmPort datasets and were cross-referenced with CD8+ T-cell-associated DEGs to generate a series of DEGs linked to immune response and CD8+ T cells. Patients with ccRCC from the Cancer Genome Atlas (TCGA) were randomly allocated into testing and training groups. A gene signature was established by conducting LASSO-Cox analysis and subsequently confirmed using both the testing and complete groups. The efficacy of this signature in evaluating immunotherapy response was assessed on the IMvigor210 cohort. Finally, we employed various techniques, including CIBERSORT, ESTIMATE, ssGSEA, and qRT-PCR, to examine the immunological characteristics, drug responses, and expression of the signature genes in ccRCC. Our findings revealed 206 DEGs linked to immune response and CD8+ T cells, among which 65 genes were correlated with overall survival (OS) in ccRCC. A risk assessment was created utilizing a set of seven genes: RARRES2, SOCS3, TNFSF14, XCL1, GRN, CLDN4, and RBP7. The group with a lower risk showed increased expression of CD274 (PD-L1), suggesting a more favorable response to anti-PD-L1 treatment. The seven-gene signature demonstrated accurate prognostic prediction for ccRCC and holds potential as a clinical reference for treatment decisions.
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Affiliation(s)
- Yubin Chen
- Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China; (Y.C.); (X.Z.); (Y.X.); (J.W.); (T.L.); (T.Y.); (Y.P.)
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China
| | - Xinyu Zhou
- Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China; (Y.C.); (X.Z.); (Y.X.); (J.W.); (T.L.); (T.Y.); (Y.P.)
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China
| | - Yanwei Xie
- Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China; (Y.C.); (X.Z.); (Y.X.); (J.W.); (T.L.); (T.Y.); (Y.P.)
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China
| | - Jianan Wu
- Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China; (Y.C.); (X.Z.); (Y.X.); (J.W.); (T.L.); (T.Y.); (Y.P.)
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China
| | - Tingting Li
- Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China; (Y.C.); (X.Z.); (Y.X.); (J.W.); (T.L.); (T.Y.); (Y.P.)
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China
| | - Tian Yu
- Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China; (Y.C.); (X.Z.); (Y.X.); (J.W.); (T.L.); (T.Y.); (Y.P.)
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China
| | - Yipeng Pang
- Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China; (Y.C.); (X.Z.); (Y.X.); (J.W.); (T.L.); (T.Y.); (Y.P.)
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China
| | - Wenlong Du
- Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China; (Y.C.); (X.Z.); (Y.X.); (J.W.); (T.L.); (T.Y.); (Y.P.)
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou 221004, China
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Wang K, Xuan Z, Liu X, Zheng M, Yang C, Wang H. Immunomodulatory role of metalloproteinase ADAM17 in tumor development. Front Immunol 2022; 13:1059376. [PMID: 36466812 PMCID: PMC9715963 DOI: 10.3389/fimmu.2022.1059376] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 11/03/2022] [Indexed: 12/25/2023] Open
Abstract
ADAM17 is a member of the a disintegrin and metalloproteinase (ADAM) family of transmembrane proteases involved in the shedding of some cell membrane proteins and regulating various signaling pathways. More than 90 substrates are regulated by ADAM17, some of which are closely relevant to tumor formation and development. Besides, ADAM17 is also responsible for immune regulation and its substrate-mediated signal transduction. Recently, ADAM17 has been considered as a major target for the treatment of tumors and yet its immunomodulatory roles and mechanisms remain unclear. In this paper, we summarized the recent understanding of structure and several regulatory roles of ADAM17. Importantly, we highlighted the immunomodulatory roles of ADAM17 in tumor development, as well as small molecule inhibitors and monoclonal antibodies targeting ADAM17.
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Affiliation(s)
- Kai Wang
- Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China
| | - Zixue Xuan
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Xiaoyan Liu
- Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China
| | - Meiling Zheng
- Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China
| | - Chao Yang
- National Engineering Research Center for Marine Aquaculture, Institute of Innovation & Application, Zhejiang Ocean University, Zhoushan, China
| | - Haiyong Wang
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
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5
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Xiang Y, Zheng G, Zhong J, Sheng J, Qin H. Advances in Renal Cell Carcinoma Drug Resistance Models. Front Oncol 2022; 12:870396. [PMID: 35619895 PMCID: PMC9128023 DOI: 10.3389/fonc.2022.870396] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 03/23/2022] [Indexed: 11/13/2022] Open
Abstract
Renal cell carcinoma (RCC) is the most common form of kidney cancer. Systemic therapy is the preferred method to eliminate residual cancer cells after surgery and prolong the survival of patients with inoperable RCC. A variety of molecular targeted and immunological therapies have been developed to improve the survival rate and prognosis of RCC patients based on their chemotherapy-resistant properties. However, owing to tumor heterogeneity and drug resistance, targeted and immunological therapies lack complete and durable anti-tumor responses; therefore, understanding the mechanisms of systemic therapy resistance and improving clinical curative effects in the treatment of RCC remain challenging. In vitro models with traditional RCC cell lines or primary cell culture, as well as in vivo models with cell or patient-derived xenografts, are used to explore the drug resistance mechanisms of RCC and screen new targeted therapeutic drugs. Here, we review the established methods and applications of in vivo and in vitro RCC drug resistance models, with the aim of improving our understanding of its resistance mechanisms, increasing the efficacy of combination medications, and providing a theoretical foundation for the development and application of new drugs, drug screening, and treatment guidelines for RCC patients.
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Affiliation(s)
- Yien Xiang
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, China
| | - Ge Zheng
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, China
| | - Jianfeng Zhong
- Department of Clinical Laboratory, Second Hospital of Jilin University, Changchun, China
| | - Jiyao Sheng
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, China
| | - Hanjiao Qin
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
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6
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Wolf C, Smith S, van Wijk SJL. Zafirlukast Induces VHL- and HIF-2α-Dependent Oxidative Cell Death in 786-O Clear Cell Renal Carcinoma Cells. Int J Mol Sci 2022; 23:ijms23073567. [PMID: 35408930 PMCID: PMC8999127 DOI: 10.3390/ijms23073567] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/14/2022] [Accepted: 03/22/2022] [Indexed: 02/01/2023] Open
Abstract
Mutations in the Von Hippel–Lindau (VHL) gene are the driving force in many forms of clear cell renal cell carcinoma (ccRCC) and promote hypoxia-inducible factor (HIF)-dependent tumor proliferation, metastasis and angiogenesis. Despite the progress that has already been made, ccRCC generally remain resistant to conventional therapies and ccRCC patients suffer from metastasis and acquired resistance, highlighting the need for novel therapeutic options. Cysteinyl leukotriene receptor 1 (CysLTR1) antagonists, like zafirlukast, are administered in bronchial asthma to control eicosanoid signaling. Intriguingly, long-term use of zafirlukast decreases cancer risk and leukotriene receptor antagonists inhibit tumor growth, but the mechanisms still remain unexplored. Therefore, we aim to understand the mechanisms of zafirlukast-mediated cell death in ccRCC cells. We show that zafirlukast induces VHL-dependent and TNFα-independent non-apoptotic and non-necroptotic cell death in ccRCC cells. Cell death triggered by zafirlukast could be rescued with antioxidants and the PARP-1 inhibitor Olaparib, and additionally relies on HIF-2α. Finally, MG-132-mediated proteasome inhibition sensitized VHL wild-type cells to zafirlukast-induced cell death and inhibition of HIF-2α rescued zafirlukast- and MG-132-triggered cell death. Together, these results highlight the importance of VHL, HIF and proteasomal degradation in zafirlukast-induced oxidative cell death with potentially novel therapeutic implications for ccRCC.
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7
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Molecular Mechanisms of Resistance to Immunotherapy and Antiangiogenic Treatments in Clear Cell Renal Cell Carcinoma. Cancers (Basel) 2021; 13:cancers13235981. [PMID: 34885091 PMCID: PMC8656474 DOI: 10.3390/cancers13235981] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/24/2021] [Accepted: 11/24/2021] [Indexed: 12/15/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype arising from renal cell carcinomas. This tumor is characterized by a predominant angiogenic and immunogenic microenvironment that interplay with stromal, immune cells, and tumoral cells. Despite the obscure prognosis traditionally related to this entity, strategies including angiogenesis inhibition with tyrosine kinase inhibitors (TKIs), as well as the enhancement of the immune system with the inhibition of immune checkpoint proteins, such as PD-1/PDL-1 and CTLA-4, have revolutionized the treatment landscape. This approach has achieved a substantial improvement in life expectancy and quality of life from patients with advanced ccRCC. Unfortunately, not all patients benefit from this success as most patients will finally progress to these therapies and, even worse, approximately 5 to 30% of patients will primarily progress. In the last few years, preclinical and clinical research have been conducted to decode the biological basis underlying the resistance mechanisms regarding angiogenic and immune-based therapy. In this review, we summarize the insights of these molecular alterations to understand the resistance pathways related to the treatment with TKI and immune checkpoint inhibitors (ICIs). Moreover, we include additional information on novel approaches that are currently under research to overcome these resistance alterations in preclinical studies and early phase clinical trials.
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8
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Hua X, Ge S, Zhang J, Xiao H, Tai S, Yang C, Zhang L, Liang C. A costimulatory molecule-related signature in regard to evaluation of prognosis and immune features for clear cell renal cell carcinoma. Cell Death Discov 2021; 7:252. [PMID: 34537809 PMCID: PMC8449780 DOI: 10.1038/s41420-021-00646-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 08/17/2021] [Accepted: 09/07/2021] [Indexed: 12/12/2022] Open
Abstract
Costimulatory molecules have been proven to enhance antitumor immune responses, but their roles in clear cell renal cell carcinoma (ccRCC) remain unexplored. In this study, we aimed to explore the gene expression profiles of costimulatory molecule genes in ccRCC and construct a prognostic signature to improve treatment decision-making and clinical outcomes. We performed the first comprehensive analysis of costimulatory molecules in patients with ccRCC and identified 13 costimulatory molecule genes with prognostic values and diagnostic values. Consensus clustering analysis based on these 13 costimulatory molecular genes showed different distribution patterns and prognostic differences for the two clusters identified. Then, a costimulatory molecule-related signature was constructed based on these 13 costimulatory molecular genes, and validated in an external dataset, showing good performance for predicting a patient’s prognosis. The signature was an independent risk factor for ccRCC patients and was significantly correlated with patients’ clinical factors, which could be used as a complement for clinical factors. In addition, the signature was associated with the tumor immune microenvironment and the response to immunotherapy. Patients identified as high-risk based on our signature exhibited a high mutation frequency, a high level of immune cell infiltration, and an immunosuppressive microenvironment. High-risk patients tended to have high cytolytic activity scores and immunophenoscore of CTLA4 and PD1/PD-L1/PD-L2 blocker than low-risk patients, suggesting these patients may be more suitable for immunotherapy. Therefore, our signature could provide clinicians with prognosis predictions and help guide treatment for ccRCC patients.
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Affiliation(s)
- Xiaoliang Hua
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China.,The Institute of Urology, Anhui Medical University, Hefei, China
| | - Shengdong Ge
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China.,The Institute of Urology, Anhui Medical University, Hefei, China
| | - Jiong Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China.,The Institute of Urology, Anhui Medical University, Hefei, China
| | - Haibing Xiao
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China.,The Institute of Urology, Anhui Medical University, Hefei, China
| | - Sheng Tai
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China.,The Institute of Urology, Anhui Medical University, Hefei, China
| | - Cheng Yang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. .,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China. .,The Institute of Urology, Anhui Medical University, Hefei, China.
| | - Li Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. .,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China. .,The Institute of Urology, Anhui Medical University, Hefei, China.
| | - Chaozhao Liang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. .,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China. .,The Institute of Urology, Anhui Medical University, Hefei, China. .,Anhui Institute of translational medicine, Hefei, China.
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Benoot T, Piccioni E, De Ridder K, Goyvaerts C. TNFα and Immune Checkpoint Inhibition: Friend or Foe for Lung Cancer? Int J Mol Sci 2021; 22:ijms22168691. [PMID: 34445397 PMCID: PMC8395431 DOI: 10.3390/ijms22168691] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor necrosis factor-alpha (TNFα) can bind two distinct receptors (TNFR1/2). The transmembrane form (tmTNFα) preferentially binds to TNFR2. Upon tmTNFα cleavage by the TNF-alpha-converting enzyme (TACE), its soluble (sTNFα) form is released with higher affinity for TNFR1. This assortment empowers TNFα with a plethora of opposing roles in the processes of tumor cell survival (and apoptosis) and anti-tumor immune stimulation (and suppression), in addition to angiogenesis and metastases. Its functions and biomarker potential to predict cancer progression and response to immunotherapy are reviewed here, with a focus on lung cancer. By mining existing sequencing data, we further demonstrate that the expression levels of TNF and TACE are significantly decreased in lung adenocarcinoma patients, while the TNFR1/TNFR2 balance are increased. We conclude that the biomarker potential of TNFα alone will most likely not provide conclusive findings, but that TACE could have a key role along with the delicate balance of sTNFα/tmTNFα as well as TNFR1/TNFR2, hence stressing the importance of more research into the potential of rationalized treatments that combine TNFα pathway modulators with immunotherapy for lung cancer patients.
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10
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Apoptosis-Inducing TNF Superfamily Ligands for Cancer Therapy. Cancers (Basel) 2021; 13:cancers13071543. [PMID: 33801589 PMCID: PMC8036978 DOI: 10.3390/cancers13071543] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/21/2021] [Accepted: 03/25/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer is a complex disease with apoptosis evasion as one of its hallmarks; therefore, apoptosis induction in transformed cells seems a promising approach as a cancer treatment. TNF apoptosis-inducing ligands, which are naturally present in the body and possess tumoricidal activity, are attractive candidates. The most studied proteins are TNF-α, FasL, and TNF-related apoptosis-inducing ligand (TRAIL). Over the years, different recombinant TNF family-derived apoptosis-inducing ligands and agonists have been designed. Their stability, specificity, and half-life have been improved because most of the TNF ligands have the disadvantages of having a short half-life and affinity to more than one receptor. Here, we review the outlook on apoptosis-inducing ligands as cancer treatments in diverse preclinical and clinical stages and summarize strategies of overcoming their natural limitations to improve their effectiveness.
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11
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Mercogliano MF, Bruni S, Mauro F, Elizalde PV, Schillaci R. Harnessing Tumor Necrosis Factor Alpha to Achieve Effective Cancer Immunotherapy. Cancers (Basel) 2021; 13:cancers13030564. [PMID: 33540543 PMCID: PMC7985780 DOI: 10.3390/cancers13030564] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/17/2021] [Accepted: 01/22/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine known to have contradictory roles in oncoimmunology. Indeed, TNFα has a central role in the onset of the immune response, inducing both activation and the effector function of macrophages, dendritic cells, natural killer (NK) cells, and B and T lymphocytes. Within the tumor microenvironment, however, TNFα is one of the main mediators of cancer-related inflammation. It is involved in the recruitment and differentiation of immune suppressor cells, leading to evasion of tumor immune surveillance. These characteristics turn TNFα into an attractive target to overcome therapy resistance and tackle cancer. This review focuses on the diverse molecular mechanisms that place TNFα as a source of resistance to immunotherapy such as monoclonal antibodies against cancer cells or immune checkpoints and adoptive cell therapy. We also expose the benefits of TNFα blocking strategies in combination with immunotherapy to improve the antitumor effect and prevent or treat adverse immune-related effects.
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Affiliation(s)
- María Florencia Mercogliano
- Laboratorio de Biofisicoquímica de Proteínas, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales-Consejo Nacional de Investigaciones Científicas y Técnicas (IQUIBICEN-CONICET), Buenos Aires 1428, Argentina;
| | - Sofía Bruni
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires 1428, Argentina; (S.B.); (F.M.); (P.V.E.)
| | - Florencia Mauro
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires 1428, Argentina; (S.B.); (F.M.); (P.V.E.)
| | - Patricia Virginia Elizalde
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires 1428, Argentina; (S.B.); (F.M.); (P.V.E.)
| | - Roxana Schillaci
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires 1428, Argentina; (S.B.); (F.M.); (P.V.E.)
- Correspondence: ; Tel.: +54-11-4783-2869; Fax: +54-11-4786-2564
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Gong K, Guo G, Beckley N, Zhang Y, Yang X, Sharma M, Habib AA. Tumor necrosis factor in lung cancer: Complex roles in biology and resistance to treatment. Neoplasia 2021; 23:189-196. [PMID: 33373873 PMCID: PMC7773536 DOI: 10.1016/j.neo.2020.12.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/17/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023]
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-κB. NF-κB, 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-κB activation. The TNF upregulation and consequent NF-κB 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.
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Affiliation(s)
- Ke Gong
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Gao Guo
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Nicole Beckley
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yue Zhang
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Xiaoyao Yang
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Mishu Sharma
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Amyn A Habib
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; VA North Texas Health Care System, Dallas, TX, USA.
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Alharbi KK, Alshammary AF, Aljabri OS, Ali Khan I. Relationship Between Serum Amyloid A1 ( SAA1) Gene Polymorphisms Studies with Obesity in the Saudi Population. Diabetes Metab Syndr Obes 2021; 14:895-900. [PMID: 33688224 PMCID: PMC7935349 DOI: 10.2147/dmso.s294948] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 01/20/2021] [Indexed: 12/29/2022] Open
Abstract
PURPOSE Limited studies have shown positive and negative associations of serum amylase A1 (SAA1) gene in childhood obesity, previously showed the relation with obesity in different ethnicity. The current study therefore investigated the impact of single nucleotide polymorphisms present in the SAA1 gene on subjects of Saudi obesity. PARTICIPANTS AND METHODS In this case-control study, we selected 140 subjects of Saudi population and categorized them into 83 cases of obesity and 57 healthy controls. Genotyping was performed with quantitative/real time-polymerase chain reaction in the SAA1 gene for rs11603089A/G, rs4638289A/T and rs7131332A/G polymorphisms. RESULTS In rs11603089 polymorphism, co-dominant model (AG vs AA+GG; OR-2.23 [95% CI:1.02-4.86]; p=0.04) and rs4638289 polymorphism, a disparity in significance was observed between the homozygous variant (TT vs AA; OR-16.8 [95% CI: 2.06-136.8]; p=0.0009), dominant model (AT+TT vs AA; OR-2.57 [95% CI: 1.28-5.19]; p=0.007), recessive model (TT vs AA+AT; OR-11.36 [95% CI: 1.45-89.06]; p=0.004) and allelic frequency for (T vs A: OR-2.35 [95% CI: 1.39-3.98]; p=0.001) between the obesity cases and control subjects. However, statistical correlations did not reveal the rs7131332A/G polymorphism either (p>0.05). CONCLUSION In conclusion, rs4638289 polymorphism was associated with risk allele and dominant model with obesity subjects. Further additional studies were warranted.
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Affiliation(s)
- Khalid Khalaf Alharbi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Amal F Alshammary
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Omar Sammar Aljabri
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Imran Ali Khan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
- Correspondence: Imran Ali Khan Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, PO Box-10219, Riyadh, 11433, Kingdom of Saudi ArabiaTel +966501112806Fax +966114693851 Email
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