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Abdul-Hafez HA, Aljouda S, Aldarwish A, Soubh BN, Najar A, Mansour M. A rare case report of insular metastatic from sarcoma with successful long term surgical and oncological management. Int J Surg Case Rep 2025; 131:111410. [PMID: 40345048 DOI: 10.1016/j.ijscr.2025.111410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 04/28/2025] [Accepted: 05/05/2025] [Indexed: 05/11/2025] Open
Abstract
INTRODUCTION AND IMPORTANCE Brain metastases are the most common intracranial tumors in adults, yet they remain rare in sarcoma patients, occurring in <6 % of cases. Metastatic spread of sarcomas typically involves the lungs, bones, and liver, with brain involvement being an unusual and poorly understood occurrence. Given the limited data, management strategies remain challenging, and prognosis is generally poor. CASE PRESENTATION A previously healthy 16-year-old female presented with left shoulder pain and restricted movement. Imaging revealed a pathological fracture of the proximal humerus with a destructive mass lesion, and biopsy confirmed a diagnosis of high-grade sarcoma. She underwent chemotherapy, tumor resection, and later a pneumonectomy for lung metastases. Thirty months post-diagnosis, she developed progressive left-sided weakness, and brain MRI demonstrated a right insular metastatic lesion. She underwent gross total resection via microscopic right pterional craniotomy, followed by whole-brain radiotherapy and rehabilitation. At 42 months post-diagnosis, she remained recurrence-free with stable neurological function. DISCUSSION Brain metastases from sarcomas are rare and associated with poor prognosis. Pulmonary metastases are the strongest risk factor, and survival remains limited despite treatment. Surgical resection improves neurological function and extends survival in select patients with a high Karnofsky Performance Scale score and controlled systemic disease. Stereotactic radiosurgery is an option for multiple lesions, while WBRT and chemotherapy are reserved for widespread disease. CONCLUSION This case highlights the potential for favorable outcomes in sarcoma brain metastases with a multidisciplinary approach. Early detection and tailored intervention may improve survival and quality of life in such patients.
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Affiliation(s)
- Hamza A Abdul-Hafez
- Department of Medicine, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine.
| | - Sulaiman Aljouda
- Department of Neurosurgery, Al-Makassed Hospital, Jerusalem, Palestine
| | - Asad Aldarwish
- Department of Neurosurgery, Al-Makassed Hospital, Jerusalem, Palestine
| | - Bashar N Soubh
- Department of Neurosurgery, Al-Makassed Hospital, Jerusalem, Palestine
| | - Alaa Najar
- Department of Neurosurgery, Al-Makassed Hospital, Jerusalem, Palestine
| | - Mamoun Mansour
- Department of Orthopedic Oncology, Al-Makassed Hospital, Jerusalem, Palestine
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Joldes C, Jimbu L, Mesaros O, Zdrenghea M, Fetica B. Tumor-Associated Macrophages as Key Modulators of Disease Progression in Diffuse Large B-Cell Lymphoma. Biomedicines 2025; 13:1099. [PMID: 40426926 PMCID: PMC12108958 DOI: 10.3390/biomedicines13051099] [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: 02/09/2025] [Revised: 04/17/2025] [Accepted: 04/27/2025] [Indexed: 05/29/2025] Open
Abstract
With the advent of new therapeutic approaches, there is hope that anticancer treatment will eventually be possible without the use of chemotherapy. Efficient immunotherapeutic options have recently emerged in many cancers, offering a less aggressive approach, with overall better tolerance, making them also suitable for frail patients. Response to immunotherapy relies on the availability, functionality, and efficacy of the host's immune effector mechanisms. One of the key factors determining the efficacy of immunotherapy is the tumor microenvironment, which encompasses various immune effectors, including macrophages, which play a crucial role in regulating immune responses through phagocytosis and antigen presentation. Macrophages are prototypically divided, according to their polarization, into either the pro-inflammatory M1 type or the anti-inflammatory M2 type. In the tumor microenvironment, M2-polarized macrophages, known as tumor-associated macrophages (TAMs), are the predominant phenotype and are associated with tumor progression. The M1/M2 paradigm contributes to the understanding of tumor progression. Due to the variable microenvironment, the mechanisms regulating TAMs can vary across different cancers. Variations in TAM polarization may account for the different treatment responses in patients with similar diseases. This paper investigates the connection between TAMs, disease progression, and treatment responses in the most frequent solid hematologic cancer, diffuse large B-cell lymphoma.
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Affiliation(s)
- Corina Joldes
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Street, 400012 Cluj-Napoca, Romania; (L.J.); (O.M.); (M.Z.)
| | - Laura Jimbu
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Street, 400012 Cluj-Napoca, Romania; (L.J.); (O.M.); (M.Z.)
- Department of Hematology, Ion Chiricuta Oncology Institute, 34–36 Republicii Street, 400015 Cluj-Napoca, Romania
| | - Oana Mesaros
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Street, 400012 Cluj-Napoca, Romania; (L.J.); (O.M.); (M.Z.)
- Department of Hematology, Ion Chiricuta Oncology Institute, 34–36 Republicii Street, 400015 Cluj-Napoca, Romania
| | - Mihnea Zdrenghea
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Street, 400012 Cluj-Napoca, Romania; (L.J.); (O.M.); (M.Z.)
- Department of Hematology, Ion Chiricuta Oncology Institute, 34–36 Republicii Street, 400015 Cluj-Napoca, Romania
| | - Bogdan Fetica
- Department of Pathology, Ion Chiricuta Oncology Institute, 34–36 Republicii Street, 400015 Cluj-Napoca, Romania;
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Jiang H, Zhou L, Zhang H, Yu Z. E2F expression profiling-based subtypes in head and neck squamous cell carcinoma: clinical relevance, prognostic implications, and personalized therapy. World J Surg Oncol 2025; 23:157. [PMID: 40275315 PMCID: PMC12023618 DOI: 10.1186/s12957-025-03808-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 04/13/2025] [Indexed: 04/26/2025] Open
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous malignancy with poor prognosis. Dysregulation of E2F transcription factors (E2Fs), which control cell proliferation and apoptosis, is implicated in HNSCC pathogenesis. This study explores HNSCC molecular heterogeneity via E2Fs expression, identifies distinct subtypes, and develops a prognostic model that integrates gene expression, immune infiltration, and drug sensitivity. METHODS We analyzed the TCGA-HNSC dataset (n = 494) and classified samples based on the expression of eight E2Fs using ConsensusClusterPlus. The optimal number of clusters (k = 2) was determined with the getOptK() function, which assesses cluster stability via internal consistency metrics. Differentially expressed genes between subtypes were identified with limma, and functional annotation was performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. A prognostic model was constructed using LASSO regression on genes significant in univariate Cox analysis and validated in an independent GSE41613 dataset (n = 97). Immune cell infiltration was estimated using CIBERSORT, and drug sensitivity predicted via pRRophetic. Confounding factors such as HPV and smoking status were not included due to incomplete data. RESULTS Two distinct E2F-based subtypes emerged. Cluster 1, characterized by lower E2Fs expression, exhibited poorer overall survival (log-rank, p = 0.035) and was enriched in genes related to epidermal development, keratinocyte differentiation, and IL-17 signaling. In contrast, Cluster 2 showed higher E2Fs expression, better survival, and enrichment in genes associated with DNA replication and repair. Notably, high-risk patients demonstrated increased infiltration of M0 and M2 macrophages (p < 0.05), suggesting an immunosuppressive tumor microenvironment that adversely affects prognosis. Our seven-gene prognostic model (AREG, CXCL14, FAM83E, FDCSP, ARHGAP4, EPHX3, and SPINK6) exhibited robust performance with AUCs of 0.692, 0.673, and 0.679 for 1-, 3-, and 5-year survival, a C-index of 0.66, and good calibration. High-risk patients also showed greater sensitivity to targeted agents such as pazopanib and imatinib. CONCLUSIONS These findings reveal two distinct E2F-based molecular subtypes of HNSCC that differ in prognosis, functional pathways, immune infiltration, and drug sensitivity. The prognostic model offers valuable risk stratification and identifies potential biomarkers and therapeutic targets, warranting further experimental and clinical validation.
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Affiliation(s)
- Huanyu Jiang
- School of Medicine, Southeast University, 87 Dingjiaqiao, Hunan Road, Nanjing, 210009, Jiangsu, China
- Department of Otolaryngology Head and Neck Surgery, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210019, Jiangsu, China
| | - Lijuan Zhou
- Department of Otolaryngology Head and Neck Surgery, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210019, Jiangsu, China
| | - Haidong Zhang
- School of Medicine, Southeast University, 87 Dingjiaqiao, Hunan Road, Nanjing, 210009, Jiangsu, China
- Department of Otolaryngology Head and Neck Surgery, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210019, Jiangsu, China
| | - Zhenkun Yu
- School of Medicine, Southeast University, 87 Dingjiaqiao, Hunan Road, Nanjing, 210009, Jiangsu, China.
- Department of Otolaryngology Head and Neck Surgery, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210019, Jiangsu, China.
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Su Y, Bai Q, Zhang W, Xu B, Hu T. The Role of Long Non-Coding RNAs in Modulating the Immune Microenvironment of Triple-Negative Breast Cancer: Mechanistic Insights and Therapeutic Potential. Biomolecules 2025; 15:454. [PMID: 40149989 PMCID: PMC11939868 DOI: 10.3390/biom15030454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/18/2025] [Accepted: 03/19/2025] [Indexed: 03/29/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly heterogeneous and aggressive subtype of breast cancer that faces therapeutic challenges due to a shortage of effective targeted therapies. The complex biology of TNBC renders its clinical management fraught with difficulties, especially regarding the immune microenvironment of the tumor. In recent years, long non-coding RNAs (lncRNAs) have been recognized as important gene regulators with key roles in tumor development and microenvironmental regulation. Previous studies have shown that lncRNAs play important roles in the immune microenvironment of TNBC, including the regulation of tumor immune escape and the function of tumor-infiltrating immune cells. However, despite the increasing research on lncRNAs, there are still many unanswered questions, such as their specific mechanism of action and how to effectively utilize them as therapeutic targets. Therefore, the aim of this study was to review the mechanisms of lncRNAs in the TNBC immune microenvironment, explore their regulatory roles in tumor immune escape and immune cell infiltration, and explore their prospects as potential therapeutic targets. By integrating the latest research results, this study aims to provide new ideas and directions for future TNBC treatment.
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Affiliation(s)
- Yongcheng Su
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (Y.S.); (Q.B.); (W.Z.)
| | - Qingquan Bai
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (Y.S.); (Q.B.); (W.Z.)
| | - Wenqing Zhang
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (Y.S.); (Q.B.); (W.Z.)
| | - Beibei Xu
- Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Tianhui Hu
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (Y.S.); (Q.B.); (W.Z.)
- Shenzhen Research Institute, Xiamen University, Shenzhen 518057, China
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Zhou HJ, Mu BX, Wen MC, Zhao Q, Li Y, Zhao WX, Yin HY, Ren S, Zhou JY, Chen M. Yiqi Huayu Jiedu Decoction reduces colorectal cancer liver metastasis by promoting N1 neutrophil chemotaxis. Front Immunol 2025; 16:1530053. [PMID: 40083557 PMCID: PMC11903724 DOI: 10.3389/fimmu.2025.1530053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 02/12/2025] [Indexed: 03/16/2025] Open
Abstract
Objective To observe the inhibitory effect and potential mechanism of Yiqi Huayu Jiedu Decoction (YHJD) on liver metastasis of colorectal cancer (CRC). Methods We compared the changes of liver weight and liver index before and after YHJD treatment in CRC liver metastasis mouse models. HE staining was employed to observe the pathological changes in mouse liver tissue sections. Flow cytometry was used to analyze the number and marker of neutrophils treated with YHJD. Transcriptomics, proteomics, and multiplex cytokine array analyses were conducted to further verify the role of YHJD on CXCL1. Differential gene analysis was performed to further explore the mechanism by which YHJD inhibits liver metastasis of CRC. Results Animal studies demonstrated that YHJD reduces liver metastases. Flow cytometry results revealed that YHJD promotes N1 neutrophils in liver. Combining multi-omics and multiple cytokine arrays, we observed a significant increase in the expression of CXCL1 in the liver and plasma. GO and KEGG enrichment analyses indicated that YHJD may regulate the chemotaxis of neutrophils to inhibit the liver metastasis of CRC by participating in the regulation of cell adhesion molecule binding, adhesion protein binding, and multiple metabolic pathways. Conclusions YHJD inhibits CRC liver metastasis by upregulating CXCL1, thereby promoting N1 neutrophil chemotaxis towards the liver, and concurrently raising the expression of N1 neutrophil markers.
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Affiliation(s)
- Hua-Jian Zhou
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Bai-Xiang Mu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Meng-Chao Wen
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Qi Zhao
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yuanxiang Li
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Wen-Xuan Zhao
- Central Laboratory, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Hong-Ye Yin
- Central Laboratory, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Shuai Ren
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jin-Yong Zhou
- Central Laboratory, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Jiangsu Province Key Laboratory of Tumor Systems Biology and Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Min Chen
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
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Kwantwi LB, Boafo JD, Egleh BE, Li M. CCL20 in the tumor microenvironment: implications for cancer progression and therapeutic approaches. Clin Transl Oncol 2025:10.1007/s12094-025-03874-5. [PMID: 39985603 DOI: 10.1007/s12094-025-03874-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 02/08/2025] [Indexed: 02/24/2025]
Abstract
Increasing knowledge of the immunosuppressive tumor microenvironment in cancer-related processes has led to the developing of novel immune-based therapies that have changed the cancer treatment paradigm. In the tumor microenvironment, the plethora of soluble factors secreted by tumor cells interacts with immune cells and non-immune components to deliver signals necessary for tumor progression. Accordingly, targeting tumor-derived factors inducing this immunosuppressive tumor microenvironment has become an appealing therapeutic potential in advancing cancer treatment. CCL20, a chemokine best known to induce leucocyte migration in response to pathological and inflammatory conditions, has been implicated in tumor proliferation, angiogenesis, metastasis, immunosuppression, and therapeutic resistance. Notably, CCL20 and its receptor CCR6 are important in tumor microenvironment interactions. This review discusses the interaction between the CCL20-CCR6 axis and the tumor microenvironment and how these interactions promote tumor progression. Also, an outline of studies utilizing CCL20 in combination with other standard cancer treatments has been shed.
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Affiliation(s)
- Louis Boafo Kwantwi
- Department of Biomedical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, 44272, USA.
| | - James Danquah Boafo
- Department of Nursing and Midwifery, Faculty of Health and Allied Sciences, Pentecost University, Sowutoum, Ghana
| | - Bevelyn Emefa Egleh
- Department of Biomedical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, 44272, USA
- Department of Biomedical Sciences, College of Arts and Sciences, Kent State University, Kent, OH, 44242, USA
| | - Mingfeng Li
- Department of Pathology, Affiliated Subei People'S Hospital of Yangzhou University, Yangzhou, 225000, Jiangsu, China
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Wiley N, Zecevic M, Ho V, Stolzberg MJ, Cox D, Soloff EV, Hall E, Wang CL. Dual-energy CT iodine concentration as a biomarker for immunotherapy treatment response in metastatic melanoma and renal cell carcinoma patients. Eur Radiol 2025:10.1007/s00330-025-11351-4. [PMID: 39873753 DOI: 10.1007/s00330-025-11351-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 11/01/2024] [Accepted: 12/10/2024] [Indexed: 01/30/2025]
Abstract
OBJECTIVE To investigate the predictive value of tumor iodine concentration obtained with dual-energy CT (DECT) for treatment response in patients treated with immune checkpoint inhibitors (ICI). MATERIALS AND METHODS Retrospective single-center study of consecutive metastatic melanoma and renal cell carcinoma (RCC) patients undergoing first-line ICI treatment. The iodine concentration measurement time points include prior to initiation of therapy (baseline [BL]), after initiation (follow-up [FU1]), and either time point nearest to 12 months or at time of progression (final follow-up [FFU]). Target lesion DECT-based whole-volume tumor normalized iodine concentration average (NICave) and size measurements were obtained. Reference standard was individual lesion FFU status categorized as responders or nonresponders per RECIST 1.1. Logistic regression model assessed NICave change and FU1 lesion response as predictors of FFU lesion outcome. Model's performance was summarized with AUC. Intraclass correlation coefficient (ICC) summarized inter-rater agreement of NICave. RESULTS Forty-six patients were included (mean age 61 ± 11 years, 12 women; 16 melanoma). Sixty-four of 175 target lesions were confirmed nonresponders at FFU. In a multivariable model, lesion status at FU1 (odds ratio [OR]: 27.4, p < 0.001) and changes in NICave from BL to FU1 (OR: 2.42 per 1-SD increase, p = 0.019) were significant predictors of lesion status at FFU. The model's AUC was 0.86 (95% CI: 0.76-0.93). Inter-rater reliability of NICave was 0.98 (95% CI: 0.97-0.99). CONCLUSIONS Changes in iodine concentration from baseline to first follow-up improve identification of delayed responding metastatic melanoma and RCC lesions treated with immune checkpoint inhibitor, initially classified as nonresponders by size change. KEY POINTS Question How can pseudoprogression/delayed treatment response in metastatic renal cell carcinoma (RCC) and melanoma patients on first-line immune checkpoint inhibitors be accurately identified? Findings Combining iodine concentration change from Dual-energy CT (baseline to first follow-up) with RECIST-based lesion size change improved prediction of final lesion outcome. Clinical relevance DECT-based whole-volume tumor iodine concentration for target lesions is useful as a predictive imaging biomarker for distinguishing delayed response from true progression in patients with metastatic RCC and melanoma treated with first-line immune checkpoint inhibitors.
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Affiliation(s)
- Natalie Wiley
- Department of Radiology, University of Washington, Seattle, WA, USA
| | - Mladen Zecevic
- Department of Radiology, University of Washington, Seattle, WA, USA
| | - Vivian Ho
- Department of Radiology, University of Washington, Seattle, WA, USA
| | | | - Danielle Cox
- Department of Radiology, University of Washington, Seattle, WA, USA
| | - Erik V Soloff
- Department of Radiology, University of Washington, Seattle, WA, USA
| | - Evan Hall
- Division of Hematology and Oncology, University of Washington, Seattle, WA, USA
| | - Carolyn L Wang
- Department of Radiology, University of Washington, Seattle, WA, USA.
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Guo S, Zhang Q, Guo Y, Yin X, Zhang P, Mao T, Tian Z, Li X. The role and therapeutic targeting of the CCL2/CCR2 signaling axis in inflammatory and fibrotic diseases. Front Immunol 2025; 15:1497026. [PMID: 39850880 PMCID: PMC11754255 DOI: 10.3389/fimmu.2024.1497026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 12/11/2024] [Indexed: 01/25/2025] Open
Abstract
CCL2, a pivotal cytokine within the chemokine family, functions by binding to its receptor CCR2. The CCL2/CCR2 signaling pathway plays a crucial role in the development of fibrosis across multiple organ systems by modulating the recruitment and activation of immune cells, which in turn influences the progression of fibrotic diseases in the liver, intestines, pancreas, heart, lungs, kidneys, and other organs. This paper introduces the biological functions of CCL2 and CCR2, highlighting their similarities and differences concerning fibrotic disorders in various organ systems, and reviews recent progress in the diagnosis and treatment of clinical fibrotic diseases linked to the CCL2/CCR2 signaling pathway. Additionally, further in-depth research is needed to explore the clinical significance of the CCL2/CCR2 axis in fibrotic conditions affecting different organs.
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Affiliation(s)
| | | | | | | | | | | | | | - Xiaoyu Li
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Wei ZH, Tuo M, Ye C, Wu XF, Wang HH, Ren WZ, Liu G, Xiang T. Prognostic value of neutrophil-to-lymphocyte ratio in gastric cancer patients undergoing neoadjuvant chemotherapy: A systematic review and meta-analysis. World J Gastrointest Oncol 2024; 16:4477-4488. [PMID: 39554738 PMCID: PMC11551644 DOI: 10.4251/wjgo.v16.i11.4477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 09/10/2024] [Accepted: 09/24/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND In recent studies, accumulating evidence has revealed a strong association between the inflammatory response and the prognosis of many tumors. There is a certain correlation of neutrophil-to-lymphocyte ratio (NLR) with the prognosis in gastric cancer (GC) patients undergoing neoadjuvant chemotherapy (NAC). However, the existing research results have remained controversial. AIM To explore the relationship between NLR ratio and prognosis of GC patients receiving NAC. METHODS A thorough systematic search was performed in databases such as PubMed, Embase, Web of Science, and Cochrane Library, the search is available until February 29, 2024, and studies exploring the interaction of NLR with clinical outcomes were collected. Relevant studies meeting pre-defined inclusion and exclusion criteria were carefully chosen. The outcomes included progression-free survival (PFS), relapse-free survival, disease-free survival (DFS), and overall survival (OS). The hazard ratio (HR) and its corresponding 95% confidence interval (CI) were utilized for estimation. RESULTS Our analysis encompassed 852 patients and incorporated data from 12 cohort studies. The comprehensive analysis revealed a significant association of high NLR with reduced OS (HR = 1.76; 95%CI: 1.22-2.54, P = 0.003), relapse-free survival (HR = 3.73; 95%CI: 1.74-7.96, P = 0.0007), and PFS (HR = 2.32; 95%CI: 1.42-3.81, P = 0.0008) in patients. However, this correlation in disease-free survival was not significant. NLR demonstrated its crucial role in effectively predicting the OS of GC patients undergoing NAC at different detection times, ages, regions, and NLR thresholds. CONCLUSION In GC patients receiving NAC, an elevated NLR is strongly associated with reduced OS and PFS. NLR has become an effective biomarker for patient prognosis evaluation, providing valuable insights for the treatment strategies of NAC in GC patients.
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Affiliation(s)
- Zhen-Hua Wei
- Hubei Minzu University, Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi 445000, Hubei Province, China
| | - Min Tuo
- Department of Breast Surgery, Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi 445000, Hubei Province, China
| | - Chen Ye
- Department of Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
| | - Xiao-Fan Wu
- Department of Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
| | - Hong-Hao Wang
- Department of Gastrointestinal Surgery, Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi 445000, Hubei Province, China
| | - Wen-Zhen Ren
- Department of Abdominal Oncology, Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi 445000, Hubei Province, China
| | - Gao Liu
- Department of Gastrointestinal Surgery, Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi 445000, Hubei Province, China
| | - Tian Xiang
- Department of Clinical Laboratory Center, Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi 445000, Hubei Province, China
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Su X, Huang Y, Wang X, Cui L. Molecular signature of immune-related new survival predictions for subtype of renal cell carcinomas. Transl Androl Urol 2024; 13:2180-2193. [PMID: 39507856 PMCID: PMC11535737 DOI: 10.21037/tau-24-225] [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: 05/08/2024] [Accepted: 09/08/2024] [Indexed: 11/08/2024] Open
Abstract
Background Kidney renal papillary cell carcinoma (KIRP), kidney chromophobe (KICH), and kidney renal clear cell carcinoma (KIRC) are three most common subtypes of renal cell carcinomas (RCC), and its development is a multifaceted process that intricately involves the interplay of numerous genes. Despite recent advances in research on renal cell carcinoma, the prognosis of KIRC patients remains dismal. Therefore, there is an urgent need to explore new prognostic biomarkers and treatment strategies to help clinicians choose more effective treatment methods and accurately predict long-term efficacy. Our study aimed to systematically evaluate the gene expression profiles of three RCC subtypes, especially KIRC, and to identify survival-related biomarker. Methods In our present study, we systematically evaluate the genes expression profile difference among three subtypes of RCC, and identify the survival-related key genes signature based on GEPIA2. GeneMANIA was used to identify the functionality-related differentially expressed genes (DEGs). Furthermore, focusing on KIRC, we intersected functionality-related and survival-related DEGs based on two datasets. Results We ascertained five DEGs (ANK3, FREM2, KIF13B, MPP7 and SOX6) as key survival-related genes in KIRC. High levels of these five DEGs expressions were strongly associated with favorable prognosis, but not correlated to metastasis. Downregulation of these five DEGs expressions was closely associated with immunomodulators, chemokines, and infiltrating levels of different immune cells, which indicated that these five DEGs were key immune-related novel prognostic biomarkers for KIRC. Conclusions The five identified DEGs serve as potential novel prognostic biomarkers for KIRC. However, the crucial factors that lead to the downregulation and functional inactivation of these five key genes need to be explored in future studies.
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Affiliation(s)
- Xichen Su
- Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Veterinary Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Yonghe Huang
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, College of Physical Education and Health, East China Normal University, Shanghai, China
| | - Xiaosen Wang
- Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Veterinary Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Li Cui
- Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Veterinary Biotechnology, Shanghai Jiao Tong University, Shanghai, China
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McClelland S, Maxwell PJ, Branco C, Barry ST, Eberlein C, LaBonte MJ. Targeting IL-8 and Its Receptors in Prostate Cancer: Inflammation, Stress Response, and Treatment Resistance. Cancers (Basel) 2024; 16:2797. [PMID: 39199570 PMCID: PMC11352248 DOI: 10.3390/cancers16162797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 07/30/2024] [Accepted: 08/05/2024] [Indexed: 09/01/2024] Open
Abstract
This review delves into the intricate roles of interleukin-8 (IL-8) and its receptors, CXCR1 and CXCR2, in prostate cancer (PCa), particularly in castration-resistant (CRPC) and metastatic CRPC (mCRPC). This review emphasizes the crucial role of the tumour microenvironment (TME) and inflammatory cytokines in promoting tumour progression and response to tumour cell targeting agents. IL-8, acting through C-X-C chemokine receptor type 1 (CXCR1) and type 2 (CXCR2), modulates multiple signalling pathways, enhancing the angiogenesis, proliferation, and migration of cancer cells. This review highlights the shift in PCa research focus from solely tumour cells to the non-cancer-cell components, including vascular endothelial cells, the extracellular matrix, immune cells, and the dynamic interactions within the TME. The immunosuppressive nature of the PCa TME significantly influences tumour progression and resistance to emerging therapies. Current treatment modalities, including androgen deprivation therapy and chemotherapeutics, encounter persistent resistance and are complicated by prostate cancer's notably "immune-cold" nature, which limits immune system response to the tumour. These challenges underscore the critical need for novel approaches that both overcome resistance and enhance immune engagement within the TME. The therapeutic potential of inhibiting IL-8 signalling is explored, with studies showing enhanced sensitivity of PCa cells to treatments, including radiation and androgen receptor inhibitors. Clinical trials, such as the ACE trial, demonstrate the efficacy of combining CXCR2 inhibitors with existing treatments, offering significant benefits, especially for patients with resistant PCa. This review also addresses the challenges in targeting cytokines and chemokines, noting the complexity of the TME and the need for precision in therapeutic targeting to avoid side effects and optimize outcomes.
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Affiliation(s)
- Shauna McClelland
- Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK; (S.M.); (P.J.M.); (C.B.)
| | - Pamela J. Maxwell
- Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK; (S.M.); (P.J.M.); (C.B.)
| | - Cristina Branco
- Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK; (S.M.); (P.J.M.); (C.B.)
| | - Simon T. Barry
- Bioscience Early Oncology, AstraZeneca, Cambridge CB2 0AA, UK; (S.T.B.); (C.E.)
| | - Cath Eberlein
- Bioscience Early Oncology, AstraZeneca, Cambridge CB2 0AA, UK; (S.T.B.); (C.E.)
| | - Melissa J. LaBonte
- Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK; (S.M.); (P.J.M.); (C.B.)
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Zhang M, Han X, Yan L, Fu Y, Kou H, Shang C, Wang J, Liu H, Jiang C, Wang J, Cheng T. Inflammatory response in traumatic brain and spinal cord injury: The role of XCL1-XCR1 axis and T cells. CNS Neurosci Ther 2024; 30:e14781. [PMID: 38887195 PMCID: PMC11183917 DOI: 10.1111/cns.14781] [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: 01/12/2024] [Revised: 04/29/2024] [Accepted: 05/11/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND Traumatic brain injury (TBI) and spinal cord injury (SCI) are acquired injuries to the central nervous system (CNS) caused by external forces that cause temporary or permanent sensory and motor impairments and the potential for long-term disability or even death. These conditions currently lack effective treatments and impose substantial physical, social, and economic burdens on millions of people and families worldwide. TBI and SCI involve intricate pathological mechanisms, and the inflammatory response contributes significantly to secondary injury in TBI and SCI. It plays a crucial role in prolonging the post-CNS trauma period and becomes a focal point for a potential therapeutic intervention. Previous research on the inflammatory response has traditionally concentrated on glial cells, such as astrocytes and microglia. However, increasing evidence highlights the crucial involvement of lymphocytes in the inflammatory response to CNS injury, particularly CD8+ T cells and NK cells, along with their downstream XCL1-XCR1 axis. OBJECTIVE This review aims to provide an overview of the role of the XCL1-XCR1 axis and the T-cell response in inflammation caused by TBI and SCI and identify potential targets for therapy. METHODS We conducted a comprehensive search of PubMed and Web of Science using relevant keywords related to the XCL1-XCR1 axis, T-cell response, TBI, and SCI. RESULTS This study examines the upstream and downstream pathways involved in inflammation caused by TBI and SCI, including interleukin-15 (IL-15), interleukin-12 (IL-12), CD8+ T cells, CD4+ T cells, NK cells, XCL1, XCR1+ dendritic cells, interferon-gamma (IFN-γ), helper T0 cells (Th0 cells), helper T1 cells (Th1 cells), and helper T17 cells (Th17 cells). We describe their proinflammatory effect in TBI and SCI. CONCLUSIONS The findings suggest that the XCL1-XCR1 axis and the T-cell response have great potential for preclinical investigations and treatments for TBI and SCI.
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Affiliation(s)
- Mingkang Zhang
- Department of OrthopaedicsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Xiaonan Han
- Department of OrthopaedicsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Liyan Yan
- Department of OrthopaedicsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Yikun Fu
- Department of OrthopaedicsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Hongwei Kou
- Department of OrthopaedicsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Chunfeng Shang
- Department of OrthopaedicsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Junmin Wang
- Department of Human Anatomy, School of Basic Medical SciencesZhengzhou UniversityZhengzhouHenanChina
| | - Hongjian Liu
- Department of OrthopaedicsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Chao Jiang
- Department of NeurologyPeople's Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Jian Wang
- Department of Human Anatomy, School of Basic Medical SciencesZhengzhou UniversityZhengzhouHenanChina
| | - Tian Cheng
- Department of OrthopaedicsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
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Vahidi S, Zabeti Touchaei A, Samadani AA. IL-15 as a key regulator in NK cell-mediated immunotherapy for cancer: From bench to bedside. Int Immunopharmacol 2024; 133:112156. [PMID: 38669950 DOI: 10.1016/j.intimp.2024.112156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 04/04/2024] [Accepted: 04/23/2024] [Indexed: 04/28/2024]
Abstract
Interleukin 15 (IL-15) has emerged as a crucial factor in the relationship between natural killer (NK) cells and immunotherapy for cancer. This review article aims to provide a comprehensive understanding of the role of IL-15 in NK cell-mediated immunotherapy. First, the key role of IL-15 signaling in NK cell immunity is discussed, highlighting its regulation of NK cell functions and antitumor properties. Furthermore, the use of IL-15 or its analogs in clinical trials as a therapeutic strategy for various cancers, including the genetic modification of NK cells to produce IL-15, has been explored. The potential of IL-15-based therapies, such as chimeric antigen receptor (CAR) T and NK cell infusion along with IL-15 in combination with checkpoint inhibitors and other treatments, has been examined. This review also addresses the challenges and advantages of incorporating IL-15 in cell-based immunotherapy. Additionally, unresolved questions regarding the detection and biological significance of the soluble IL-15/IL-15Rα complex, as well as the potential role of IL-15/IL-15Rα in human cancer and the immunological consequences of prolonged exposure to soluble IL-15 for NK cells, are discussed.
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Affiliation(s)
- Sogand Vahidi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | | | - Ali Akbar Samadani
- Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran.
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Fellhofer-Hofer J, Franz C, Vey JA, Kahlert C, Kalkum E, Mehrabi A, Halama N, Probst P, Klupp F. Chemokines as Prognostic Factor in Colorectal Cancer Patients: A Systematic Review and Meta-Analysis. Int J Mol Sci 2024; 25:5374. [PMID: 38791414 PMCID: PMC11121014 DOI: 10.3390/ijms25105374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/09/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Chemokines orchestrate many aspects of tumorigenic processes such as angiogenesis, apoptosis and metastatic spread, and related receptors are expressed on tumor cells as well as on inflammatory cells (e.g., tumor-infiltrating T cells, TILs) in the tumor microenvironment. Expressional changes of chemokines and their receptors in solid cancers are common and well known, especially in affecting colorectal cancer patient outcomes. Therefore, the aim of this current systematic review and meta-analysis was to classify chemokines as a prognostic biomarker in colorectal cancer patients. A systematic literature search was conducted in PubMed, CENTRAL and Web of Science. Information on the chemokine expression of 25 chemokines in colorectal cancer tissue and survival data of the patients were investigated. The hazard ratio of overall survival and disease-free survival with chemokine expression was examined. The risk of bias was analyzed using Quality in Prognosis Studies. Random effects meta-analysis was performed to determine the impact on overall respectively disease survival. For this purpose, the pooled hazard ratios (HR) and their 95% confidence intervals (CI) were used for calculation. Twenty-five chemokines were included, and the search revealed 5556 publications. A total of thirty-one publications were included in this systematic review and meta-analysis. Overexpression of chemokine receptor CXCR4 was associated with both a significantly reduced overall survival (HR = 2.70, 95%-CI: 1.57 to 4.66, p = 0.0003) as well as disease-free survival (HR = 2.68, 95%-CI: 1.41 to 5.08, p = 0.0026). All other chemokines showed either heterogeneous results or few studies were available. The overall risk of bias for CXCR4 was rated low. At the current level of evidence, this study demonstrates that CXCR4 overexpression in patients with colorectal cancer is associated with a significantly diminished overall as well as disease-free survival. Summed up, this systematic review and meta-analysis reveals CXCR4 as a promising prognostic biomarker. Nevertheless, more evidence is needed to evaluate CXCR4 and its antagonists serving as new therapeutic targets.
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Affiliation(s)
- Johanna Fellhofer-Hofer
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany; (J.F.-H.); (C.F.); (C.K.); (A.M.); (P.P.)
| | - Clemens Franz
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany; (J.F.-H.); (C.F.); (C.K.); (A.M.); (P.P.)
| | - Johannes A. Vey
- Institute of Medical Biometry (IMBI), University Hospital Heidelberg, Im Neuenheimer Feld 130/3, 69120 Heidelberg, Germany;
| | - Christoph Kahlert
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany; (J.F.-H.); (C.F.); (C.K.); (A.M.); (P.P.)
| | - Eva Kalkum
- Study Center of the German Society of Surgery (SDGC), University of Heidelberg, Im Neuenheimer Feld 130/3, 69120 Heidelberg, Germany;
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany; (J.F.-H.); (C.F.); (C.K.); (A.M.); (P.P.)
| | - Niels Halama
- National Center for Tumor Diseases, Medical Oncology and Internal Medicine VI, Tissue Imaging and Analysis Center, Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany;
- Helmholtz Institute for Translational Oncology (HI-TRON), Department of Cancer Immunology & Cancer Immunotherapy, German Cancer Research Center (DKFZ), 55131 Mainz, Germany
| | - Pascal Probst
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany; (J.F.-H.); (C.F.); (C.K.); (A.M.); (P.P.)
- Department of Surgery, Cantonal Hospital Thurgau, Pfaffenholzstrasse 4, 8501 Frauenfeld, Switzerland
| | - Fee Klupp
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany; (J.F.-H.); (C.F.); (C.K.); (A.M.); (P.P.)
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Lopez-Bujanda ZA, Hadavi SH, Ruiz De Porras V, Martínez-Balibrea E, Dallos MC. Chemotactic signaling pathways in prostate cancer: Implications in the tumor microenvironment and as potential therapeutic targets. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 388:162-205. [PMID: 39260936 DOI: 10.1016/bs.ircmb.2024.03.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
Prostate cancer (PCa) stands as a significant global health concern, ranking among the leading causes of cancer deaths in men. While there are several treatment modalities for localized PCa, metastatic castration-resistant PCa (mCRPC) remains incurable. Despite therapeutic advancements showing promise in mCRPC, their impact on overall survival has been limited. This chapter explores the process by which tumors form, reviews our current understanding of PCa progression to mCRPC, and addresses the challenges of boosting anti-tumor immune responses in these tumors. It specifically discusses how chemotactic signaling affects the tumor microenvironment and its role in immune evasion and cancer progression. The chapter further examines the rationale of directly or indirectly targeting these pathways as adjuvant therapies for mCRPC, highlighting recent pre-clinical and clinical studies currently underway. The discussion emphasizes the potential of targeting specific chemokines and chemokine receptors as combination therapies with mainstream treatments for PCa and mCRPC to maximize long-term survival for this deadly disease.
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Affiliation(s)
- Zoila A Lopez-Bujanda
- Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, United States.
| | - Shawn H Hadavi
- Division of Hematology and Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, United States
| | - Vicenç Ruiz De Porras
- Badalona Applied Research Group of Oncology (B-ARGO), Catalan Institute of Oncology, Badalona, BCN, Spain; CARE program, Germans Trias i Pujol Research Institute (IGTP), Badalona, BCN, Spain
| | - Eva Martínez-Balibrea
- CARE program, Germans Trias i Pujol Research Institute (IGTP), Badalona, BCN, Spain; ProCURE Program, Catalan Institute of Oncology, Badalona, BCN, Spain
| | - Matthew C Dallos
- Memorial Solid Tumor Group, Memorial Sloan Kettering Cancer Center, New York, NY, United States
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Guan M, Liu S, Yang YG, Song Y, Zhang Y, Sun T. Chemokine systems in oncology: From microenvironment modulation to nanocarrier innovations. Int J Biol Macromol 2024; 268:131679. [PMID: 38641274 DOI: 10.1016/j.ijbiomac.2024.131679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 04/16/2024] [Accepted: 04/16/2024] [Indexed: 04/21/2024]
Abstract
Over the past few decades, significant strides have been made in understanding the pivotal roles that chemokine networks play in tumor biology. These networks, comprising chemokines and their receptors, wield substantial influence over cancer immune regulation and therapeutic outcomes. As a result, targeting these chemokine systems has emerged as a promising avenue for cancer immunotherapy. However, therapies targeting chemokines face significant challenges in solid tumor treatment, due to the complex and fragile of the chemokine networks. A nuanced comprehension of the complicacy and functions of chemokine networks, and their impact on the tumor microenvironment, is essential for optimizing their therapeutic utility in oncology. This review elucidates the ways in which chemokine networks interact with cancer immunity and tumorigenesis. We particularly elaborate on recent innovations in manipulating these networks for cancer treatment. The review also highlights future challenges and explores potential biomaterial strategies for clinical applications.
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Affiliation(s)
- Meng Guan
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital of Jilin University, Changchun, Jilin 130021, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin 130021, China; Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Shuhan Liu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital of Jilin University, Changchun, Jilin 130021, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin 130021, China; Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital of Jilin University, Changchun, Jilin 130021, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin 130021, China; International Center of Future Science, Jilin University, Changchun, Jilin 130021, China
| | - Yanqiu Song
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
| | - Yuning Zhang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital of Jilin University, Changchun, Jilin 130021, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin 130021, China.
| | - Tianmeng Sun
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital of Jilin University, Changchun, Jilin 130021, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin 130021, China; International Center of Future Science, Jilin University, Changchun, Jilin 130021, China; State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun, Jilin 130021, China.
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17
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Tushoski-Alemán GW, Herremans KM, Underwood PW, Akki A, Riner AN, Trevino JG, Han S, Hughes SJ. Infiltration of CD3+ and CD8+ lymphocytes in association with inflammation and survival in pancreatic cancer. PLoS One 2024; 19:e0297325. [PMID: 38346068 PMCID: PMC10861089 DOI: 10.1371/journal.pone.0297325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 01/02/2024] [Indexed: 02/15/2024] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinomas (PDAC) have heterogeneous tumor microenvironments relatively devoid of infiltrating immune cells. We aimed to quantitatively assess infiltrating CD3+ and CD8+ lymphocytes in a treatment-naïve patient cohort and assess associations with overall survival and microenvironment inflammatory proteins. METHODS Tissue microarrays were immunohistochemically stained for CD3+ and CD8+ lymphocytes and quantitatively assessed using QuPath. Levels of inflammation-associated proteins were quantified by multiplexed, enzyme-linked immunosorbent assay panels on matching tumor and tissue samples. RESULTS Our findings revealed a significant increase in both CD3+ and CD8+ lymphocytes populations in PDAC compared with non-PDAC tissue, except when comparing CD8+ percentages in PDAC versus intraductal papillary mucinous neoplasms (IPMN) (p = 0.5012). Patients with quantitatively assessed CD3+ low tumors (lower 50%) had shorter survival (median 273 days) compared to CD3+ high tumors (upper 50%) with a median overall survival of 642.5 days (p = 0.2184). Patients with quantitatively assessed CD8+ low tumors had significantly shorter survival (median 240 days) compared to CD8+ high tumors with a median overall survival of 1059 days (p = 0.0003). Of 41 proteins assessed in the inflammation assay, higher levels of IL-1B and IL-2 were significantly associated with decreased CD3+ infiltration (r = -0.3704, p = 0.0187, and r = -0.4275, p = 0.0074, respectively). Higher levels of IL-1B were also significantly associated with decreased CD8+ infiltration (r = -0.4299, p = 0.0045), but not IL-2 (r = -0.0078, p = 0.9616). Principal component analysis of the inflammatory analytes showed diverse inflammatory responses in PDAC. CONCLUSION In this work, we found a marked heterogeneity in infiltrating CD3+ and CD8+ lymphocytes and individual inflammatory responses in PDAC. Future mechanistic studies should explore personalized therapeutic strategies to target the immune and inflammatory components of the tumor microenvironment.
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Affiliation(s)
- Gerik W. Tushoski-Alemán
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Kelly M. Herremans
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Patrick W. Underwood
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Ashwin Akki
- Department of Pathology, College of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Andrea N. Riner
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Jose G. Trevino
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Song Han
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Steven J. Hughes
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, United States of America
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Kamal MV, Damerla RR, Parida P, Rao M, Belle VS, Dikhit PS, Palod A, Gireesh R, Kumar NAN. Expression of PTGS2 along with genes regulating VEGF signalling pathway and association with high-risk factors in locally advanced oral squamous cell carcinoma. Cancer Med 2024; 13:e6986. [PMID: 38426619 PMCID: PMC10905678 DOI: 10.1002/cam4.6986] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 01/15/2024] [Accepted: 01/22/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND PTGS2 encodes cyclooxygenase-2 (COX-2), which catalyses the committed step in prostaglandin synthesis. Various in vivo and in vitro data suggest that COX-2 mediates the VEGF signalling pathway. In silico analysis performed in TCGA, PanCancer Atlas for head and neck cancers, demonstrated significant expression and co-expression of PTGS2 and genes that regulate VEGF signalling. This study was designed to elucidate the expression pattern of PTGS2 and genes regulating VEGF signalling in patients with locally advanced oral squamous cell carcinoma (OSCC). METHODOLOGY Tumour and normal tissue samples were collected from patients with locally advanced OSCC. RNA was isolated from tissue samples, followed by cDNA synthesis. The cDNA was used for gene expression analysis (RT-PCR) using target-specific primers. The results obtained were compared with the in silico gene expression of the target genes in the TCGA datasets. Co-expression analysis was performed to establish an association between PTGS2 and VEGF signalling genes. RESULTS Tumour and normal tissue samples were collected from 24 OSCC patients. Significant upregulation of PTGS2 expression was observed. Furthermore, VEGFA, KDR, CXCR1 and CXCR2 were significantly upregulated in tumour samples compared with paired normal samples, except for VEGFB, whose expression was not statistically significant. A similar expression pattern was observed in silico, except for CXCR2 which was highly expressed in the normal samples. Co-expression analysis showed a significant positive correlation between PTGS2 and VEGF signalling genes, except for VEGFB which showed a negative correlation. CONCLUSION PTGS2 and VEGF signalling genes are upregulated in OSCC, which has a profound impact on clinical outcomes.
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Affiliation(s)
- Mehta Vedant Kamal
- Department of Surgical Oncology, Manipal Comprehensive Cancer Care Centre, Kasturba Medical College, ManipalManipal Academy of Higher EducationManipalKarnatakaIndia
| | - Rama Rao Damerla
- Department of Medical Genetics, Kasturba Medical College, ManipalManipal Academy of Higher EducationManipalKarnatakaIndia
| | - Preetiparna Parida
- Department of Medical Genetics, Kasturba Medical College, ManipalManipal Academy of Higher EducationManipalKarnatakaIndia
| | - Mahadev Rao
- Department of Pharmacy Practice, Centre for Translational Research, Manipal College of Pharmaceutical SciencesManipal Academy of Higher EducationManipalKarnatakaIndia
| | - Vijetha Shenoy Belle
- Department of Biochemistry, Kasturba Medical College, ManipalManipal Academy of Higher EducationManipalKarnatakaIndia
| | - Punit Singh Dikhit
- Department of Surgical Oncology, Manipal Comprehensive Cancer Care Centre, Kasturba Medical College, ManipalManipal Academy of Higher EducationManipalKarnatakaIndia
| | - Akhil Palod
- Department of Surgical Oncology, Manipal Comprehensive Cancer Care Centre, Kasturba Medical College, ManipalManipal Academy of Higher EducationManipalKarnatakaIndia
| | - Rinsha Gireesh
- Department of Surgical Oncology, Manipal Comprehensive Cancer Care Centre, Kasturba Medical College, ManipalManipal Academy of Higher EducationManipalKarnatakaIndia
| | - Naveena AN Kumar
- Department of Surgical Oncology, Manipal Comprehensive Cancer Care Centre, Kasturba Medical College, ManipalManipal Academy of Higher EducationManipalKarnatakaIndia
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Dai Z, Wang Y, Sun N, Zhang C. Characterizing ligand-receptor interactions and unveiling the pro-tumorigenic role of CCL16-CCR1 axis in the microenvironment of hepatocellular carcinoma. Front Immunol 2024; 14:1299953. [PMID: 38274805 PMCID: PMC10808667 DOI: 10.3389/fimmu.2023.1299953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 12/26/2023] [Indexed: 01/27/2024] Open
Abstract
Background The heterogeneity of the tumor microenvironment significantly influences the prognosis of hepatocellular carcinoma (HCC) patients, with cell communication through ligand-receptor complexes playing a central role. Methods We conducted single-cell transcriptomic analysis on ten HCC tissues to identify ligand-receptor genes involved in malignant HCC cell communication using CellChat. Leveraging RNA-Seq data from the TCGA Liver Cancer (TCGA-LIHC) and Liver Cancer - RIKEN, JP (LIRI-JP) cohorts, we employed Cox regression analysis to screen for prognosis-related genes. Prognostic risk models were constructed through unsupervised clustering and differential gene expression analysis. Subsequently, a co-culture system involving tumor cells and macrophages was established. A series of experiments, including Transwell assays, immunofluorescence staining, immunoprecipitation, flow cytometry, and immunohistochemistry, were conducted to elucidate the mechanism through which HCC cells recruit macrophages via the CCL16-CCR1 axis. Results Single-cell analysis unveiled significant interactions between malignant HCC cells and macrophages, identifying 76 related ligand-receptor genes. Patients were classified into three subtypes based on the expression patterns of eight prognosis-related ligand-receptor genes. The subtype with the worst prognosis exhibited reduced infiltration of T cell-related immune cells, downregulation of immune checkpoint genes, and increased M2-like tumor-associated macrophage scores. In vitro experiments confirmed the pivotal role of the CCL16-CCR1 axis in the recruitment and M2 polarization of tumor-associated macrophages. Clinical samples demonstrated a significant association between CCL16 protein expression levels and advanced stage, lymph node metastasis, and distant metastasis. Immunohistochemistry and immunofluorescence staining further confirmed the correlation between CCL16 and CCR1, CD68, and CD206, as well as CD68+CCR1+ macrophage infiltration. Conclusions Our study identified molecular subtypes, a prognostic model, and immune microenvironment features based on ligand-receptor interactions in malignant HCC cell communication. Moreover, we revealed the pro-tumorigenic role of HCC cells in recruiting M2-like tumor-associated macrophages through the CCL16-CCR1 axis.
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Affiliation(s)
- Zongbo Dai
- Hepabobiliary Surgery Department, First Hospital of China Medical University, Shenyang, China
| | - Yu Wang
- Department of General Surgery, Anshan Central Hospital, Anshan, China
| | - Ning Sun
- Hepabobiliary Surgery Department, First Hospital of China Medical University, Shenyang, China
| | - Chengshuo Zhang
- Hepabobiliary Surgery Department, First Hospital of China Medical University, Shenyang, China
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Boopathy LK, Roy A, Gopal T, Kandy RRK, Arumugam MK. Potential molecular mechanisms of myrtenal against colon cancer: A systematic review. J Biochem Mol Toxicol 2024; 38:e23525. [PMID: 37665681 DOI: 10.1002/jbt.23525] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 08/12/2023] [Accepted: 08/24/2023] [Indexed: 09/06/2023]
Abstract
Colon cancer is a serious health problem across the globe with various dietary lifestyle modifications. It arises as an inflammation mediated crypts in the colon epithelial cells and undergoes uncontrolled cell division and proliferation. Bacterial enzymes contribute to a major outbreak in colon cancer development upon the release of toxic metabolites from the gut microflora. Pathogen associated molecular patterns and damage associated molecular patterns triggers the NLPR3 inflammasome pathways that releases pro-inflammatory cytokines to induce cancer of the colon. Contributing to this, specific chemokines and receptor complexes attribute to cellular proliferation and metastasis. Bacterial enzymes synergistically attack the colon mucosa and degenerate the cellular integrity causing lysosomal discharge. These factors further instigate the Tol like receptors (TLRs) and Nod like receptors (NLRs) to promote angiogenesis and supply nutrients for the cancer cells. Myrtenal, a monoterpene, is gaining more importance in recent times and it is being widely utilized against many diseases such as cancers, neurodegenerative diseases and diabetes. Based on the research data's, the reviews focus on the anticancer property of myrtenal by emphasizing its therapeutic properties which downregulate the inflammasome pathways and other signalling pathways. Combination therapy is gaining more importance as they can target every variant in the cellular stress condition. Clinical studies with compounds like myrtenal of the monoterpenes family is provided with positive results which might open an effective anticancer drug therapy. This review highlights myrtenal and its biological potency as a cost effective drug for prevention and treatment of colon cancer.
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Affiliation(s)
- Lokesh Kumar Boopathy
- Centre for Laboratory Animal Technology and Research, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Anitha Roy
- Department of Pharmacology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - Thiyagarajan Gopal
- Centre for Laboratory Animal Technology and Research, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Rakhee Rathnam Kalari Kandy
- Department of Biochemistry and Molecular Biology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland, USA
| | - Madan Kumar Arumugam
- Cancer Biology Lab, Centre for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
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21
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Wu WS, Cheng CC, Lee YH, Wei JL, Chen RF, Lin CF, You RI, Chen YC, Shih HM, Hu CT, Chang HH, Lee MC, Chen YC. Preclinical trial of targeting the Hic-5-mediated pathway to prevent the progression of hepatocellular carcinoma. Am J Cancer Res 2023; 13:4903-4917. [PMID: 37970347 PMCID: PMC10636688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 09/23/2023] [Indexed: 11/17/2023] Open
Abstract
The poor prognosis of hepatocellular carcinoma (HCC) was ascribed to metastasis. Targeted therapy aiming at the molecules along the metastatic pathway is a promising therapeutic strategy. Among them, hydrogen peroxide inducible clone-5 (Hic-5) is highlighted. Hic-5, discovered as a reactive oxygen species (ROS)-inducible gene, was identified to be an adaptor protein in focal adhesion and a critical signaling mediator upregulated in various cancers including HCC. Moreover, Hic-5 may regulate epithelial-mesenchymal transition (EMT) transcription factor Snail and its downstream mesenchymal genes including fibronectin and matrix metalloproteinase-9 required for migration and invasion of HCC. However, the comprehensive Hic-5-mediated pathway was not established and whether Hic-5 can be a target for preventing HCC progression has not been validated in vivo. Using whole-transcriptome mRNA sequencing, we found reactive oxygen species modulator (ROMO) and ZNF395 were upregulated by Hic-5 in a patient-derived HCC cell line, HCC372. Whereas ROMO was involved in Hic-5-mediated ROS signaling, ZNF395 locates downstream of Snail for mesenchymal genes expression required for cell migration. Also, ZNF395 but not ROMO was upregulated by Hic-5 for migration in another patient-derived HCC cell line, HCC374. Further, by in vivo knock down of Hic-5 using the Stable Nucleic Acids Lipid nanoparticles (SNALP)-carried Hic-5 siRNA, progression of HCC372 and HCC374 in SCID mice was prevented, coupled with the decrease of the downstream mesenchymal genes. Our study provides the preclinical evidence that targeting Hic-5 is potentially able to prevent the progression of HCCs with Hic-5 overexpression.
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Affiliation(s)
- Wen-Sheng Wu
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualien 97004, Taiwan
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi UniversityHualien 97004, Taiwan
| | - Chuan-Chu Cheng
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualien 97004, Taiwan
| | - Yi-Hsuan Lee
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualien 97004, Taiwan
| | - Jia-Ling Wei
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualien 97004, Taiwan
| | - Rui-Fang Chen
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualien 97004, Taiwan
| | - Chen-Fang Lin
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualien 97004, Taiwan
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi UniversityHualien 97004, Taiwan
| | - Ren-In You
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi UniversityHualien 97004, Taiwan
| | - Yen-Chang Chen
- Department of Anatomical Pathology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualien 97004, Taiwan
- Department of Pathology, School of Medicine, Tzu Chi UniversityHualien 97004, Taiwan
| | - Hsiu-Ming Shih
- Institute of Biomedical Sciences, Academia SinicaTaipei 11529, Taiwan
| | - Chi-Tan Hu
- Division of Gastroenterology, Department of Medicine, Research Centre for Hepatology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualien 97004, Taiwan
| | - Hsin-Hou Chang
- Department of Molecular Biology and Human Genetics, Tzu Chi UniversityHualien 97004, Taiwan
| | - Ming-Che Lee
- Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical UniversityTaipei 110, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical UniversityTaipei 110, Taiwan
| | - Yen-Cheng Chen
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualien 97004, Taiwan
- School of Medicine, Tzu Chi UniversityHualien 97004, Taiwan
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22
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Xu H, Lin S, Zhou Z, Li D, Zhang X, Yu M, Zhao R, Wang Y, Qian J, Li X, Li B, Wei C, Chen K, Yoshimura T, Wang JM, Huang J. New genetic and epigenetic insights into the chemokine system: the latest discoveries aiding progression toward precision medicine. Cell Mol Immunol 2023; 20:739-776. [PMID: 37198402 PMCID: PMC10189238 DOI: 10.1038/s41423-023-01032-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 04/14/2023] [Indexed: 05/19/2023] Open
Abstract
Over the past thirty years, the importance of chemokines and their seven-transmembrane G protein-coupled receptors (GPCRs) has been increasingly recognized. Chemokine interactions with receptors trigger signaling pathway activity to form a network fundamental to diverse immune processes, including host homeostasis and responses to disease. Genetic and nongenetic regulation of both the expression and structure of chemokines and receptors conveys chemokine functional heterogeneity. Imbalances and defects in the system contribute to the pathogenesis of a variety of diseases, including cancer, immune and inflammatory diseases, and metabolic and neurological disorders, which render the system a focus of studies aiming to discover therapies and important biomarkers. The integrated view of chemokine biology underpinning divergence and plasticity has provided insights into immune dysfunction in disease states, including, among others, coronavirus disease 2019 (COVID-19). In this review, by reporting the latest advances in chemokine biology and results from analyses of a plethora of sequencing-based datasets, we outline recent advances in the understanding of the genetic variations and nongenetic heterogeneity of chemokines and receptors and provide an updated view of their contribution to the pathophysiological network, focusing on chemokine-mediated inflammation and cancer. Clarification of the molecular basis of dynamic chemokine-receptor interactions will help advance the understanding of chemokine biology to achieve precision medicine application in the clinic.
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Affiliation(s)
- Hanli Xu
- College of Life Sciences and Bioengineering, School of Physical Science and Engineering, Beijing Jiaotong University, 3 ShangyuanCun, Haidian District, 100044, Beijing, P.R. China
| | - Shuye Lin
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, 101149, Beijing, China
| | - Ziyun Zhou
- College of Life Sciences and Bioengineering, School of Physical Science and Engineering, Beijing Jiaotong University, 3 ShangyuanCun, Haidian District, 100044, Beijing, P.R. China
| | - Duoduo Li
- College of Life Sciences and Bioengineering, School of Physical Science and Engineering, Beijing Jiaotong University, 3 ShangyuanCun, Haidian District, 100044, Beijing, P.R. China
| | - Xiting Zhang
- College of Life Sciences and Bioengineering, School of Physical Science and Engineering, Beijing Jiaotong University, 3 ShangyuanCun, Haidian District, 100044, Beijing, P.R. China
| | - Muhan Yu
- College of Life Sciences and Bioengineering, School of Physical Science and Engineering, Beijing Jiaotong University, 3 ShangyuanCun, Haidian District, 100044, Beijing, P.R. China
| | - Ruoyi Zhao
- College of Life Sciences and Bioengineering, School of Physical Science and Engineering, Beijing Jiaotong University, 3 ShangyuanCun, Haidian District, 100044, Beijing, P.R. China
| | - Yiheng Wang
- College of Life Sciences and Bioengineering, School of Physical Science and Engineering, Beijing Jiaotong University, 3 ShangyuanCun, Haidian District, 100044, Beijing, P.R. China
| | - Junru Qian
- College of Life Sciences and Bioengineering, School of Physical Science and Engineering, Beijing Jiaotong University, 3 ShangyuanCun, Haidian District, 100044, Beijing, P.R. China
| | - Xinyi Li
- College of Life Sciences and Bioengineering, School of Physical Science and Engineering, Beijing Jiaotong University, 3 ShangyuanCun, Haidian District, 100044, Beijing, P.R. China
| | - Bohan Li
- College of Life Sciences and Bioengineering, School of Physical Science and Engineering, Beijing Jiaotong University, 3 ShangyuanCun, Haidian District, 100044, Beijing, P.R. China
| | - Chuhan Wei
- College of Life Sciences and Bioengineering, School of Physical Science and Engineering, Beijing Jiaotong University, 3 ShangyuanCun, Haidian District, 100044, Beijing, P.R. China
| | - Keqiang Chen
- Laboratory of Cancer Innovation, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, 21702, USA
| | - Teizo Yoshimura
- Laboratory of Cancer Innovation, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, 21702, USA
| | - Ji Ming Wang
- Laboratory of Cancer Innovation, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, 21702, USA
| | - Jiaqiang Huang
- College of Life Sciences and Bioengineering, School of Physical Science and Engineering, Beijing Jiaotong University, 3 ShangyuanCun, Haidian District, 100044, Beijing, P.R. China.
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, 101149, Beijing, China.
- Laboratory of Cancer Innovation, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, 21702, USA.
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23
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Yoshimura T, Li C, Wang Y, Matsukawa A. The chemokine monocyte chemoattractant protein-1/CCL2 is a promoter of breast cancer metastasis. Cell Mol Immunol 2023; 20:714-738. [PMID: 37208442 PMCID: PMC10310763 DOI: 10.1038/s41423-023-01013-0] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 03/17/2023] [Indexed: 05/21/2023] Open
Abstract
Breast cancer is the most prevalent cancer worldwide, and metastasis is the leading cause of death in cancer patients. Human monocyte chemoattractant protein-1 (MCP-1/CCL2) was isolated from the culture supernatants of not only mitogen-activated peripheral blood mononuclear leukocytes but also malignant glioma cells based on its in vitro chemotactic activity toward human monocytes. MCP-1 was subsequently found to be identical to a previously described tumor cell-derived chemotactic factor thought to be responsible for the accumulation of tumor-associated macrophages (TAMs), and it became a candidate target of clinical intervention; however, the role of TAMs in cancer development was still controversial at the time of the discovery of MCP-1. The in vivo role of MCP-1 in cancer progression was first evaluated by examining human cancer tissues, including breast cancers. Positive correlations between the level of MCP-1 production in tumors and the degree of TAM infiltration and cancer progression were established. The contribution of MCP-1 to the growth of primary tumors and metastasis to the lung, bone, and brain was examined in mouse breast cancer models. The results of these studies strongly suggested that MCP-1 is a promoter of breast cancer metastasis to the lung and brain but not bone. Potential mechanisms of MCP-1 production in the breast cancer microenvironment have also been reported. In the present manuscript, we review studies in which the role of MCP-1 in breast cancer development and progression and the mechanisms of its production were examined and attempt to draw a consensus and discuss the potential use of MCP-1 as a biomarker for diagnosis.
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Affiliation(s)
- Teizo Yoshimura
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.
| | - Chunning Li
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan
| | - Yuze Wang
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan
| | - Akihiro Matsukawa
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan
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24
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Prajapati DR, Molczyk C, Purohit A, Saxena S, Sturgeon R, Dave BJ, Kumar S, Batra SK, Singh RK. Small molecule antagonist of CXCR2 and CXCR1 inhibits tumor growth, angiogenesis, and metastasis in pancreatic cancer. Cancer Lett 2023; 563:216185. [PMID: 37062329 PMCID: PMC10218365 DOI: 10.1016/j.canlet.2023.216185] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/06/2023] [Accepted: 04/11/2023] [Indexed: 04/18/2023]
Abstract
Pancreatic cancer (PC) has a poor prognosis, and current therapeutic strategies are ineffective in advanced diseases. We and others have shown the aberrant expression of CXCR2 and its ligands in PC development and progression. Our objective for this study was to evaluate the therapeutic utility of CXCR2/1 targeting using an small molecule antagonist, SCH-479833, in different PC preclinical murine models (syngeneic or xenogeneic). Our results demonstrate that CXCR2/1 antagonist had both antitumor and anti-metastatic effects in PC. CXCR2/1 antagonist treatment inhibited tumor cell proliferation, migration, angiogenesis, and recruitment of neutrophils, while it increased apoptosis. Treatment with the antagonist enhanced fibrosis, tumor necrosis, and extramedullary hematopoiesis. Together, these findings suggest that selectively targeting CXCR2/1 with small molecule inhibitors is a promising therapeutic approach for inhibiting PC growth, angiogenesis, and metastasis.
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Affiliation(s)
- Dipakkumar R Prajapati
- Department of Pathology and Microbiology, 985950, Nebraska Medical Center, Omaha, NE, 68198-5900, United States
| | - Caitlin Molczyk
- Department of Pathology and Microbiology, 985950, Nebraska Medical Center, Omaha, NE, 68198-5900, United States
| | - Abhilasha Purohit
- Department of Pathology and Microbiology, 985950, Nebraska Medical Center, Omaha, NE, 68198-5900, United States
| | - Sugandha Saxena
- Department of Pathology and Microbiology, 985950, Nebraska Medical Center, Omaha, NE, 68198-5900, United States
| | - Reegan Sturgeon
- Department of Pathology and Microbiology, 985950, Nebraska Medical Center, Omaha, NE, 68198-5900, United States
| | - Bhavana J Dave
- Department of Pathology and Microbiology, 985950, Nebraska Medical Center, Omaha, NE, 68198-5900, United States
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5845, United States
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5845, United States
| | - Rakesh K Singh
- Department of Pathology and Microbiology, 985950, Nebraska Medical Center, Omaha, NE, 68198-5900, United States.
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25
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Nasrolahi A, Azizidoost S, Radoszkiewicz K, Najafi S, Ghaedrahmati F, Anbiyaee O, Khoshnam SE, Farzaneh M, Uddin S. Signaling pathways governing glioma cancer stem cells behavior. Cell Signal 2023; 101:110493. [PMID: 36228964 DOI: 10.1016/j.cellsig.2022.110493] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/03/2022] [Accepted: 10/05/2022] [Indexed: 11/30/2022]
Abstract
Glioma is the most common malignant brain tumor that develops in the glial tissue. Several studies have identified that glioma cancer stem cells (GCSCs) play important roles in tumor-initiating features in malignant gliomas. GCSCs are a small population in the brain that presents an essential role in the metastasis of glioma cells to other organs. These cells can self-renew and differentiate, which are thought to be involved in the pathogenesis of glioma. Therefore, targeting GCSCs might be a novel strategy for the treatment of glioma. Accumulating evidence revealed that several signaling pathways, including Notch, TGF-β, Wnt, STAT3, AKT, and EGFR mediated GCSC growth, proliferation, migration, and invasion. Besides, non-coding RNAs (ncRNAs), including miRNAs, circular RNAs, and long ncRNAs have been found to play pivotal roles in the regulation of GCSC pathogenesis and drug resistance. Therefore, targeting these pathways could open a new avenue for glioma management. In this review, we summarized critical signaling pathways involved in the stimulation or prevention of GCSCs tumorigenesis and invasiveness.
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Affiliation(s)
- Ava Nasrolahi
- Infectious Ophthalmologic Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Shirin Azizidoost
- Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Klaudia Radoszkiewicz
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, Poland
| | - Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farhoodeh Ghaedrahmati
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Omid Anbiyaee
- Cardiovascular Research Center, Nemazi Hospital, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Esmaeil Khoshnam
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Shahab Uddin
- Translational Research Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
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26
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Maurya SK, Khan P, Rehman AU, Kanchan RK, Perumal N, Mahapatra S, Chand HS, Santamaria-Barria JA, Batra SK, Nasser MW. Rethinking the chemokine cascade in brain metastasis: Preventive and therapeutic implications. Semin Cancer Biol 2022; 86:914-930. [PMID: 34968667 PMCID: PMC9234104 DOI: 10.1016/j.semcancer.2021.12.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 01/27/2023]
Abstract
Brain metastasis (BrM) is one of the major causes of death in cancer patients and is associated with an estimated 10-40 % of total cancer cases. The survival rate of brain metastatic patients has not improved due to intratumor heterogeneity, the survival adaptations of brain homing metastatic cells, and the lack of understanding of underlying molecular mechanisms that limit the availability of effective therapies. The heterogeneous population of immune cells and tumor-initiating cells or cancer stem cells in the tumor microenvironment (TME) release various factors, such as chemokines that upon binding to their cognate receptors enhance tumor growth at primary sites and help tumor cells metastasize to the brain. Furthermore, brain metastatic sites have unique heterogeneous microenvironment that fuels cancer cells in establishing BrM. This review explores the crosstalk of chemokines with the heterogeneous TME during the progression of BrM and recognizes potential therapeutic approaches. We also discuss and summarize different targeted, immunotherapeutic, chemotherapeutic, and combinatorial strategies (with chemo-/immune- or targeted-therapies) to attenuate chemokines mediated BrM.
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Affiliation(s)
- Shailendra Kumar Maurya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Parvez Khan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Asad Ur Rehman
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Ranjana K Kanchan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Naveenkumar Perumal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Sidharth Mahapatra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Hitendra S Chand
- Department of Immunology and Nanomedicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA
| | | | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Mohd Wasim Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68108, USA.
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27
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Ahmad M, Dhasmana A, Harne PS, Zamir A, Hafeez BB. Chemokine clouding and liver cancer heterogeneity: Does it impact clinical outcomes? Semin Cancer Biol 2022; 86:1175-1185. [PMID: 35189322 DOI: 10.1016/j.semcancer.2022.02.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 02/11/2022] [Accepted: 02/12/2022] [Indexed: 02/08/2023]
Abstract
Tumor heterogeneity is a predominant feature of hepatocellular carcinoma (HCC) that plays a crucial role in chemoresistance and limits the efficacy of available chemo/immunotherapy regimens. Thus, a better understanding regarding the molecular determinants of tumor heterogeneity will help in developing newer strategies for effective HCC management. Chemokines, a sub-family of cytokines are one of the key molecular determinants of tumor heterogeneity in HCC and are involved in cell survival, growth, migration, and angiogenesis. Herein, we provide a panoramic insight into the role of chemokines in HCC heterogeneity at genetic, epigenetic, metabolic, immune cell composition, and tumor microenvironment levels and its impact on clinical outcomes. Interestingly, our in-silico analysis data showed that expression of chemokine receptors impacts infiltration of various immune cell populations into the liver tumor and leads to heterogeneity. Thus, it is evident that aberrant chemokines clouding impacts HCC tumor heterogeneity and understanding this phenomenon in depth could be harnessed for the development of personalized medicine strategies in future.
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Affiliation(s)
- Mudassier Ahmad
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, TX 78504, United States
| | - Anupam Dhasmana
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, TX 78504, United States; Department of Biosciences and Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, India
| | - Prateek Suresh Harne
- DHR Health Gastroenterology, 5520 Leonardo da Vinci Drive, Suite 100, Edinburg, TX 78539, United States
| | - Asif Zamir
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, TX 78504, United States; DHR Health Gastroenterology, 5520 Leonardo da Vinci Drive, Suite 100, Edinburg, TX 78539, United States
| | - Bilal Bin Hafeez
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, TX 78504, United States; Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, TX 78504, United States.
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28
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Mughees M, Kaushal JB, Sharma G, Wajid S, Batra SK, Siddiqui JA. Chemokines and cytokines: Axis and allies in prostate cancer pathogenesis. Semin Cancer Biol 2022; 86:497-512. [PMID: 35181473 PMCID: PMC9793433 DOI: 10.1016/j.semcancer.2022.02.017] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 02/09/2022] [Accepted: 02/10/2022] [Indexed: 01/27/2023]
Abstract
Chemokines are recognized as the major contributor to various tumorigenesis, tumor heterogeneity, and failures of current cancer therapies. The tumor microenvironment (TME) is enriched with chemokines and cytokines and plays a pivotal role in cancer progression. Chronic inflammation is also considered an instructive process of cancer progression, where chemokines are spatiotemporally secreted by malignant cells and leukocyte subtypes that initiate cell trafficking into the TME. In various cancers, prostate cancer (PCa) is reported as one of the leading cancers in the worldwide male population. The chemokines-mediated signaling pathways are intensively involved in PCa progression and metastasis. Emerging evidence suggests that chemokines and cytokines are responsible for the pleiotropic actions in cancer, including the growth, angiogenesis, endothelial mesenchymal transition, leukocyte infiltration, and hormone escape for advanced PCa and therapy resistance. Chemokine's system and immune cells represent a promising target to suppress tumorigenic environments and serve as potential therapy/immunotherapy for the PCa. In this review, an attempt has been made to shed light on the alteration of chemokine and cytokine profiles during PCa progression and metastasis. We also discussed the recent findings of the diverse molecular signaling of these circulating chemokines and their corresponding receptors that could become future targets for therapeutic management of PCa.
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Affiliation(s)
- Mohd Mughees
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India; Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA(1)
| | - Jyoti Bala Kaushal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Gunjan Sharma
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Saima Wajid
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Surinder Kumar Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Jawed Akhtar Siddiqui
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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Queen A, Bhutto HN, Yousuf M, Syed MA, Hassan MI. Carbonic anhydrase IX: A tumor acidification switch in heterogeneity and chemokine regulation. Semin Cancer Biol 2022; 86:899-913. [PMID: 34998944 DOI: 10.1016/j.semcancer.2022.01.001] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/30/2021] [Accepted: 01/03/2022] [Indexed: 02/07/2023]
Abstract
The primary physiological process of respiration produces carbon dioxide (CO2) that reacts with water molecules which subsequently liberates bicarbonate (HCO-3) and protons. Carbonic anhydrases (CAs) are the primary catalyst involved in this conversion. More than 16 isoforms of human CAs show organ or subcellular specific activity. Dysregulation of each CA is associated with multiple pathologies. Out of these members, the overexpression of membrane-bound carbonic anhydrase IX (CAIX) is associated explicitly with hypoxic tumors or various solid cancers. CAIX helps tumors deal with higher CO2 by sequestering it with bicarbonate ions and helping cancer cells to grow in a comparatively hypoxic or acidic environment, thus acting as a pH adaptation switch. CAIX-mediated adaptations in cancer cells include angiogenesis, metabolic alterations, tumor heterogeneity, drug resistance, and regulation of cancer-specific chemokines. This review comprehensively collects and describe the cancer-specific expression mechanism and role of CAIX in cancer growth, progression, heterogeneity, and its structural insight to develop future combinatorial targeted cancer therapies.
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Affiliation(s)
- Aarfa Queen
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Humaira Naaz Bhutto
- Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Mohd Yousuf
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Mansoor Ali Syed
- Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India.
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30
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Seliger B, Koehl U. Underlying mechanisms of evasion from NK cells as rational for improvement of NK cell-based immunotherapies. Front Immunol 2022; 13:910595. [PMID: 36045670 PMCID: PMC9422402 DOI: 10.3389/fimmu.2022.910595] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 07/20/2022] [Indexed: 11/13/2022] Open
Abstract
Natural killer (NK) cells belong to the family of innate immune cells with the capacity to recognize and kill tumor cells. Different phenotypes and functional properties of NK cells have been described in tumor patients, which could be shaped by the tumor microenvironment. The discovery of HLA class I-specific inhibitory receptors controlling NK cell activity paved the way to the fundamental concept of modulating immune responses that are regulated by an array of inhibitory receptors, and emphasized the importance to explore the potential of NK cells in cancer therapy. Although a whole range of NK cell-based approaches are currently being developed, there are still major challenges that need to be overcome for improved efficacy of these therapies. These include escape of tumor cells from NK cell recognition due to their expression of inhibitory molecules, immune suppressive signals of NK cells, reduced NK cell infiltration of tumors, an immune suppressive micromilieu and limited in vivo persistence of NK cells. Therefore, this review provides an overview about the NK cell biology, alterations of NK cell activities, changes in tumor cells and the tumor microenvironment contributing to immune escape or immune surveillance by NK cells and their underlying molecular mechanisms as well as the current status and novel aspects of NK cell-based therapeutic strategies including their genetic engineering and their combination with conventional treatment options to overcome tumor-mediated evasion strategies and improve therapy efficacy.
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Affiliation(s)
- Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
- Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
- *Correspondence: Barbara Seliger,
| | - Ulrike Koehl
- Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
- Institute of Clinical Immunology, University of Leipzig, Leipzig, Germany
- Institute of Cellular Therapeutics, Hannover Medical School, Hannover, Germany
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31
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Kwiatkowska I, Hermanowicz JM, Iwinska Z, Kowalczuk K, Iwanowska J, Pawlak D. Zebrafish—An Optimal Model in Experimental Oncology. Molecules 2022; 27:molecules27134223. [PMID: 35807468 PMCID: PMC9268704 DOI: 10.3390/molecules27134223] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 06/10/2022] [Accepted: 06/28/2022] [Indexed: 02/02/2023] Open
Abstract
A thorough understanding of cancer pathogenesis is a necessary step in the development of more effective and safer therapy. However, due to the complexity of the process and intricate interactions, studying tumor development is an extremely difficult and challenging task. In bringing this issue closer, different scientific models with various advancement levels are helpful. Cell cultures is a system that is too simple and does not allow for multidirectional research. On the other hand, rodent models, although commonly used, are burdened with several limitations. For this reason, new model organisms that will allow for the studying of carcinogenesis stages and factors reliably involved in them are urgently sought after. Danio rerio, an inconspicuous fish endowed with unique features, is gaining in importance in the world of scientific research. Including it in oncological research brings solutions to many challenges afflicting modern medicine. This article aims to illustrate the usefulness of Danio rerio as a model organism which turns out to be a powerful and unique tool for studying the stages of carcinogenesis and solving the hitherto incomprehensible processes that lead to the development of the disease.
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Affiliation(s)
- Iwona Kwiatkowska
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (J.M.H.); (Z.I.); (J.I.); (D.P.)
- Correspondence: ; Tel./Fax: +48-8574-856-01
| | - Justyna Magdalena Hermanowicz
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (J.M.H.); (Z.I.); (J.I.); (D.P.)
- Department of Clinical Pharmacy, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland
| | - Zaneta Iwinska
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (J.M.H.); (Z.I.); (J.I.); (D.P.)
| | - Krystyna Kowalczuk
- Department of Integrated Medical Care, Medical University of Bialystok, ul. M Skłodowskiej-Curie 7A, 15-096 Bialystok, Poland;
| | - Jolanta Iwanowska
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (J.M.H.); (Z.I.); (J.I.); (D.P.)
| | - Dariusz Pawlak
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (J.M.H.); (Z.I.); (J.I.); (D.P.)
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Braoudaki M, Ahmad MS, Mustafov D, Seriah S, Siddiqui MN, Siddiqui SS. Chemokines and chemokine receptors in colorectal cancer; multifarious roles and clinical impact. Semin Cancer Biol 2022; 86:436-449. [PMID: 35700938 DOI: 10.1016/j.semcancer.2022.06.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/07/2022] [Accepted: 06/08/2022] [Indexed: 11/19/2022]
Abstract
Colorectal cancer (CRC) is considered the second cause of cancer death worldwide. The early diagnosis plays a key role in patient prognosis and subsequently overall survival. Similar to several types of cancer, colorectal cancer is also characterised by drug resistance and heterogeneity that contribute to its complexity -especially at advanced stages. However, despite the extensive research related to the identification of biomarkers associated to early diagnosis, accurate prognosis and the management of CRC patients, little progress has been made thus far. Therefore, the mortality rates, especially at advanced stages, remain high. A large family of chemoattractant cytokines called chemokines are known for their significant role in inflammation and immunity. Chemokines released by the different tumorous cells play a key role in increasing the complexity of the tumour's microenvironment. The current review investigates the role of chemokines and chemokine receptors in colorectal cancer and their potential as clinical molecular signatures that could be effectively used as a personalised therapeutic approach. We discussed how chemokine and chemokine receptors regulate the microenvironment and lead to heterogeneity in CRC. An important aspect of chemokines is their role in drug resistance which has been extensively discussed. This review also provides an overview of the current advances in the search for chemokines and chemokine receptors in CRC.
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Affiliation(s)
- Maria Braoudaki
- Dept of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK
| | - Mohammed Saqif Ahmad
- Dept of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK
| | - Denis Mustafov
- Dept of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK
| | - Sara Seriah
- Dept of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK
| | - Mohammad Naseem Siddiqui
- Department of Biosciences, Faculty of Natural Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Shoib Sarwar Siddiqui
- Dept of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK.
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Mu L, Hu S, Li G, Wu P, Ren C, Lin T, Zhang S. Characterization of the Prognostic Values of CXCL Family in Epstein-Barr Virus Associated Gastric Cancer. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2218140. [PMID: 35693706 PMCID: PMC9177340 DOI: 10.1155/2022/2218140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 04/12/2022] [Accepted: 04/18/2022] [Indexed: 12/14/2022]
Abstract
Background CXCL family is a class of secreted growth factors signaling through G-protein-coupled receptors, and abnormal expression is associated with the growth and progression of many tumors. However, their prognostic value has been poorly studied in Epstein-Barr virus- (EBV-) associated gastric cancer (EBVaGC). Therefore, it is of great significance to explore the prognostic value of the CXCL family in EBVaGC. Methods CXCL family mRNA expression was analyzed in STAD data from The Cancer Genome Atlas (TCGA). Kaplan-Meier Plotter was used to assess the prognostic value of the CXCL family. Transcription factors (TFs) and miRNAs associated with the CXCL family were identified by TFCheckpoint, miRWalk, and ViRBase databases. The prognostic model was evaluated using the EBVaGC patient cohort GSE51575. Results The mRNA expression of CXCL1/3/5/6/8/9/10/11/16 was significantly upregulated, while the expression of CXCL12/14 was downregulated in EBVaGC compared with normal tissues from TCGA-STAD. The mRNA expressions of CXCL9, CXCL10, CXCL11, and CXCL17 in EBVaGCs were higher than those in EBVnGCs, but the mRNA expressions of CXCL6, CXCL12, and CXCL17 were lower than those in EBVnGCs. The mRNA expression levels of CXCL9, CXCL10, and CXCL11 in EBVaGCs were higher than those in EBVnGCs regardless of the tumor stage. High mRNA expression of CXCL8 was associated with better OS in patients with EBVaGC, while high expression of CXCL9 was associated with better OS in patients with EBVnGC. We obtained 10 candidate potential transcription factors (TFs) associated with CXCLs: OTOP3, NKX6-2, NKX2-2, FEV, SMYD1, TRIMSO, TBX10, CDX1, SLC26A3, and ARC. 576 miRNA-mRNA interactions were obtained. Among them, 65 miRNAs were predicted to be correlated with CXCL6, CXCL9, CXCL10, and CXCL11. Similar to the results of TCGA-STAD, the GSE51575 dataset also showed that the mRNA expression levels of CXCL1/3/9/10/11/16 were markedly enhanced in EBVaGC tissues compared with corresponding normal gastric mucosa tissues, while the mRNA expression levels of CXCL12/14 were significantly reduced. The mRNA expression levels of CXCL3/9/10/11/13/17 were increased in EBVaGC compared with EBVnGC tissues. Conclusions The expression differences of CXCL family members are closely associated with the progression of EBVaGC. Expression of CXCL9/10/11/17 mRNA may be a promising prognostic indicator for EBVaGC patients.
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Affiliation(s)
- Li Mu
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Shun Hu
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Guoping Li
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Ping Wu
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Caihong Ren
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Taiyu Lin
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Sheng Zhang
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
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Yang H, Shen Z, Luo L, Gao J, Chen S, Che J, Xu L, Wu M, Dong X. Molecular dynamics insights into the selectivity toward CXCR1 and CXCR2 antagonists. Chem Phys Lett 2022. [DOI: 10.1016/j.cplett.2022.139539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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35
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Jasinski-Bergner S, Eckstein M, Taubert H, Wach S, Fiebig C, Strick R, Hartmann A, Seliger B. The Human Leukocyte Antigen G as an Immune Escape Mechanism and Novel Therapeutic Target in Urological Tumors. Front Immunol 2022; 13:811200. [PMID: 35185904 PMCID: PMC8855320 DOI: 10.3389/fimmu.2022.811200] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 01/13/2022] [Indexed: 02/06/2023] Open
Abstract
The non-classical human leukocyte antigen G (HLA-G) is a potent regulatory protein involved in the induction of immunological tolerance. This is based on the binding of membrane-bound as well as soluble HLA-G to inhibitory receptors expressed on various immune effector cells, in particular NK cells and T cells, leading to their attenuated functions. Despite its restricted expression on immune-privileged tissues under physiological conditions, HLA-G expression has been frequently detected in solid and hematopoietic malignancies including urological cancers, such as renal cell and urothelial bladder carcinoma and has been associated with progression of urological cancers and poor outcome of patients: HLA-G expression protects tumor cells from anti-tumor immunity upon interaction with its inhibitory receptors by modulating both the phenotype and function of immune cells leading to immune evasion. This review will discuss the expression, regulation, functional and clinical relevance of HLA-G expression in urological tumors as well as its use as a putative biomarker and/or potential therapeutic target for the treatment of renal cell carcinoma as well as urothelial bladder cancer.
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Affiliation(s)
- Simon Jasinski-Bergner
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Markus Eckstein
- Institute of Pathology, Universitätsklinikum Erlangen, Erlangen, Germany.,Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nürnberg (CCC ER-EMN), Erlangen, Germany
| | - Helge Taubert
- Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nürnberg (CCC ER-EMN), Erlangen, Germany.,Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Sven Wach
- Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nürnberg (CCC ER-EMN), Erlangen, Germany.,Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Fiebig
- Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nürnberg (CCC ER-EMN), Erlangen, Germany.,Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Reiner Strick
- Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nürnberg (CCC ER-EMN), Erlangen, Germany.,Laboratory of Molecular Medicine, Department of Gynecology & Obstetrics, University Hospital Erlangen, Friedrich Alexander University (FAU), Erlangen-Nürnberg, Erlangen, Germany
| | - Arndt Hartmann
- Institute of Pathology, Universitätsklinikum Erlangen, Erlangen, Germany.,Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nürnberg (CCC ER-EMN), Erlangen, Germany
| | - Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.,Main Department of GMP Cell and Gene Therapy, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
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Mehraj U, Mushtaq U, Mir MA, Saleem A, Macha MA, Lone MN, Hamid A, Zargar MA, Ahmad SM, Wani NA. Chemokines in Triple-Negative Breast Cancer Heterogeneity: New Challenges for Clinical Implications. Semin Cancer Biol 2022; 86:769-783. [PMID: 35278636 DOI: 10.1016/j.semcancer.2022.03.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 03/01/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022]
Abstract
Tumor heterogeneity is a hallmark of cancer and one of the primary causes of resistance to therapies. Triple-negative breast cancer (TNBC), which accounts for 15% to 20% of all breast cancers and is the most aggressive subtype, is very diverse, connected to metastatic potential and response to therapy. It is a very diverse disease at the molecular, pathologic, and clinical levels. TNBC is substantially more likely to recur and has a worse overall survival rate following diagnosis than other breast cancer subtypes. Chemokines, low molecular weight proteins that stimulate chemotaxis, have been shown to control the cues responsible for TNBC heterogeneity. In this review, we have focused on tumor heterogeneity and the role of chemokines in modulating tumor heterogeneity, since this is the most critical issue in treating TNBC. Additionally, we examined numerous cues mediated by chemokine networks that contribute to the heterogeneity of TNBC. Recent developments in our knowledge of the chemokine networks that regulate TNBC heterogeneity may pave the door for developing difficult-to-treat TNBC treatment options.
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Affiliation(s)
- Umar Mehraj
- Department of Bioresources, School of Life Sciences, University of Kashmir, Srinagar, Jammu & Kashmir India
| | - Umer Mushtaq
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India
| | - Manzoor A Mir
- Department of Bioresources, School of Life Sciences, University of Kashmir, Srinagar, Jammu & Kashmir India
| | - Afnan Saleem
- Division of Animal Biotechnology Faculty of Veterinary Sciences and Animal Husbandry, Shuhama Sher-e- Kashmir University of Agricultural Sciences and Technology-Kashmir, India
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science & Technology Awantipora, Jammu & Kashmir, India
| | - Mohammad Nadeem Lone
- Department of Chemistry, School of Physical & Chemical Sciences, Central University of Kashmir, Ganderbal J & K, India
| | - Abid Hamid
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India
| | - Mohammed A Zargar
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India
| | - Syed Mudasir Ahmad
- Division of Animal Biotechnology Faculty of Veterinary Sciences and Animal Husbandry, Shuhama Sher-e- Kashmir University of Agricultural Sciences and Technology-Kashmir, India
| | - Nissar Ahmad Wani
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India.
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Aramini B, Masciale V, Grisendi G, Bertolini F, Maur M, Guaitoli G, Chrystel I, Morandi U, Stella F, Dominici M, Haider KH. Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence. Cancers (Basel) 2022; 14:cancers14040976. [PMID: 35205721 PMCID: PMC8869911 DOI: 10.3390/cancers14040976] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 02/12/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary Cancer is one of the most debated problems all over the world. Cancer stem cells are considered responsible of tumor initiation, metastasis, drug resistance, and recurrence. This subpopulation of cells has been found into the tumor bulk and showed the capacity to self-renew, differentiate, up to generate a new tumor. In the last decades, several studies have been set on the molecular mechanisms behind their specific characteristics as the Wnt/β-catenin signaling, Notch signaling, Hedgehog signaling, transcription factors, etc. The most powerful part of CSCs is represented by the niches as “promoter” of their self-renewal and “protector” from the common oncological treatment as chemotherapy and radiotherapy. In our review article we highlighted the primary mechanisms involved in CSC tumorigenesis for the setting of further targets to control the metastatic process. Abstract Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs’ self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future therapeutic approaches. Regarding self-renewal, CSCs are modulated by the same molecular pathways found in normal stem cells, such as Wnt/β-catenin signaling, Notch signaling, and Hedgehog signaling. Another key characteristic of CSCs is their resistance to standard chemotherapy and radiotherapy treatments, due to their capacity to rest in a quiescent state. This review will analyze the primary mechanisms involved in CSC tumorigenesis, with particular attention to the roles of CSCs in tumor progression in benign and malignant diseases; and will examine future perspectives on the identification of new markers to better control tumorigenesis, as well as dissecting the metastasis process.
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Affiliation(s)
- Beatrice Aramini
- Division of Thoracic Surgery, Department of Experimental Diagnostic and Specialty Medicine–DIMES of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, 47121 Forlì, Italy;
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (V.M.); (U.M.)
- Correspondence:
| | - Valentina Masciale
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (V.M.); (U.M.)
| | - Giulia Grisendi
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Federica Bertolini
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Michela Maur
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Giorgia Guaitoli
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Isca Chrystel
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Uliano Morandi
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (V.M.); (U.M.)
| | - Franco Stella
- Division of Thoracic Surgery, Department of Experimental Diagnostic and Specialty Medicine–DIMES of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, 47121 Forlì, Italy;
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
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Jiang C, Li X, Sun B, Zhang N, Li J, Yue S, Hu X. Extracellular vesicles promotes liver metastasis of lung cancer by ALAHM increasing hepatocellular secretion of HGF. iScience 2022; 25:103984. [PMID: 35281743 PMCID: PMC8914534 DOI: 10.1016/j.isci.2022.103984] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/09/2022] [Accepted: 02/21/2022] [Indexed: 11/18/2022] Open
Affiliation(s)
- Chunyang Jiang
- Department of Thoracic Surgery, Tianjin Union Medical Center, Nankai University, 190 Jieyuan Road, Hongqiao District, Tianjin 300121, Tianjin, China
- Corresponding author
| | - Xu Li
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian Province, China
| | - Bingsheng Sun
- Department of Thoracic Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, Tianjin, China
| | - Na Zhang
- Department of Respiratory Medicine, Tianjin Union Medical Center, Nankai University, 190 Jieyuan Road, Hongqiao District, Tianjin 300121, Tianjin, China
| | - Jing Li
- Department of Respiratory Medicine, Tianjin Union Medical Center, Nankai University, 190 Jieyuan Road, Hongqiao District, Tianjin 300121, Tianjin, China
| | - Shijing Yue
- The State Key Laboratory of Medicinal Chemical Biology, School of Medicine, The State International Science & Technology Cooperation Base of Tumor Immunology and Biological Vaccines, Nankai University, 94 Weijin Road, Nankai District, Tianjin 300071, Tianjin, China
- Corresponding author
| | - Xiaoli Hu
- Department of Respiratory Medicine, The Second People’|'s Hospital of Linhai City, 198 Dubei Road, Linhai 317016, Zhejiang Province, China
- Corresponding author
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Saxena S, Molczyk C, Purohit A, Ehrhorn E, Goel P, Prajapati DR, Atri P, Kaur S, Grandgenett PM, Hollingsworth MA, Batra SK, Singh RK. Differential expression profile of CXC-receptor-2 ligands as potential biomarkers in pancreatic ductal adenocarcinoma. Am J Cancer Res 2022; 12:68-90. [PMID: 35141005 PMCID: PMC8822283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 12/03/2021] [Indexed: 06/14/2023] Open
Abstract
The discovery of early detection markers of pancreatic cancer (PC) disease is highly warranted. We analyzed the expression profile of different CXC-receptor-2 (CXCR2) ligands in PC cases for the potential of biomarker candidates. Analysis of different PDAC microarray datasets with matched normal and pancreatic tumor samples and next-generation sequenced transcriptomics data using an online portal showed significantly high expression of CXCL-1, 3, 5, 6, 8 in the tumors of PC patients. High CXCL5 expression was correlated to poor PC patient survival. Interestingly, mRNA and protein expression analysis of human PC cell lines showed higher CXCL2, 3, and 5 expressions in cell lines derived from metastatic sites than primary tumors. Furthermore, we utilized immunohistochemistry (IHC) to evaluate the expression of CXCR2 ligands in the human PC tumors and observed positive staining for CXCL1, 3, and 8 with a higher average IHC composite score of CXCL3 in the PC tissue specimens than the normal pancreas. We also observed an increase in the expression of mouse CXCL1, 3, and 5 in the pre-cancerous lesions of tumors and metastasis tissues derived from the PDX-cre-LSL-KrasG12D mouse model. Together, our data suggest that different CXCR2 ligands show the potential of being utilized as a diagnostic biomarker in PC patients.
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Affiliation(s)
- Sugandha Saxena
- Department of Pathology and Microbiology, 985950 Nebraska Medical CenterOmaha, NE 68198-5900, USA
| | - Caitlin Molczyk
- Department of Pathology and Microbiology, 985950 Nebraska Medical CenterOmaha, NE 68198-5900, USA
| | - Abhilasha Purohit
- Department of Pathology and Microbiology, 985950 Nebraska Medical CenterOmaha, NE 68198-5900, USA
| | - Evie Ehrhorn
- Department of Pathology and Microbiology, 985950 Nebraska Medical CenterOmaha, NE 68198-5900, USA
| | - Paran Goel
- Department of Pathology and Microbiology, 985950 Nebraska Medical CenterOmaha, NE 68198-5900, USA
| | - Dipakkumar R Prajapati
- Department of Pathology and Microbiology, 985950 Nebraska Medical CenterOmaha, NE 68198-5900, USA
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical CenterOmaha, NE 68198-5845, USA
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical CenterOmaha, NE 68198-5845, USA
| | - Paul M Grandgenett
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical CenterOmaha, NE 68198, USA
| | - Michael A Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical CenterOmaha, NE 68198, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical CenterOmaha, NE 68198-5845, USA
| | - Rakesh K Singh
- Department of Pathology and Microbiology, 985950 Nebraska Medical CenterOmaha, NE 68198-5900, USA
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Adams R, Moser B, Karagiannis SN, Lacy KE. Chemokine Pathways in Cutaneous Melanoma: Their Modulation by Cancer and Exploitation by the Clinician. Cancers (Basel) 2021; 13:cancers13225625. [PMID: 34830780 PMCID: PMC8615762 DOI: 10.3390/cancers13225625] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/04/2021] [Accepted: 11/06/2021] [Indexed: 01/01/2023] Open
Abstract
The incidence of cutaneous malignant melanoma is rising globally and is projected to continue to rise. Advances in immunotherapy over the last decade have demonstrated that manipulation of the immune cell compartment of tumours is a valuable weapon in the arsenal against cancer; however, limitations to treatment still exist. Cutaneous melanoma lesions feature a dense cell infiltrate, coordinated by chemokines, which control the positioning of all immune cells. Melanomas are able to use chemokine pathways to preferentially recruit cells, which aid their growth, survival, invasion and metastasis, and which enhance their ability to evade anticancer immune responses. Aside from this, chemokine signalling can directly influence angiogenesis, invasion, lymph node, and distal metastases, including epithelial to mesenchymal transition-like processes and transendothelial migration. Understanding the interplay of chemokines, cancer cells, and immune cells may uncover future avenues for melanoma therapy, namely: identifying biomarkers for patient stratification, augmenting the effect of current and emerging therapies, and designing specific treatments to target chemokine pathways, with the aim to reduce melanoma pathogenicity, metastatic potential, and enhance immune cell-mediated cancer killing. The chemokine network may provide selective and specific targets that, if included in current therapeutic regimens, harbour potential to improve outcomes for patients.
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Affiliation(s)
- Rebecca Adams
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London, London WC2R 2LS, UK;
| | - Bernhard Moser
- Division of Infection & Immunity, Henry Wellcome Building, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4YS, UK;
| | - Sophia N. Karagiannis
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London, London WC2R 2LS, UK;
- Guy’s Cancer Centre, Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King’s College London, London WC2R 2LS, UK
- Correspondence: (S.N.K.); (K.E.L.); Tel.: +44-0-20-7188-6355 (K.E.L.)
| | - Katie E. Lacy
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London, London WC2R 2LS, UK;
- Correspondence: (S.N.K.); (K.E.L.); Tel.: +44-0-20-7188-6355 (K.E.L.)
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