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Chahat, Kumar B, Gupta S, Wahajuddin M, Joshi G. Reconnecting the roots of hydrogen sulfide (H 2S) with medicinal chemistry: Lessons accomplished and challenges so far. Bioorg Chem 2025; 161:108569. [PMID: 40359841 DOI: 10.1016/j.bioorg.2025.108569] [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: 12/16/2024] [Revised: 04/14/2025] [Accepted: 05/06/2025] [Indexed: 05/15/2025]
Abstract
Previously known for its unpleasant odour and mortality in elevated concentrations, hydrogen sulfide (H2S) is currently considered a complex molecule having significant physiological advantages. After nitric oxide (NO) and carbon monoxide (CO), H2S is regarded as the third endogenous gasotransmitter, performing many biological functions in the human body. The essential functions include but are not limited to regulating inflammation, maintaining the redox potential, cellular signalling, and metabolic processes. Moreover, an imbalance in its expression or dysfunction of its precursors and associated enzymes in its biosynthesis leads to multiple pathological conditions, including cancer, diabetes, neurodegenerative disorders, COVID-19, etc. Nonetheless, its upregulation is also reported to dysregulate normal physiological conditions and precipitate different diseases and cancer, thus acting as a "Double-edged sword." Despite this, H2S is still being widely explored for its therapeutic potential in various disease states. The present review is put forth to focus on hydrogen sulfide's dichotomous properties, emphasising its critical functions and therapeutic applications. This compilation provides a state-of-the-art analysis of the broad application of H2S donors in developing therapeutic interventions, release mechanisms, and their use in numerous diseases and disorders. Furthermore, various analytical techniques for detecting and quantifying the H2S release in biological samples via the hybrid donors are also discussed. We herein expect that an in-depth comprehension of the multiple activities of H2S can aid in discovering novel therapeutic interventions critical for holistic disease management measures in the future.
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Affiliation(s)
- Chahat
- Department of Pharmaceutical Science, Hemvati Nandan Bahuguna Garhwal (A Central) University, Srinagar 246174,Dist Garhwal, (Uttarakhand), India
| | - Bhupinder Kumar
- Department of Pharmaceutical Science, Hemvati Nandan Bahuguna Garhwal (A Central) University, Srinagar 246174,Dist Garhwal, (Uttarakhand), India
| | - Shankar Gupta
- Department of Pharmaceutical Science, Hemvati Nandan Bahuguna Garhwal (A Central) University, Srinagar 246174,Dist Garhwal, (Uttarakhand), India
| | - Muhammad Wahajuddin
- Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, University of Bradford, United Kingdom.
| | - Gaurav Joshi
- Department of Pharmaceutical Science, Hemvati Nandan Bahuguna Garhwal (A Central) University, Srinagar 246174,Dist Garhwal, (Uttarakhand), India; Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, University of Bradford, United Kingdom.
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2
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Gupta T, Murtaza M. Advancing targeted therapies in pancreatic cancer: Leveraging molecular abberrations for therapeutic success. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2025; 196:19-32. [PMID: 39988056 DOI: 10.1016/j.pbiomolbio.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 02/03/2025] [Accepted: 02/20/2025] [Indexed: 02/25/2025]
Abstract
Pancreatic cancer is one of the most deadly with poor prognosis and overall survival rate due to the dense stroma in the tumors which often is challenging for the delivery of drug to penetrate deep inside the tumor bed and usually results in the progression of cancer. The conventional treatment such as chemotherapy, radiotherapy or surgery shows a minimal benefit in the survival due to the drug resistance, poor penetration, less radiosensitivity or recurrence of tumor. There is an urgent demand to develop molecular-level targeted therapies to achieve therapeutic efficacy in the pancreatic ductal adenocarcinoma (PDAC) patients. The precision oncology focuses on the unique attributes of the patient such as epigenome, proteome, genome, microbiome, lifestyle and diet habits which contributes to promote oncogenesis. The targeted therapy helps to target the mutated proteins responsible for controlling growth, division and metastasis of tumor in the cancer cells. It is very important to consider all the attributes of the patient to provide the suitable personalized treatment to avoid any severe side effects. In this review, we have laid emphasis on the precision medicine; the utmost priority is to improve the survival of cancer patients by targeting molecular mutations through transmembrane proteins, inhibitors, signaling pathways, immunotherapy, gene therapy or the use of nanocarriers for the delivery at the tumor site. It will become beneficial therapeutic window to be considered for the advanced stage pancreatic cancer patients to prolong their survival rate.
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Affiliation(s)
- Tanvi Gupta
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan.
| | - Mohd Murtaza
- Fermentation & Microbial Biotechnology Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180016, India.
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3
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Zhu Y, Wu W, Hou D, Zhao Y, Ye J, Shen L, Zhao T, Wu X. Mechanism of Curcumol Targeting the OTUB1/TGFBI Ubiquitination Pathway in the Inhibition of Angiogenesis in Colon Cancer. Int J Mol Sci 2025; 26:4899. [PMID: 40430059 PMCID: PMC12112734 DOI: 10.3390/ijms26104899] [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: 04/10/2025] [Revised: 05/13/2025] [Accepted: 05/19/2025] [Indexed: 05/29/2025] Open
Abstract
Tumor angiogenesis and metastasis are critical processes in the progression of colon carcinoma. Curcumol, a bioactive sesquiterpenoid derived from curcuma, exhibits anti-angiogenic properties, though its underlying mechanisms remain unclear. In this study, an HT-29 xenograft mouse model demonstrated that curcumol combined with oxaliplatin significantly suppressed tumor growth (Ki67↓) and microvessel density (CD31↓). In vitro assays revealed that curcumol dose dependently inhibited proliferation (MTT), migration (Transwell), and tube formation (CAM assay) in Caco-2/HT-29 and HUVEC cells. Mechanistically, curcumol downregulated OTUB1 expression, promoting TGFB1 degradation via the ubiquitin-proteasome pathway. OTUB1 overexpression activated the TGFB1/VEGF axis, enhancing cell invasiveness and angiogenesis-effects reversed by high-dose curcumol. These findings identify the OTUB1-TGFB1/VEGF axis as a key target of curcumol in inhibiting colon cancer angiogenesis, elucidating its anti-tumor mechanism and offering a novel therapeutic strategy for targeted treatment.
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Affiliation(s)
- Yimiao Zhu
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210046, China; (Y.Z.)
| | - Wenya Wu
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210046, China; (Y.Z.)
| | - Dahai Hou
- School of Integrated Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yu Zhao
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210046, China; (Y.Z.)
| | - Jinshu Ye
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210046, China; (Y.Z.)
| | - Lizong Shen
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210046, China; (Y.Z.)
- Nanjing Medical University, Nanjing 211166, China
| | - Tong Zhao
- School of Integrated Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Xiaoyu Wu
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210046, China; (Y.Z.)
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4
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Kant S, Caliz AD, Yoo HJ, Kaur G, Learnard H, Khalil HA, Davis RJ, Keaney JFJ. Mixed lineage kinase (MLK) controls tumor development and angiogenesis. Angiogenesis 2025; 28:29. [PMID: 40314847 DOI: 10.1007/s10456-025-09978-4] [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: 01/30/2025] [Accepted: 03/31/2025] [Indexed: 05/03/2025]
Abstract
Cancer is among the leading causes of death in the USA and worldwide. Solid tumors require the formation of new blood vessels (angiogenesis) for their growth. The endothelium plays a crucial role in angiogenesis and tumor progression. Hypoxic stress generated by tumors can activate stress kinases such as mixed lineage kinases (MLKs). Publicly available datasets on lung adenocarcinoma, along with our experimental findings, indicate that MLK2 and MLK3 are expressed in human lung tumors. In this study, using three distinct mouse models of tumor development, we demonstrated that MLK2 (MAP3K10) and MLK3 (MAP3K11) are essential for tumor growth and angiogenesis. Furthermore, MLK2 and MLK3 are highly expressed in the endothelium and are necessary for endothelial proliferation, migration, and angiogenesis. In the endothelium, MLKs regulate the expression of angiogenic growth factors and metalloproteinases, including Pgf, Vegfa, Angptl4, Adam8, and Mmp9. Additionally, the MLK family of kinases acts through the long noncoding RNA (lncRNA) H19 to control the expression of these pro-angiogenic factors in the endothelium. Collectively, these findings suggest that the MLK-H19 axis coordinates endothelial function, angiogenesis, and tumor growth.
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Affiliation(s)
- Shashi Kant
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
| | - Amada D Caliz
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Hyung-Jin Yoo
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Gaganpreet Kaur
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Heather Learnard
- Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Hassan A Khalil
- Division of Division of Thoracic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Roger J Davis
- Program of Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - John F Jr Keaney
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
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Deng H, Wu D, He Y, Yu X, Liu J, Zhang Y, Leng B, Yuan X, Xiao L. E2F1-driven EXOSC10 transcription promotes hepatocellular carcinoma growth and stemness: a potential therapeutic target. Hereditas 2025; 162:60. [PMID: 40221814 PMCID: PMC11992873 DOI: 10.1186/s41065-025-00430-7] [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: 01/14/2025] [Accepted: 04/01/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND E2F Transcription Factor 1 (E2F1) is a transcription factor that plays a crucial role in the growth of many cancers, including hepatocellular carcinoma (HCC). Herein, this study probed the functions and underlying mechanisms of E2F1 in HCC tumorigenesis. METHODS The expression profiles of E2F1 and Exosome Component 10 (EXOSC10) were detected using qRT-PCR and western blotting. Functional experiments were carried out using 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, tube formation, and sphere formation assays in vitro, as well as xenograft experiments in vivo, respectively. Stemness-related proteins were assayed using western blotting. The interaction between E2F1 and EXOSC10 was verified using bioinformatics analysis and dual-luciferase reporter assay. RESULTS E2F1 was highly expressed in HCC tissues and cells, and was associated with advanced TNM stage, distant metastasis, and short survival rate. Functionally, knockdown of E2F1 suppressed HCC cell proliferation, angiogenesis, and stemness, and induced cell apoptosis. Mechanistically, E2F1 directly bound to the promoter region of EXOSC10 to up-regulate its expression. EXOSC10 silencing impaired HCC cell proliferation, angiogenesis, and stemness. Moreover, the anticancer effects of E2F1 knockdown were reversed by EXOSC10 elevation. In vivo assay, E2F1 deficiency suppressed HCC tumor growth and eliminated cancer stemness, while these effects were abolished by EXOSC10 up-regulation. CONCLUSION E2F1 promotes EXOSC10 transcription and then facilitates HCC growth and cancer stemness, revealing a potential target for HCC therapy.
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Affiliation(s)
- Haoyue Deng
- Department of Pathology, Suining Central Hospital, Suining, 629000, Sichuan, China
| | - Dingyong Wu
- Department of Oncology, Songshan General Hospital, Chongqing, 401120, China
| | - Yongpeng He
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Inaffiliationidualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, 400030, China
| | - Xiaolei Yu
- Department of Oncology, Fengning Manchu Autonomous County Hospital, No.737 Binhe Road, Chengde, 067000, Hebei, China
| | - Jifei Liu
- Department of Oncology, Fengning Manchu Autonomous County Hospital, No.737 Binhe Road, Chengde, 067000, Hebei, China
| | - Yanrui Zhang
- Department of Oncology, Fengning Manchu Autonomous County Hospital, No.737 Binhe Road, Chengde, 067000, Hebei, China
| | - Bing Leng
- Department of Oncology, Fengning Manchu Autonomous County Hospital, No.737 Binhe Road, Chengde, 067000, Hebei, China
| | - Xiaofeng Yuan
- Department of Oncology, Fengning Manchu Autonomous County Hospital, No.737 Binhe Road, Chengde, 067000, Hebei, China.
| | - Liguo Xiao
- Department of Oncology, Fengning Manchu Autonomous County Hospital, No.737 Binhe Road, Chengde, 067000, Hebei, China.
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6
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Lin C, Xie S, Wang M, Yang B, Shen J. Angiogenesis-related gene signature for prognostic prediction and immune microenvironment characterization in diffuse large B-cell lymphoma. Clin Exp Med 2025; 25:108. [PMID: 40198448 PMCID: PMC11978719 DOI: 10.1007/s10238-025-01628-9] [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: 01/06/2025] [Accepted: 03/07/2025] [Indexed: 04/10/2025]
Abstract
Diseases often result from multiple factors, and angiogenesis-related genes (ARGs) have been demonstrated to be associated with cancer. However, their role in diffuse large B-cell lymphoma (DLBCL) has not been fully elucidated. ARGs associated with DLBCL prognosis were identified utilizing Cox regression and LASSO analyses. A prognostic model was constructed based on 7 ARGs, and its biological function was analyzed. Differences in the tumor immune microenvironment based on the prognostic signature were evaluated. Finally, DLBCL cell experiments confirmed the differential expression of genes in DLBCL. The prognostic value of ARGs in DLBCL patients was comprehensively analyzed for the first time, identifying 7 ARGs with prognostic significance. A prognostic risk model was constructed based on these 7 ARGs and validated on an independent external DLBCL dataset. In DLBCL patients, this prognostic feature was an independent risk factor and significantly correlated with clinical characteristics. This feature was also associated with the immune microenvironment of DLBCL. DLBCL cell experiments confirmed significant expression of the 7 ARGs in DLBCL cells. This research provides a fundamental theoretical basis for improving the diagnosis and treatment of DLBCL in clinical practice.
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MESH Headings
- Humans
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/immunology
- Lymphoma, Large B-Cell, Diffuse/pathology
- Lymphoma, Large B-Cell, Diffuse/mortality
- Tumor Microenvironment/immunology
- Tumor Microenvironment/genetics
- Prognosis
- Neovascularization, Pathologic/genetics
- Male
- Female
- Middle Aged
- Gene Expression Regulation, Neoplastic
- Gene Expression Profiling
- Biomarkers, Tumor/genetics
- Transcriptome
- Aged
- Cell Line, Tumor
- Angiogenesis
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Affiliation(s)
- Chuanming Lin
- Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, China
- Department of Hematology, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Shuiling Xie
- Department of Hematology, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Menger Wang
- Gannan Medical University, Ganzhou, 341000, China
| | - Bin Yang
- Gannan Medical University, Ganzhou, 341000, China
| | - Jianzhen Shen
- Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, China.
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7
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Hu ZY, Ding D, Song Y, Deng YF, Zhang CM, Yu T. Molecular mechanism of pancreatic ductal adenocarcinoma: The heterogeneity of cancer-associated fibroblasts and key signaling pathways. World J Clin Oncol 2025; 16:97007. [PMID: 39995552 PMCID: PMC11686552 DOI: 10.5306/wjco.v16.i2.97007] [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: 05/20/2024] [Revised: 10/04/2024] [Accepted: 11/04/2024] [Indexed: 12/11/2024] Open
Abstract
Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis, leading to a notably low five-year survival rate. This study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers, such as mutations in CDKN2A, KRAS, SMAD4, and TP53, along with the influence of cancer-associated fibroblasts (CAFs) on disease progression. In particular, we focused on the pivotal roles of signaling pathways such as the transforming growth factor-β and Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic strategies. This study provides new scientific perspectives on pancreatic cancer treatment, especially in the development of precision medicine and targeted therapeutic strategies, and demonstrates the importance of signaling pathway research in the development of effective therapeutic regimens. Future studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.
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Affiliation(s)
- Zhong-Yuan Hu
- First School of Clinical Medicine, Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, China
| | - Ding Ding
- First School of Clinical Medicine, Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, China
| | - Yu Song
- College of Acupuncture and Massage, Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, China
| | - Ya-Feng Deng
- Graduate School, Guangzhou University of Chinese Medicine, Guangzhou 510000, Guangdong Province, China
| | - Cheng-Ming Zhang
- Digestive Department I, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi’an 710000, Shaanxi Province, China
| | - Tao Yu
- Digestive Department I, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi’an 710000, Shaanxi Province, China
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8
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Liu F, Wang Y, Xia L, Sun C, Li Y, Xia Y. Immunological characterization and prognostic of colon cancer evaluated by angiogenesis-related features: a computational analysis and in vitro experiments. Discov Oncol 2025; 16:101. [PMID: 39881026 PMCID: PMC11780071 DOI: 10.1007/s12672-025-01835-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 01/20/2025] [Indexed: 01/31/2025] Open
Abstract
BACKGROUND Diseases are often caused by multiple factors, angiogenesis-related genes (ARGs) have been shown to be associated with cancer, however, their role in colon cancer had not been fully explored. This study investigated potential biomarkers based on ARGs to improve prognosis and treatment effect in colon cancer. METHODS ARGs associated with colon cancer prognosis were identified using Cox regression analysis and LASSO analysis. Furthermore, a prognostic model was constructed in colon cancer based on the 3 ARGs, and its biological function were analyzed. We evaluated the differences in tumor immune microenvironment based on prognostic signature. Finally, cell experiments confirmed the function of genes in colon cancer. RESULTS The prognostic value of ARGs in colon cancer patients has been comprehensively analyzed for the first time and identified 3 ARGs with prognostic values. A prognosis risk model was constructed based on 3 ARGs and its prognostic value was validated on an independent external colon cancer dataset. In colon cancer patients, this prognostic feature was an independent risk factor and was significantly correlated with clinical feature information of colon cancer patients. This feature was also related to the immune microenvironment of colon cancer. Cell experiments showed that high expression of TNF Receptor Superfamily Member 1B (TNFRSF1B) significantly promoted apoptosis and inhibited proliferation of colon cancer cells. Therefore, TNFRSF1B may become an important regulatory factor in the progression of colon cancer by participating in intracellular functional regulation. CONCLUSIONS This study constructed a prognostic risk model based on three ARGs and for the first time discovered that TNFRSF1B may become an important regulatory factor in cancer progression by participating in intracellular functional regulation.
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Affiliation(s)
- Fei Liu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Oncology, Anhui Public Health Clinical Center, Hefei, China
| | - Yi Wang
- Department of Oncology, The Third Affiliated Hospital of Anhui Medical University, Anhui, China
| | - Leiming Xia
- Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Hematology, Anhui Public Health Clinical Center, Hefei, China
| | - Chen Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Oncology, Anhui Public Health Clinical Center, Hefei, China
| | - Yun Li
- School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan, China
| | - Yunhong Xia
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
- Department of Oncology, Anhui Public Health Clinical Center, Hefei, China.
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9
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Wagner BJ, Ettner-Sitter A, Ihlo NA, Behr M, Koelbl S, Brunner SM, Weber F, Rau BM, Schlitt HJ, Brochhausen C, Schoenmehl R, Artinger A, Schott D, Pizon M, Pachmann K, Aung T, Haerteis S, Hackl C. Patient-derived xenografts from circulating cancer stem cells as a preclinical model for personalized pancreatic cancer research. Sci Rep 2025; 15:2896. [PMID: 39843495 PMCID: PMC11754431 DOI: 10.1038/s41598-025-87054-z] [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: 07/03/2024] [Accepted: 01/15/2025] [Indexed: 01/24/2025] Open
Abstract
Patient-derived xenografts (PDXs) provide biologically relevant models and potential platforms for the development of treatment strategies for precision medicine in pancreatic cancer. Furthermore, circulating epithelial tumor cells (CETCs/CTCs) are released into the bloodstream by solid tumors and a rare subpopulation-circulating cancer stem cells (cCSCs) - is considered to be responsible for recurrence and plays a key role in metastasis. For the identification of cCSCs, an innovative in vitro assay to generate tumorspheres was established in this study. The number of tumorspheres and CETCs/CTCs was analyzed perioperatively in 25 pancreatic cancer patients. Additionally, an individual in vivo chorioallantoic membrane (CAM) culture system was used to generate PDXs from these tumorspheres. While overall correlations of CETCs/CTCs with clinicopathological parameters did not reach statistical significance, a significant difference in the number of tumorspheres was observed between patient subgroups with lower and higher UICC stages. This finding underscores their potential as biomarkers, providing valuable insights into clinical decision-making and tumor progression. The application of tumorspheres on the CAM successfully established PDXs within 7 days. These xenografts closely resembled the histological features of the primary tumor. Hence, this model represents a novel and fast option for individualized testing of new therapies for PDAC.
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Affiliation(s)
- Benedikt J Wagner
- Department of Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany
| | - Andreas Ettner-Sitter
- Institute for Molecular and Cellular Anatomy, University of Regensburg, Universitaetsstrasse 31, 93053, Regensburg, Germany
| | - Nicolas A Ihlo
- Faculty of Informatics and Data Science, University of Regensburg, Bajuwarenstrasse 4, 93053, Regensburg, Germany
| | - Merle Behr
- Faculty of Informatics and Data Science, University of Regensburg, Bajuwarenstrasse 4, 93053, Regensburg, Germany
| | - Sebastian Koelbl
- Technology Campus Hutthurm, Deggendorf Institute of Technology, Hochleiten 1, 94116, Hutthurm, Germany
| | - Stefan M Brunner
- Department of Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany
| | - Florian Weber
- Institute of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany
| | - Bettina M Rau
- Department of General, Visceral and Thoracic Surgery, Academic Teaching Hospital Neumarkt, Nuernberger Strasse 12, 92318, Neumarkt in der Oberpfalz, Germany
| | - Hans J Schlitt
- Department of Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany
| | - Christoph Brochhausen
- Institute of Pathology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Rebecca Schoenmehl
- Institute of Pathology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Annalena Artinger
- Institute of Pathology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | | | - Monika Pizon
- Simfo GmbH, Kurpromenade 2, 95448, Bayreuth, Germany
- Labor Dr. Pachmann Bayreuth, Kurpromenade 2, 95448, Bayreuth, Germany
| | - Katharina Pachmann
- Simfo GmbH, Kurpromenade 2, 95448, Bayreuth, Germany
- Labor Dr. Pachmann Bayreuth, Kurpromenade 2, 95448, Bayreuth, Germany
| | - Thiha Aung
- Institute for Molecular and Cellular Anatomy, University of Regensburg, Universitaetsstrasse 31, 93053, Regensburg, Germany
- Faculty of Applied Healthcare Science, Deggendorf Institute of Technology, Dieter-Goerlitz-Platz 1, 94469, Deggendorf, Germany
| | - Silke Haerteis
- Institute for Molecular and Cellular Anatomy, University of Regensburg, Universitaetsstrasse 31, 93053, Regensburg, Germany.
| | - Christina Hackl
- Department of Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany
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10
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Liu J, Zhang B, Huang B, Zhang K, Guo F, Wang Z, Shang D. A stumbling block in pancreatic cancer treatment: drug resistance signaling networks. Front Cell Dev Biol 2025; 12:1462808. [PMID: 39872846 PMCID: PMC11770040 DOI: 10.3389/fcell.2024.1462808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 12/30/2024] [Indexed: 01/30/2025] Open
Abstract
The primary node molecules in the cell signaling network in cancer tissues are maladjusted and mutated in comparison to normal tissues, which promotes the occurrence and progression of cancer. Pancreatic cancer (PC) is a highly fatal cancer with increasing incidence and low five-year survival rates. Currently, there are several therapies that target cell signaling networks in PC. However, PC is a "cold tumor" with a unique immunosuppressive tumor microenvironment (poor effector T cell infiltration, low antigen specificity), and targeting a single gene or pathway is basically ineffective in clinical practice. Targeted matrix therapy, targeted metabolic therapy, targeted mutant gene therapy, immunosuppressive therapy, cancer vaccines, and other emerging therapies have shown great therapeutic potential, but results have been disappointing. Therefore, we summarize the identified and potential drug-resistant cell signaling networks aimed at overcoming barriers to existing PC therapies.
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Affiliation(s)
- Jinming Liu
- Department of General Surgery, Pancreas and Biliary Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Biao Zhang
- Department of General Surgery, Pancreas and Biliary Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Bingqian Huang
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Department of Clinical Pharmacy, Affiliated Hangzhou First People’s Hospital, Westlake University, Hangzhou, China
| | - Kexin Zhang
- Central Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fujia Guo
- Central Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhizhou Wang
- Department of General Surgery, Pancreas and Biliary Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Dong Shang
- Department of General Surgery, Pancreas and Biliary Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
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11
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Guo Y, Yang P, Wu Z, Zhang S, You F. Mechanisms of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao (huang qi) and Angelica sinensis (Oliv.) Diels (dang gui) in Ameliorating Hypoxia and Angiogenesis to Delay Pulmonary Nodule Malignant Transformation. Integr Cancer Ther 2025; 24:15347354241311917. [PMID: 39882753 PMCID: PMC11780663 DOI: 10.1177/15347354241311917] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 12/09/2024] [Accepted: 12/19/2024] [Indexed: 01/31/2025] Open
Abstract
Screening for pulmonary nodules (PN) using low-dose CT has proven effective in reducing lung cancer (LC) mortality. However, current treatments relying on follow-up and surgical excision fail to fully address clinical needs. Pathological angiogenesis plays a pivotal role in supplying oxygen necessary for the progression of PN to LC. The interplay between hypoxia and angiogenesis establishes a vicious cycle, rendering anti-angiogenesis therapy alone insufficient to prevent PN to LC transformation. In traditional Chinese medicine (TCM), PN is referred to as "Feiji," which is mainly attributed to Qi and blood deficiency, correspondingly, the most commonly prescribed medicines are Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao (huang qi) (AR) and Angelica sinensis (Oliv.) Diels (dang gui) (ARS). Modern pharmacological studies have demonstrated that AR and ARS possess immune-enhancing, anti-tumor, anti-inflammatory, and anti-angiogenic properties. However, the precise mechanisms through which AR and ARS exert anti-angiogenic effects to delay PN progression to LC remain inadequately understood. This review explores the critical roles of hypoxia and angiogenesis in the transition from PN to LC. It emphasizes that, compared to therapies targeting angiogenic growth factors alone, AR, ARS, and their compound-based prescriptions offer additional benefits. These include ameliorating hypoxia by restoring blood composition, enhancing vascular structure, accelerating circulation, promoting vascular normalization, and blocking or inhibiting various pro-angiogenic expressions and receptor interactions. Collectively, these actions inhibit angiogenesis and delay the PN-to-LC transformation. Finally, this review summarizes recent advancements in related research, identifies existing limitations and gaps in knowledge, and proposes potential strategies and recommendations to address these challenges.
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Affiliation(s)
- Ying Guo
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Peng Yang
- Chengdu Fifth People’s Hospital, Chengdu, China
| | - Zihong Wu
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Sanyin Zhang
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Chengdu Integrated TCM & Western Medicine Hospital, Chengdu, China
| | - Fengming You
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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12
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Liu Z, Du D, Zhang S. Tumor-derived exosomal miR-1247-3p promotes angiogenesis in bladder cancer by targeting FOXO1. Cancer Biol Ther 2024; 25:2290033. [PMID: 38073044 PMCID: PMC10761019 DOI: 10.1080/15384047.2023.2290033] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Tumor-derived exosomes are highly correlated with tumor progression and angiogenesis. This study was designed to probe the role of tumor-derived exosomal miR-1247-3p in mediating the angiogenesis in bladder cancer. Exosomes isolation from the culture medium of normal or bladder cancer cell lines was performed using a differential centrifugation method. miR-1247-3p expression in exosomes and cells was detected by quantitative real-time PCR (qRT-PCR). The effect of exosomes on the angiogenesis of human umbilical vein endothelial cells (HUVECs) was assessed using cell counting kit-8 (CCK-8), transwell and tube formation assays. The interaction between miR-1247-3p and forkhead box protein O1 (FOXO1) was studied using luciferase reporter and RNA pull down assays. Exosomes were successfully isolated from T24, UM-UC-3, and SV-HUC-1 cells, as confirmed by corresponding identifications. Functional experiments revealed that exosomes derived from T24 and UM-UC-3 cells significantly enhanced the abilities of proliferation, migration, angiogenesis, and vascular endothelial-derived growth factor (VEGF) secretion in HUVECs. miR-1247-3p was highly expressed in exosomes derived from T24 and UM-UC-3 cells, and exosomes derived from miR-1247-3p inhibitor-transfected cells reduced HUVEC viability, migration, tube formation, and VEGF level. FOXO1 was confirmed as a direct target of miR-1247-3p. Rescue assays suggested that the effect of miR-1247-3p inhibition on the viability, migration, and angiogenesis of HUVECs was partly abrogated by the knockdown of FOXO1. Our data suggest that miR-1247-3p is up-regulated in tumor-derived exosomes, thereby inhibiting FOXO1 expression and facilitating angiogenesis in bladder cancer.
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Affiliation(s)
- Zonglai Liu
- Medical College, China Three Gorges University, Yichang, Hubei, China
- Department of Urology, The Second People’s Hospital of China Three Gorges University, Yichang, Hubei, China
| | - Dan Du
- Medical College, China Three Gorges University, Yichang, Hubei, China
- Department of Urology, The Second People’s Hospital of China Three Gorges University, Yichang, Hubei, China
| | - Shizhong Zhang
- Medical College, China Three Gorges University, Yichang, Hubei, China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, Hubei, China
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13
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Yan T, Shi J. Angiogenesis and EMT regulators in the tumor microenvironment in lung cancer and immunotherapy. Front Immunol 2024; 15:1509195. [PMID: 39737184 PMCID: PMC11682976 DOI: 10.3389/fimmu.2024.1509195] [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: 10/10/2024] [Accepted: 11/28/2024] [Indexed: 01/01/2025] Open
Abstract
Lung cancer remains the primary cause of cancer-related mortality, with factors such as postoperative tumor recurrence, metastasis, and therapeutic drug resistance exacerbating patient outcomes. Immunotherapy has emerged as a transformative approach, challenging conventional treatment paradigms for lung cancer. Consequently, advancing research in lung cancer immunotherapy is imperative. Recent studies indicate that numerous regulators within the tumor microenvironment (TME) drive tumor angiogenesis and epithelial-mesenchymal transition (EMT); these processes are interdependent, reciprocal, and collectively contribute to tumor progression. Tumor angiogenesis not only supplies adequate oxygen and nutrients for cellular proliferation but also establishes pathways facilitating tumor metastasis and creating hypoxic regions that foster drug resistance. Concurrently, EMT enhances metastatic potential and reinforces drug-resistance genes within tumor cells, creating a reciprocal relationship with angiogenesis. This interplay ultimately results in tumor invasion, metastasis, and therapeutic resistance. This paper reviews key regulators of angiogenesis and EMT, examining their impact on lung cancer immunotherapy and progression, and investigates whether newly identified regulators could influence lung cancer treatment, thus offering valuable insights for developing future therapeutic strategies.
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Affiliation(s)
- Taotao Yan
- Medical School of Nantong University, Nantong University, Nantong, China
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jiahai Shi
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
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14
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Hegde M, P R A, Mumbrekar KD. Exploring baicalein: A natural flavonoid for enhancing cancer prevention and treatment. Heliyon 2024; 10:e40809. [PMID: 39691196 PMCID: PMC11650287 DOI: 10.1016/j.heliyon.2024.e40809] [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: 02/18/2024] [Revised: 10/12/2024] [Accepted: 11/27/2024] [Indexed: 12/19/2024] Open
Abstract
Despite years of development in cancer therapy, achieving successful cancer treatment remains a major research topic. Primary means of cancer treatment include chemotherapy, radiotherapy, and surgery. However, these modalities are associated with limitations and adverse effects on normal tissues. Therefore, there is a search for novel therapeutic approaches that will increase the efficacy of the available treatment while minimizing side effects. Naturally occurring bioactive chemicals such as flavonoids have long been used in traditional medicine to treat various illnesses. Baicalein, an active ingredient in Scutellaria baicalensis Georgi, is utilised in traditional medicine to treat conditions such as hypertension, cardiovascular disease, inflammation, and infections. This review focuses on summarizing the data available on cancer prevention and treatment usage of baicalein. Baicalein is thought to prevent cancer progression by inducing apoptosis, autophagy, and genome instability, and its ability to promote chemo-potentiation, anti-metastatic effects, and regulate specific signalling molecules and transcription factors. Baicalein can be a promising option for cancer treatment, either alone or in combination with established anticancer drugs.
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Affiliation(s)
- Madhu Hegde
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Archana P R
- Department of Basic Medical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Kamalesh Dattaram Mumbrekar
- Department of Radiation Biology & Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, India
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15
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Cao Z, Hu Z, Wang Y, Zhao F, Li J, Li R, Hu W, Liu B, Tang S, Wang P, Li F, Chen Z, Wang L, Ma X. Letrozole-Based Near-Infrared Dynamic Imaging Targeting Ductal-Vascular RhoJ From Pancreatic Intraepithelial Neoplasia to Pancreatic Ductal Adenocarcinoma. Adv Healthc Mater 2024; 13:e2402913. [PMID: 39329457 DOI: 10.1002/adhm.202402913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Indexed: 09/28/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) relies heavily on neoangiogenesis for its progression, making early detection crucial. Here, LTZi-MHI148 (Letrozole inhibitor bonding with MHI-148 dye), a near-infrared (NIR) fluorescent agent is developed, to target RhoJ (Ras Homolog Family Member J), a protein expressed in neonatal vasculature, for both imaging and therapy of early PDAC. This agent is synthesized by conjugating Letrozole with MHI-148, exhibiting excellent NIR characteristics and photostability. In vitro studies showed that LTZi-MHI148 selectively accumulated within pancreatic cancer cells through Organic Anion Transporting Polypeptide (OATP) transporters and bound to cytoplasmic RhoJ. In vivo, the probe effectively targeted neoangiogenesis and Pancreatic Intraepithelial Neoplasias (PanINs) in various PDAC models, including the orthotopic, ectopic, spontaneous, and tamoxifen-induced tumors. Notably, LTZi-MHI148 detected preneoplastic PanIN lesions with Overexpressed RhoJ and active neoangiogenesis in both spontaneous and tamoxifen-induced PDAC murine models. Longitudinal imaging studies revealed that RhoJ-targeted neoangiogenesis tracks lesion progression, highlighting LTZi-MHI148's utility in monitoring disease progression. Furthermore, multiple LTZi-MHI148 administrations attenuated PanINs to PDAC progression, suggesting its potential as a therapeutic intervention. These findings underscore the translational potential of LTZi-MHI148 for the early detection and targeted therapy of PDAC, utilizing NIR-I/II imaging to monitor RhoJ overexpression in precancerous ductal neoplasia associated with neoangiogenesis.
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Affiliation(s)
- Zhi Cao
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, China
- School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, 430071, China
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, Guangdong, 510631, China
| | - Zhuang Hu
- School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, 430071, China
| | - Yishu Wang
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, Guangdong, 510631, China
| | - Fengyun Zhao
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, Guangdong, 528403, China
| | - Jingmin Li
- Internal medicine department, Guangzhou women and children's Medical Center, Guangzhou, Guangdong, 510620, China
| | - Ruihan Li
- School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, 430071, China
| | - Weibin Hu
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, Guangdong, 510631, China
| | - Bei Liu
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, Guangdong, 510631, China
| | - Shaohui Tang
- Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, 510630, China
| | - Ping Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, China
| | - Fugui Li
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, Guangdong, 528403, China
| | - Zilin Chen
- School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, 430071, China
| | - Lisheng Wang
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, China
| | - Xiaodong Ma
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, Guangdong, 510631, China
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16
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Hao Y, Long Z, Gu X. Farrerol suppresses epithelial-mesenchymal transition in hepatocellular carcinoma via suppression of TGF-β1/Smad2/3 signaling. Pathol Res Pract 2024; 264:155719. [PMID: 39541767 DOI: 10.1016/j.prp.2024.155719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 10/08/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Epithelial-mesenchymal transition (EMT) is an essential process for the metastasis of multiple malignancies, including hepatocellular carcinoma (HCC). Farrerol is a plant-derived flavonoid and has significant pharmacological effects. However, the anticancer activities of farrerol have not been fully elucidated. Here, we investigated the effects of farrerol on HCC progression. METHODS The potential of farrerol to prevent HCC cell migration and invasiveness was evaluated by wound healing and transwll matrix assays. Immunoblotting, immunofluorescence, and qPCR were used to detect the levels of EMT-related proteins. Transforming growth factor beta (TGF-β) (10 ng/ml) was used to stimulate HCC cells, followed by measurement of cell migration, invasiveness, and the EMT. TGF-β1/Smads signaling was examined by immunoblotting. A xenograft mouse model was used to assess the anticancer efficacy of farrerol in vivo. The expression levels of EMT- and angiogenesis-related proteins in xenograft tumors were evaluated by immunoblotting or immunohistochemistry. RESULTS We found that farrerol blocked HCC cell migration and invasiveness. Farrerol upregulated E-cadherin levels and reduced N-cadherin and vimentin levels. Farrerol also downreuglated the expression levels of EMT-related transcription factors including slug, snail, twist, and zeb1. Furthermore, farrerol suppressed TGF-β-stimulated migration, invasiveness, and the EMT in HCC cells. The phosphorylation of Smad 2/3 induced by TGF-β was inhibited by farrerol. Importantly, farrerol suppressed HCC growth and the EMT in vivo. Farrerol also inhibited tumor angiogenesis by inhibiting hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in vivo. CONCLUSION Overall, farrerol suppresss HCC by inhibiting migration, invasiveness, the EMT, and angiogenesis, implying that farrerol could be a promising antimetastasis agent for HCC.
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Affiliation(s)
- Yaming Hao
- Department of Traditional Chinese Medicine, Wuhan Fifth Hospital, Wuhan 430050, China.
| | - Zhixiong Long
- Department of Oncology, Wuhan Fifth Hospital, Wuhan 430050, China
| | - Xiufeng Gu
- Clinical College of TCM, Hubei University of Traditional Chinese Medicine, Wuhan 430050, China
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17
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Zhang Y, Luan M. Unraveling the role of PBK in glioblastoma: from molecular mechanisms to therapeutic targets. Ann Med Surg (Lond) 2024; 86:7147-7154. [PMID: 39649886 PMCID: PMC11623866 DOI: 10.1097/ms9.0000000000002708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 10/24/2024] [Indexed: 12/11/2024] Open
Abstract
BACKGROUND This study investigates the gene expression characteristics of glioma-initiating cells (GIC), an important subgroup of glioblastoma (GBM), after knockdown of PBK (PDZ-binding kinase). Differentially expressed genes (DEGs) between PBK knockdown GIC and control groups were screened through bioinformatics methods. The authors analyzed the mechanisms and roles of these DEGs in GBM tumorigenesis and patient prognosis. METHODS Microarray data (GSE53800) were obtained from the Gene Expression Omnibus (GEO) database, selecting 18 GIC cell line samples with or without PBK knockdown. Each control and knockdown group contained three samples. DEGs were screened using R software. GO enrichment analysis, KEGG pathway analysis, PPI network analysis, and hub gene identification were conducted to explore DEG mechanisms. Western blot analysis was also performed to detect EIF4E protein expression, one of the key hub genes, after PBK knockdown in the HS683 glioma cell line. RESULTS A total of 175 upregulated and 145 downregulated genes were identified. GO analysis showed that DEGs were mainly enriched in the positive regulation of cell proliferation, cell adhesion, and angiogenesis. KEGG pathway analysis revealed that DEGs were mainly involved in neuroactive ligand-receptor interactions, calcium signaling, and HIF-1 signaling pathways. Western blot results indicated that EIF4E was downregulated after PBK knockdown. CONCLUSION A group of genes, such as EIF4E, were closely associated with PBK expression and functions. These findings may provide insight into the molecular mechanism of PBK in GBM.
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Affiliation(s)
| | - Mingyuan Luan
- Medicine Faculty, University of Tübingen, Tübingen, Germany
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18
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Wan Q, Ren Q, Qiao S, Lyu A, He X, Li F. Therapeutic potential of flavonoids from traditional Chinese medicine in pancreatic cancer treatment. Front Nutr 2024; 11:1477140. [PMID: 39650709 PMCID: PMC11620852 DOI: 10.3389/fnut.2024.1477140] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 11/04/2024] [Indexed: 12/11/2024] Open
Abstract
Pancreatic cancer (PC) is a highly aggressive malignancy with rising mortality rates globally. Its diagnosis is often challenging due to its asymptomatic nature in the early stages. Consequently, most patients receive a poor prognosis, with low survival rates within 5 years, as the disease is typically detected at an advanced stage, complicating effective treatment. Flavonoids, especially those derived from traditional Chinese herbal medicines, have attracted considerable attention for their potent anti-PC properties. This review highlights the therapeutic potential of these bioactive compounds, which modulate key biological pathways, making them promising candidates for PC intervention. Their mechanisms of action include the regulation of autophagy, apoptosis, cell growth, epithelial-mesenchymal transition, and oxidative stress, as well as enhancing chemotherapeutic sensitivity, exerting antiangiogenic effects, and potentially boosting immunomodulatory responses. The demonstrated benefits of these natural compounds in cancer management have spurred extensive academic interest. Beyond their role as anti-cancer agents, flavonoids may provide both preventive and therapeutic advantages for PC, resonating with the core principles of traditional Chinese medicine for disease prevention and holistic treatment.
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Affiliation(s)
- Qi Wan
- Acupuncture Department, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
- Graduate School, Jiangxi University of Chinese Medicine, Nanchang, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - Qing Ren
- Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Shuangying Qiao
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - Aiping Lyu
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - Xingwei He
- Acupuncture Department, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
| | - Fangfei Li
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
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19
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Sun J, Zhang S, Liu Y, Liu K, Gu X. Exploring tumor endothelial cells heterogeneity in hepatocellular carcinoma: insights from single-cell sequencing and pseudotime analysis. PeerJ 2024; 12:e18362. [PMID: 39484208 PMCID: PMC11526786 DOI: 10.7717/peerj.18362] [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: 07/18/2024] [Accepted: 09/29/2024] [Indexed: 11/03/2024] Open
Abstract
Objective This study aimed to explore the heterogeneity of tumor endothelial cells (TECs) in hepatocellular carcinoma (HCC) and their role in tumor progression, with the goal of identifying new therapeutic targets and strategies to improve patient prognosis. Methods Single-cell RNA sequencing data from nine primary liver cancer samples were analyzed, obtained from the Gene Expression Omnibus (GEO) database. Data preprocessing, normalization, dimensionality reduction, and batch effect correction were performed based on the Seurat package. HCC cell types were identified using uniform manifold approximation and projection (UMAP) and cluster analysis, and the different cell types were annotated using the CellMarker database. Pseudotime trajectory analysis was conducted with Monocle to explore the differentiation trajectory of TECs. MAPK signaling pathway activity and copy number variations (CNV) in TECs were analyzed in conjunction with data from The Cancer Genome Atlas (TCGA), the trans-well and wound healing assay was used for cell invasion and migration activity assessment. Results Two subgroups of TECs (TECs 1 and TECs 2) were identified, exhibiting distinct functional activities and signaling pathways. Specifically, TECs 1 may be involved in tumor cell proliferation and inflammatory responses, whereas TECs 2 is not only involved in cell proliferation pathways, but also enriched in pathways such as metabolic synthesis. Pseudotime analysis revealed dynamic changes in TECs subgroups during HCC progression, correlating specific gene expressions (such as PDGFRB, PGF, JUN, and NR4A1). Subsequently, the JUN gene was predicted by performing binding sites and was shown to act as a transcription factor that may regulate the expression of the PGF gene. CNV analysis highlighted key genes and pathways in TECs that might influence HCC progression, and the PGF as key regulatory factor mediated cell proliferation and migration. Conclusion The study revealed the heterogeneity of TECs in HCC and their potential roles in tumor progression, offering new perspectives and potential therapeutic targets for HCC molecular mechanisms. The findings emphasize the importance of further exploring TECs heterogeneity for understanding HCC pathogenesis and developing personalized treatment strategies.
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Affiliation(s)
- Jiachun Sun
- Department of Oncology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, China
| | - Shujun Zhang
- Department of Infectious Diseases, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, China
| | - Yafeng Liu
- Department of Infectious Diseases, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, China
| | - Kaijie Liu
- Department of Infectious Diseases, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, China
| | - Xinyu Gu
- Department of Oncology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, China
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20
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Limbu KR, Chhetri RB, Kim S, Shrestha J, Oh YS, Baek DJ, Park EY. Targeting sphingosine 1-phosphate and sphingosine kinases in pancreatic cancer: mechanisms and therapeutic potential. Cancer Cell Int 2024; 24:353. [PMID: 39462385 PMCID: PMC11514880 DOI: 10.1186/s12935-024-03535-7] [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: 07/17/2024] [Accepted: 10/15/2024] [Indexed: 10/29/2024] Open
Abstract
Pancreatic cancer is known to be the most lethal cancer. Fewer new treatments are being developed for pancreatic cancer as compared to other cancers. The bioactive lipid S1P, which is mainly regulated by sphingosine kinase 1 (SK1) and sphingosine kinase 2 (SK2) enzymes, plays significant roles in pancreatic cancer initiation and exacerbation. S1P controls many signaling pathways to modulate the progression of pancreatic cancer through the G-coupled receptor S1PR1-5. Several papers reporting amelioration of pancreatic cancer via modulation of S1P levels or downstream signaling pathways have previously been published. In this paper, for the first time, we have reviewed the results of previous studies to understand how S1P and its receptors contribute to the development of pancreatic cancer, and whether S1P can be a therapeutic target. In addition, we have also reviewed papers dealing with the effects of SK1 and SK2, which are kinases that regulate the level of S1P, on the pathogenesis of pancreatic cancer. We have also listed available drugs that particularly focus on S1P, S1PRs, SK1, and SK2 for the treatment of pancreatic cancer. Through this review, we would like to suggest that the SK/S1P/S1PR signaling system can be an important target for treating pancreatic cancer, where a new treatment target is desperately warranted.
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Affiliation(s)
- Khem Raj Limbu
- College of Pharmacy, Mokpo National University, Joennam, 58554, South Korea
| | | | - Subin Kim
- College of Pharmacy, Mokpo National University, Joennam, 58554, South Korea
| | - Jitendra Shrestha
- Massachusetts General Hospital Cancer Center, Boston, MA, 02114, USA
| | - Yoon Sin Oh
- Department of Food and Nutrition, Eulji University, Seongnam, 13135, South Korea
| | - Dong Jae Baek
- College of Pharmacy, Mokpo National University, Joennam, 58554, South Korea.
| | - Eun-Young Park
- College of Pharmacy, Mokpo National University, Joennam, 58554, South Korea.
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Chen C, Yuan M, Xia L, Wu X, Zhong X, Zhang H, Zhang L, Liu X, Wang Z, Sun C. Expression of CREBBP and EP300 Associated With Tumor Volume in Patients With Grade-3 Glioma: A Retrospective Analysis. Clin Med Insights Oncol 2024; 18:11795549241287777. [PMID: 39429683 PMCID: PMC11490948 DOI: 10.1177/11795549241287777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 09/11/2024] [Indexed: 10/22/2024] Open
Abstract
Background Reliable predictive data are crucial for making accurate treatment decisions in glioma patients, but it can be challenging to obtain due to limited information in many cases. Numerous research studies have indicated the involvement of cyclic adenosine monophosphate (cAMP)-response element binding protein (CREBBP) and E1A binding protein p300 (EP300) in tumorigenesis and tumor progression across various types. Methods The messenger RNA (mRNA) expression levels of CREBBP and EP300 were retrospectively analyzed in 17 grade-3 glioma patients. The SYBR Green real-time polymerase chain reaction (RT-PCR) technique was employed for mRNA expression analysis, with the glyceraldehyde-3-phosphate dehydrogenase gene (GAPDH) used as a reference gene for data normalization. In addition, the relationship between CREBBP, EP300 expression and patients' clinical information, imaging features, histologic features, immune factors, and overall survival was assessed through univariate analyses. Results The analysis of the data unveiled a statistically significant upregulation of CREBBP and EP300 mRNA expression levels in large gliomas as compared with their smaller counterparts (P < .05). Histological examination using hematoxylin and eosin (H&E) staining exhibited marked cellular heterogeneity, with heightened cell density observed specifically within tumors displaying elevated CREBBP expression levels. In contrast, there was a substantial downregulation of complement 3 and complement 4 within larger tumor volumes when compared with smaller ones (P < .05). However, these findings do not serve as clinically relevant prognostic indicators for glioma. Conclusions It is suggested that higher expression levels of CREBBP and EP300 are positively associated with increased tumor volume. Inhibition of CREBBP and EP300 enhances local immunogenicity, leading to the recruitment of immune cells and release of cytokines for effective tumor eradication, ultimately resulting in the inhibition of tumor growth.
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Affiliation(s)
- Cuiwei Chen
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
| | - Meiqin Yuan
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
- School of Medicine, Zhejiang University, Hangzhou, China
| | - Liang Xia
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
| | - Xin Wu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xingguang Zhong
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
| | - Huangjie Zhang
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
| | - Lidan Zhang
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
| | - Xuan Liu
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
| | - Zeng Wang
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
- The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
- Integrated Traditional Chinese and Western Medicine Oncology Laboratory, Key Laboratory of Traditional Chinese Medicine of Zhejiang Province, Hangzhou, China
| | - Caixing Sun
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
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22
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Li X, Hou W, Xiao C, Yang H, Zhao C, Cao D. Panoramic tumor microenvironment in pancreatic ductal adenocarcinoma. Cell Oncol (Dordr) 2024; 47:1561-1578. [PMID: 39008192 DOI: 10.1007/s13402-024-00970-6] [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] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is notorious for its resistance to various treatment modalities. The genetic heterogeneity of PDAC, coupled with the presence of a desmoplastic stroma within the tumor microenvironment (TME), contributes to an unfavorable prognosis. The mechanisms and consequences of interactions among different cell types, along with spatial variations influencing cellular function, potentially play a role in the pathogenesis of PDAC. Understanding the diverse compositions of the TME and elucidating the functions of microscopic neighborhoods may contribute to understanding the immune microenvironment status in pancreatic cancer. As we delve into the spatial biology of the microscopic neighborhoods within the TME, aiding in deciphering the factors that orchestrate this intricate ecosystem. This overview delineates the fundamental constituents and the structural arrangement of the PDAC microenvironment, highlighting their impact on cancer cell biology.
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Affiliation(s)
- Xiaoying Li
- Department of Abdominal Oncology, Division of Abdominal Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China
| | - Wanting Hou
- Department of Abdominal Oncology, Division of Abdominal Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China
| | - Chaoxin Xiao
- State Key Laboratory of Biotherapy and Cancer Center, West China HospitaL, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China
| | - Heqi Yang
- Department of Abdominal Oncology, Division of Abdominal Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China
| | - Chengjian Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China HospitaL, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China
| | - Dan Cao
- Department of Abdominal Oncology, Division of Abdominal Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China.
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23
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Wang M, Wang X, Zhang Y, Gu J, Zhang J, Wen X. Transcription Factor FOSL1 Promotes Angiogenesis of Colon Carcinoma by Regulating the VEGF Pathway Through Activating TIMP1. Biochem Genet 2024; 62:3389-3402. [PMID: 38103125 DOI: 10.1007/s10528-023-10547-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 10/07/2023] [Indexed: 12/17/2023]
Abstract
Angiogenesis is the critical media for tumor growth and migration. Tissue Inhibitor Matrix Metalloproteinase-1 (TIMP1) acts as an oncogene in colon carcinoma (CC), but the biological effects of TIMP1 on angiogenesis remain an open issue. This study sought to explore the exact function and mechanism of TIMP1 in the angiogenesis of CC. Bioinformatics methods were utilized to analyze the expression of TIMP1 and its upstream transcription factor FOS-like antigen 1 (FOSL1) in the tumor tissue of CC. Meanwhile, in CC cell lines, real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot were utilized to verify the expression of TIMP1 and FOSL1. Cell counting kit-8 and tube formation assays were utilized to analyze the proliferation and angiogenesis abilities of human umbilical vein endothelial cells (HUVECs). Western blot was used to detect the protein expression of VEGFA, VEGFR-2, and VEGFR-3. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were carried out to explore the specific interaction between FOSL1 and TIMP1. The present study discovered that TIMP1 and FOSL1 were evidently up-regulated in CC tissue and cells. Meanwhile, TIMP1 was found to participate in regulating the signaling pathway of vascular endothelial growth factor (VEGF). Silenced TIMP1 conspicuously suppressed the proliferation and angiogenesis of HUVECs and reduced the protein expression of VEGFA, VEGFR-2, and VEGFR-3. Moreover, FOSL1 could promote TIMP1 transcription by binding with its promoter and the inhibition of TIMP1 expression obviously reversed the promotion effects of FOSL1 overexpression on the proliferation and angiogenesis of HUVECs. FOSL1 activated VEGF pathway by up-regulating TIMP1 expression, thereby advancing CC angiogenesis. We provided theoretical basis that the FOSL1/TIMP1/VEGF pathway might be a novel option for anti-angiogenesis therapy of CC.
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Affiliation(s)
- Meng Wang
- Department of General Surgery, Center of Gastrointestinal and Minimally Invasive Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, 19 Yangshi Street, Chengdu, 610031, Sichuan, China
| | - Xian Wang
- Department of Anorectal, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu, 610031, Sichuan, China
| | - Yuanchuan Zhang
- Department of General Surgery, Center of Gastrointestinal and Minimally Invasive Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, 19 Yangshi Street, Chengdu, 610031, Sichuan, China
| | - Jianhui Gu
- Department of General Surgery, Center of Gastrointestinal and Minimally Invasive Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, 19 Yangshi Street, Chengdu, 610031, Sichuan, China
| | - Jie Zhang
- Department of General Surgery, Center of Gastrointestinal and Minimally Invasive Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, 19 Yangshi Street, Chengdu, 610031, Sichuan, China
| | - Xing Wen
- Department of General Surgery, Center of Gastrointestinal and Minimally Invasive Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, 19 Yangshi Street, Chengdu, 610031, Sichuan, China.
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24
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Luo J, Liang M, Ma T, Dong B, Jia L, Su M. Identification of angiogenesis-related subtypes and risk models for predicting the prognosis of gastric cancer patients. Comput Biol Chem 2024; 112:108174. [PMID: 39191168 DOI: 10.1016/j.compbiolchem.2024.108174] [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: 05/28/2024] [Revised: 08/02/2024] [Accepted: 08/14/2024] [Indexed: 08/29/2024]
Abstract
Gastric cancer (GC) is a leading cause of cancer-related mortality and is characterized by significant heterogeneity, highlighting the need for further studies aimed at personalized treatment strategies. Tumor angiogenesis is critical for tumor development and metastasis, yet its role in molecular subtyping and prognosis prediction remains underexplored. This study aims to identify angiogenesis-related subtypes and develop a prognostic model for GC patients. Using data from The Cancer Genome Atlas (TCGA), we performed consensus cluster analysis on differentially expressed angiogenesis-related genes (ARGs), identifying two patient subtypes with distinct survival outcomes. Differentially expressed genes between the subtypes were analyzed via Cox and LASSO regression, leading to the establishment of a subtype-based prognostic model using a machine learning algorithm. Patients were classified into high- and low-risk groups based on the risk score. Validation was performed using independent datasets (ICGC and GSE15459). We utilized a deconvolution algorithm to investigate the tumor immune microenvironment in different risk groups and conducted analyses on genetic profiling, sensitivity and combination of anti-tumor drug. Our study identified ten prognostic signature genes, enabling the calculation of a risk score to predict prognosis and overall survival. This provides critical data for stratified diagnosis and treatment upon patient admission, monitoring disease progression throughout the entire course, evaluating immunotherapy efficacy, and selecting personalized medications for GC patients.
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Affiliation(s)
- Jie Luo
- Department of Medical Affairs, Huanggang Central Hospital, Huanggang, China
| | - Mengyun Liang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Tengfei Ma
- Clinical Trial Centers, Huanggang Central Hospital, Huanggang, China; Huanggang Institute of Translational Medicine, Huanggang, China
| | - Bizhen Dong
- Huanggang Institute of Translational Medicine, Huanggang, China
| | - Liping Jia
- Department of Respiratory and Critical Care Medicine, Huanggang Central Hospital, Huanggang, China.
| | - Meifang Su
- Department of Hematopathology, Huanggang Central Hospital, Huanggang, China.
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Xie Y, Qi J, Liu J. Curcumin suppresses the malignant phenotype of laryngeal squamous cell carcinoma through downregulating E2F1 to inhibit FLNA. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:6929-6939. [PMID: 38592439 DOI: 10.1007/s00210-024-03059-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 03/18/2024] [Indexed: 04/10/2024]
Abstract
Curcumin is a kind of polyphenol substance extracted from the rhizome of Curcuma longa. Because of its good biological activity and pharmacological effects, it has been used in anti-tumor research. The aim of this study was to investigate the anti-cancer mechanism of curcumin on laryngeal squamous cell carcinoma (LSCC). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to check the expression level of transcription factor E2F1 (E2F1) and filamin A (FLNA) mRNA. E2F1 and FLNA protein and proliferation-associated protein were detected through western blot. Cell viability was showed by MTT assay, and flow cytometry was used to exhibit cell cycle distribution and cell apoptosis. Tube formation assay was used to detect the angiogenesis ability of cells. Transwell was used as a method to observe cell migration and invasion. The online website JASPAR predicted the binding site of E2F1 and FLNA promoter, and chromatin immunoprecipitation (ChIP) and dual-luciferase report experiment verified the combination. Curcumin treatment made LSCC cells viability reduce, cell cycle retardant, angiogenesis decrease, metastasis inhibition and apoptosis increase. And curcumin treatment could downregulate the expression of E2F1, and E2F1 overexpression would reverse the influence of curcumin treatment in LSCC cells. Moreover, E2F1 could bind to FLAN promoter and promote FLNA expression. The expression level of FLNA was higher in LSCC tissue and cells compared with normal tissue and cells. E2F1 knockdown inhibited malignant phenotype of LSCC cells, which would be reversed by FLNA addition. In addition, FLNA had high level in LSCC tissue and cells. Curcumin regulated FLNA expression via inhibiting E2F1. Finally, in vivo assay showed that curcumin inhibition restrained LSCC tumor formation. Curcumin downregulated FLNA expression through inhibiting E2F1, thereby suppressing the malignant phenotype and angiogenesis of LSCC cells, which was a new regulatory pathway in LSCC.
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Affiliation(s)
- Yuanchun Xie
- Department of Otorhinolaryngology-Head and Neck Surgery, Jingmen People's Hospital, Jingmen, China.
| | - Jingjing Qi
- Department of Otorhinolaryngology-Head and Neck Surgery, Jingmen No.2 People's Hospital, No.39, Xiangshan Avenue, Jingmen City, 448000, Hubei, China.
| | - Ju Liu
- Department of Operating Theatre, Jingmen No.2 People's Hospital, Jingmen City, 448000, Hubei, China
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26
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Zhang X, Zhong Y, Yang Q. FOXM1 Upregulates O-GlcNAcylation Level Via The Hexosamine Biosynthesis Pathway to Promote Angiogenesis in Hepatocellular Carcinoma. Cell Biochem Biophys 2024; 82:2767-2785. [PMID: 39031247 DOI: 10.1007/s12013-024-01393-8] [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] [Accepted: 06/29/2024] [Indexed: 07/22/2024]
Abstract
Hepatocellular carcinoma (HCC) presents significant challenges in treatment and prognosis because of its aggressive nature and high metastatic potential. This study aims to investigate the role of the hexosamine biosynthesis pathway (HBP) and its association with HCC progression and prognosis. We identified SPP1 and FOXM1 as hub genes within the HBP pathway, showing their correlation with poor prognosis and late-stage progression. In addition, the analysis uncovered the complex participation of the HBP pathway in nutrients and oxygen reactions, PI3K-AKT signaling, AMPK activation, and angiogenesis regulation. The disruption of these pathways is pivotal in influencing the growth and progression of HCC. Targeting the HBP presents a promising therapeutic approach to modulate the tumor microenvironment, thereby enhancing the efficacy of immunotherapy. In addition, FOXM1 was identified as the HBP pathway regulator, influencing cellular O-GlcNAcylation level and VEGF secretion, thereby promoting angiogenesis in HCC. Inhibition of O-GlcNAcylation significantly hindered angiogenesis, which is suggested as a potential avenue for therapeutic intervention. Our research demonstrates the practicality of using the HBP-related gene as a prognostic marker in liver cancer patients and suggests targeting FOXM1 as a novel avenue for personalized therapy.
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Affiliation(s)
- Xiaorong Zhang
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin Province, China
| | - Yifan Zhong
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin Province, China
| | - Qing Yang
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin Province, China.
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27
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AbuQeis I, Zou Y, Ba YC, Teeti AA. Neuroscience of cancer: Research progress and emerging of the field. IBRAIN 2024; 10:305-322. [PMID: 39346791 PMCID: PMC11427805 DOI: 10.1002/ibra.12172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 07/27/2024] [Accepted: 07/29/2024] [Indexed: 10/01/2024]
Abstract
Cancer cells immediately expand and penetrate adjoining tissues, as opposed to metastasis, that is the spread of cancer cells through the circulatory or lymphatic systems to more distant places via the invasion process. We found that a lack of studies discussed tumor development with the nervous system, by the aspects of cancer-tissue invasion (biological) and chemical modulation of growth that cascades by releasing neural-related factors from the nerve endings via chemical substances known as neurotransmitters. In this review, we aimed to carefully demonstrate and describe the cancer invasion and interaction with the nervous system, as well as reveal the research progress and the emerging neuroscience of cancer. An initial set of 160 references underwent systematic review and summarization. Through a meticulous screening process, these data were refined, ultimately leading to the inclusion of 98 studies that adhered to predetermined criteria. The outcomes show that one formidable challenge in the realm of cancer lies in its intrinsic heterogeneity and remarkable capacity for rapid adaptation. Despite advancements in genomics and precision medicine, there is still a need to identify new molecular targets. Considering cancer within its molecular and cellular environment, including neural components, is crucial for addressing this challenge. In conclusion, this review provides good referential data for direct, indirect, biological, and chemical interaction for nerve tissue-tumor interaction, suggesting the establishment of new therapy techniques and mechanisms by controlling and modifying neuron networks that supply signals to tumors.
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Affiliation(s)
- Issam AbuQeis
- Department of Radiology Palestinian Ministry of Health Ramallah Palestine
- Department of Anatomy, Institute of Neuroscience, School of Basic Medicine Kunming Medical University Kunming China
| | - Yu Zou
- Department of Anatomy, Institute of Neuroscience, School of Basic Medicine Kunming Medical University Kunming China
| | - Ying-Chun Ba
- Department of Anatomy, Institute of Neuroscience, School of Basic Medicine Kunming Medical University Kunming China
| | - Abeer A Teeti
- Department of Chemistry, School of Science Hebron University Hebron Palestine
- Department of Epidemiology, School of Public Health Kunming Medical University Kunming China
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28
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Chen A, Wang K, Qi L, Hu W, Zhou B. Development of a novel prognostic signature for colorectal cancer based on angiogenesis-related genes. Heliyon 2024; 10:e33662. [PMID: 39040272 PMCID: PMC11261139 DOI: 10.1016/j.heliyon.2024.e33662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 06/20/2024] [Accepted: 06/25/2024] [Indexed: 07/24/2024] Open
Abstract
Background Colorectal cancer (CRC) is the third most common malignant tumor worldwide. Angiogenesis is closely related to tumor metastasis, which is the main cause of cancer death. Although several angiogenesis signatures have been proposed in some cancer types, no angiogenic signature has been developed to predict the prognosis and efficacy of antiangiogenic bevacizumab in CRC patients. Methods We developed a novel CRC angiogenic signature by refining seven publicly available angiogenic gene sets using least absolute shrinkage and selection operator (LASSO). Immune and stromal cells within the tumor microenvironment were compared between the high- and low-risk groups in more than 1000 CRC samples classified by calculating the risk score based on the customized angiogenic signature. The correlation of this new gene set with the efficacy of bevacizumab was also compared. Results A new prognostic-associated angiogenesis signature gene set was constructed that can divide CRC patients into two high- and low-risk groups. The high-risk angiogenic group was significantly associated with extracellular matrix organization, epithelial-mesenchymal transition (EMT), and myogenesis. In addition, the high-risk group had higher infiltration of stromal and immune cells and was more resistant to bevacizumab than the low-risk group. Conclusion Briefly, we constructed a novel angiogenic signature that can predict the prognosis of CRC patients and the efficacy of bevacizumab in treating CRC. Our results provide new insights into the relationships among angiogenesis, metastasis, and medication for CRC.
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Affiliation(s)
- Aiqin Chen
- Department of Nursing, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Kailai Wang
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Lina Qi
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Wangxiong Hu
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Biting Zhou
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
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Deiana C, Agostini M, Brandi G, Giovannetti E. The trend toward more target therapy in pancreatic ductal adenocarcinoma. Expert Rev Anticancer Ther 2024; 24:525-565. [PMID: 38768098 DOI: 10.1080/14737140.2024.2357802] [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: 12/19/2023] [Accepted: 05/16/2024] [Indexed: 05/22/2024]
Abstract
INTRODUCTION Despite the considerable progress made in cancer treatment through the development of target therapies, pancreatic ductal adenocarcinoma (PDAC) continues to exhibit resistance to this category of drugs. As a result, chemotherapy combination regimens remain the primary treatment approach for this aggressive cancer. AREAS COVERED In this review, we provide an in-depth analysis of past and ongoing trials on both well-known and novel targets that are being explored in PDAC, including PARP, EGFR, HER2, KRAS, and its downstream and upstream pathways (such as RAF/MEK/ERK and PI3K/AKT/mTOR), JAK/STAT pathway, angiogenesis, metabolisms, epigenetic targets, claudin, and novel targets (such as P53 and plectin). We also provide a comprehensive overview of the significant trials for each target, allowing a thorough glimpse into the past and future of target therapy. EXPERT OPINION The path toward implementing a target therapy capable of improving the overall survival of PDAC is still long, and it is unlikely that a monotherapy target drug will fulfill a meaningful role in addressing the complexity of this cancer. Thus, we discuss the future direction of target therapies in PDAC, trying to identify the more promising target and combination treatments, with a special focus on the more eagerly awaited ongoing trials.
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Affiliation(s)
- Chiara Deiana
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Margherita Agostini
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giovanni Brandi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, The Netherlands
- Cancer Pharmacology Lab, Associazione Italiana per la Ricerca sul Cancro (AIRC) Start-Up Unit, Fondazione Pisana per la Scienza, Pisa, San Giuliano, Italy
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30
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Chen Y, Xia H, Zhong X. In Vitro evaluation of the anti-pancreatic cancer activity of epimedium herb. Front Pharmacol 2024; 15:1389221. [PMID: 39011503 PMCID: PMC11246921 DOI: 10.3389/fphar.2024.1389221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 06/13/2024] [Indexed: 07/17/2024] Open
Abstract
Introduction: Pancreatic cancer (PC) is a particularly aggressive malignancy with limited therapeutic options. The search for innovative treatments has focused on traditional Chinese medicine, specifically epimedium. This research investigates epimedium's active ingredients, potential targets, and underlying mechanisms in treating PC. Methods: High-performance liquid chromatography (HPLC) was used to quantify the active components of epimedium and HPLC-Q-TOF-MS was employed for qualitative identification. Potential targets of epimedium's active ingredients were identified using the TCMSP, ETCM, CTD, and Swiss Target Prediction databases. Potential PC-related targets were sourced from DisGeNET, GeneCards, and OMIM databases. A Venn diagram was utilized to identify overlapping PC-related and epimedium targets. Core targets and pathways were elucidated through protein-protein interaction (PPI) network analysis, Gene Ontology (GO) assessments, and Reactome pathway enrichment analyses. Molecular docking techniques investigated interactions between active compounds and these targets. The expression and prognostic implications of target genes were evaluated using GEPIA2 and the Human Protein Atlas (HPA) databases. In vitro studies assessed the impact of epimedium extract (EPE) on Panc-1 cell viability, and Western blot analysis examined the expression levels of key targets. Results: Network pharmacological indicate that epimedium econtains active components such as baohuoside I, icariin, hyperoside, and epimedin B, which have potential therapeutic effects against PC. In vitro assays confirmed that EPE significantly reduced the viability of Panc-1 cells. Western blot analysis revealed a considerable decrease in the expression of key targets in EPE-treated cells, including AKT1, EGFR, p-EGFR, JUN, BCL2, IL6, and SRC. The R-HSA-1280215: Interleukin-4 and Interleukin-13 signaling pathways involving these genes were identified as potential therapeutic targets. Discussion: Epimedium holds promise as a candidate for treating PC. The modulation of interleukin-4 and interleukin-13 signaling pathways could be a pivotal mechanism by which epimedium impedes tumor development. Further research is warranted to validate these findings and explore the clinical applicability of epimedium in PC treatment.
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Affiliation(s)
- Yangfeng Chen
- College of Horticulture, Hunan Agricultural University, Changsha, China
| | - Han Xia
- Changsha Central Hospital, Changsha, China
| | - Xiaohong Zhong
- College of Horticulture, Hunan Agricultural University, Changsha, China
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Li S, Liu W, Liu J, Yang Z, Zhang L, Nie F, Yang P, Guo H, Yang C. Low-dose TNF-α promotes angiogenesis of oral squamous cell carcinoma cells via TNFR2/Akt/mTOR axis. Oral Dis 2024; 30:3004-3017. [PMID: 37964399 DOI: 10.1111/odi.14802] [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: 10/12/2022] [Revised: 10/08/2023] [Accepted: 10/23/2023] [Indexed: 11/16/2023]
Abstract
OBJECTIVES To assess the role of TNF-α/TNFR2 axis on promoting angiogenesis in oral squamous cell carcinoma (OSCC) cells and uncover the underlying mechanisms. MATERIALS AND METHODS The expression of TNFR2 and CD31 in OSCC tissues was examined; gene expression relationship between TNF-α/TNFR2 and angiogenic markers or signaling molecules was analyzed; the expression of angiogenic markers, signaling molecules, TNFR1, and TNFR2 in TNF-α-stimulated OSCC cells treated with or without TNFR2 neutralizing antibody (TNFR2 Nab) were assessed; the concentration of angiogenic markers in the supernatant of OSCC cells was detected; conditioned mediums of OSCC cells treated with TNF-α or TNF-α + TNFR2 Nab were applied to human umbilical vein endothelial cells (HUVECs), followed by tube formation and cell migration assays. RESULTS Significantly elevated expression of TNFR2 and CD31 in OSCC tissues was observed. A positive gene expression correlation was identified between TNF-α/TNFR2 and angiogenic markers or signaling molecules. TNFR2 Nab inhibited the effects of TNF-α on enhancing the expression of angiogenic factors and TNFR2, the phosphorylation of the Akt/mTOR signaling pathway, HUVECs migration, and tube formation. CONCLUSIONS TNFR2 Nab counteracts the effect of TNF-α on OSCC cells through the TNFR2/Akt/mTOR axis, indicating that blocking TNFR2 might be a promising strategy against cancer.
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Affiliation(s)
- Shutong Li
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration and Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Wenchuan Liu
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration and Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Junze Liu
- School of Information and Computer Sciences, Institute for Genomics and Bioinformatics, University of California Irvine, Irvine, California, USA
| | - Zongcheng Yang
- Division of Life Sciences and Medicine, Department of Stomatology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China
| | - Liguo Zhang
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration and Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Fujiao Nie
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration and Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Pishan Yang
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration and Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Hongmei Guo
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration and Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Chengzhe Yang
- Department of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Institute of Stomatology, Shandong University, Jinan, Shandong, China
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Wang D, Liu X, Hong W, Xiao T, Xu Y, Fang X, Tang H, Zheng Q, Meng X. Muscone abrogates breast cancer progression through tumor angiogenic suppression via VEGF/PI3K/Akt/MAPK signaling pathways. Cancer Cell Int 2024; 24:214. [PMID: 38898449 PMCID: PMC11188526 DOI: 10.1186/s12935-024-03401-6] [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: 03/16/2024] [Accepted: 06/09/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Angiogenesis strongly reflects poor breast cancer outcome and an important contributor to breast cancer (BC) metastasis; therefore, anti-angiogenic intervention is a potential tool for cancer treatment. However, currently used antibodies against vascular endothelial growth factor A (VEGFA) or inhibitors that target the VEGFA receptor are not effective due to weak penetration and low efficiency. Herein, we assessed the anti-BC angiogenic role of muscone, a natural bioactive musk constituent, and explored possible anti-cancer mechanisms of this compound. METHODS CCK-8, EdU, scratch and Transwell assessments were employed to detect the muscone-mediated regulation of breast cancer (BC) and human umbilical vein endothelial cells (HUVECs) proliferation and migration. Tube formation, matrigel plug assay and zebrafish assay were employed for assessment of regulation of tumor angiogenesis by muscone. In vivo xenograft mouse model was constructed to compare microvessel density (MVD), vascular leakage, vascular maturation and function in muscone-treated or untreated mice. RNA sequencing was performed for gene screening, and Western blot verified the effect of the VEGFA-VEGFR2 pathway on BC angiogenic inhibition by muscone. RESULTS Based on our findings, muscone suppressed BC progression via tumor angiogenic inhibition in cellular and animal models. Functionally, muscone inhibited BC cell proliferation and migration as well as tumor cell-conditioned medium-based endothelial cell proliferation and migration. Muscone exhibited a strong suppressive influence on tumor vasculature in cellular and animal models. It abrogated tumor cell growth in a xenograft BC mouse model and minimized tumor microvessel density and hypoxia, and increased vascular wall cell coverage and perfusion. Regarding the mechanism of action, we found that muscone suppressed phosphorylation of members of the VEGF/PI3K/Akt/MAPK axis, and it worked synergistically with a VEGFR2 inhibitor, an Akt inhibitor, and a MAPK inhibitor to further inhibit tube formation. CONCLUSION Overall, our results demonstrate that muscone may proficiently suppress tumor angiogenesis via modulation of the VEGF/PI3K/Akt/MAPK axis, facilitating its candidacy as a natural small molecule drug for BC treatment.
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Affiliation(s)
- Danhong Wang
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, 310014, Zhejiang, China
- Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
- Key Laboratory for Diagnosis and Treatment of Upper Limb Edema and Stasis of Breast Cancer, Hangzhou, 310014, Zhejiang, China
| | - Xiaozhen Liu
- Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
- Key Laboratory for Diagnosis and Treatment of Upper Limb Edema and Stasis of Breast Cancer, Hangzhou, 310014, Zhejiang, China
| | - Weimin Hong
- Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310053, Zhejiang, China
- Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
- Key Laboratory for Diagnosis and Treatment of Upper Limb Edema and Stasis of Breast Cancer, Hangzhou, 310014, Zhejiang, China
| | - Tianzheng Xiao
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, 310014, Zhejiang, China
- Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
- Key Laboratory for Diagnosis and Treatment of Upper Limb Edema and Stasis of Breast Cancer, Hangzhou, 310014, Zhejiang, China
| | - Yadan Xu
- Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310053, Zhejiang, China
- Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
- Key Laboratory for Diagnosis and Treatment of Upper Limb Edema and Stasis of Breast Cancer, Hangzhou, 310014, Zhejiang, China
| | - Xiang Fang
- Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
- Key Laboratory for Diagnosis and Treatment of Upper Limb Edema and Stasis of Breast Cancer, Hangzhou, 310014, Zhejiang, China
- College of Clinical Medicine, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Hongchao Tang
- Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
- Key Laboratory for Diagnosis and Treatment of Upper Limb Edema and Stasis of Breast Cancer, Hangzhou, 310014, Zhejiang, China
| | - Qinghui Zheng
- Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
- Key Laboratory for Diagnosis and Treatment of Upper Limb Edema and Stasis of Breast Cancer, Hangzhou, 310014, Zhejiang, China.
| | - Xuli Meng
- Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
- Key Laboratory for Diagnosis and Treatment of Upper Limb Edema and Stasis of Breast Cancer, Hangzhou, 310014, Zhejiang, China.
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Seifi Z, Khazaei M, Cheraghali D, Rezakhani L. Decellularized tissues as platforms for digestive system cancer models. Heliyon 2024; 10:e31589. [PMID: 38845895 PMCID: PMC11153114 DOI: 10.1016/j.heliyon.2024.e31589] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 05/17/2024] [Accepted: 05/20/2024] [Indexed: 06/09/2024] Open
Abstract
The extracellular matrix (ECM) is a multifunctional network of macromolecules that regulate various cellular functions and physically support the tissues. Besides physiological conditions, the ECM also changes during pathological conditions such as cancer. As tumor cells proliferate, notable changes occur in the quantity and makeup of the surrounding ECM. Therefore, the role of this noncellular component of tissues in studies of tumor microenvironments should be considered. So far, many attempts have been made to create 2-dimensional (2D) or 3-dimensional (3D) models that can replicate the intricate connections within the tumor microenvironment. Decellularized tissues are proper scaffolds that imitate the complex nature of native ECM. This review aims to summarize 3D models of digestive system cancers based on decellularized ECMs. These ECM-based scaffolds will enable us to study the interactive communication between cells and their surrounding environment which brings new potential for a better understanding of the pathophysiology of cancer.
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Affiliation(s)
- Zahra Seifi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mozafar Khazaei
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Danial Cheraghali
- Department of Mechanical Engineering, New Jersey Institute of Technology, NJ, USA
| | - Leila Rezakhani
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Zhu J, Zhang K, Chen Y, Ge X, Wu J, Xu P, Yao J. Progress of single-cell RNA sequencing combined with spatial transcriptomics in tumour microenvironment and treatment of pancreatic cancer. J Transl Med 2024; 22:563. [PMID: 38867230 PMCID: PMC11167806 DOI: 10.1186/s12967-024-05307-3] [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: 11/27/2023] [Accepted: 05/16/2024] [Indexed: 06/14/2024] Open
Abstract
In recent years, single-cell analyses have revealed the heterogeneity of the tumour microenvironment (TME) at the genomic, transcriptomic, and proteomic levels, further improving our understanding of the mechanisms of tumour development. Single-cell RNA sequencing (scRNA-seq) technology allow analysis of the transcriptome at the single-cell level and have unprecedented potential for exploration of the characteristics involved in tumour development and progression. These techniques allow analysis of transcript sequences at higher resolution, thereby increasing our understanding of the diversity of cells found in the tumour microenvironment and how these cells interact in complex tumour tissue. Although scRNA-seq has emerged as an important tool for studying the tumour microenvironment in recent years, it cannot be used to analyse spatial information for cells. In this regard, spatial transcriptomics (ST) approaches allow researchers to understand the functions of individual cells in complex multicellular organisms by understanding their physical location in tissue sections. In particular, in related research on tumour heterogeneity, ST is an excellent complementary approach to scRNA-seq, constituting a new method for further exploration of tumour heterogeneity, and this approach can also provide unprecedented insight into the development of treatments for pancreatic cancer (PC). In this review, based on the methods of scRNA-seq and ST analyses, research progress on the tumour microenvironment and treatment of pancreatic cancer is further explained.
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Affiliation(s)
- Jie Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People's Hospital Affiliated Yangzhou University, Jiangsu Province, China
| | - Ke Zhang
- Dalian Medical University, Dalian, China
| | - Yuan Chen
- Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People's Hospital Affiliated Yangzhou University, Jiangsu Province, China
| | - Xinyu Ge
- Dalian Medical University, Dalian, China
| | - Junqing Wu
- Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People's Hospital Affiliated Yangzhou University, Jiangsu Province, China
| | - Peng Xu
- Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People's Hospital Affiliated Yangzhou University, Jiangsu Province, China.
| | - Jie Yao
- Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People's Hospital Affiliated Yangzhou University, Jiangsu Province, China.
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Maruya Y, Akazawa Y, Norimatsu K, Sailaubekova Y, Zhumagazhiyeva N, Kobayashi S, Higashi M, Hashiguchi K, Yamaguchi N, Nakashima M, Nakao K, Kanetaka K, Eguchi S. Long-term prognosis and DNA damage status after oral mucosal epithelial cell sheet transplantation following esophageal endoscopic submucosal dissection for squamous cell carcinoma: A case series. Regen Ther 2024; 26:557-563. [PMID: 39228905 PMCID: PMC11369366 DOI: 10.1016/j.reth.2024.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 07/04/2024] [Accepted: 08/02/2024] [Indexed: 09/05/2024] Open
Abstract
Autologous oral mucosal epithelial cell sheet (AOMECS) transplantation has recently been applied in human patients to prevent postprocedural stenosis following endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma. However, the long-term safety of AOMECS transplantation remains unclear. We evaluated the long-term outcomes of 10 patients who participated in a clinical trial of AOMECS transplantation after esophageal ESD. Additionally, we assessed the local DNA damage response in the esophageal epithelium using p53 binding protein 1 (53BP1) immunofluorescence in post-AOMECS biopsy specimens. The median follow-up period was 118.5 months (range: 46-130 months). Two patients developed primary esophageal cancer near the AOMECS site and successfully underwent additional ESD. One patient developed lymph node metastasis and underwent chemotherapy. None of the patients died from the original disease, although one patient died from unrelated causes. The rate of abnormal 53BP1 nuclear foci, indicative of increased genome instability, increased with the progression of neoplasia in patients post AOMECS. Our case series suggests that AOMECS transplantation provides an acceptable long-term prognosis and 53BP1 foci may serve as a useful marker for assessing DNA instability in the post-AOMECS esophageal epithelium.
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Affiliation(s)
- Yasuhiro Maruya
- Tissue Engineering and Regenerative Therapeutics in Gastrointestinal Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yuko Akazawa
- Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kiyuu Norimatsu
- Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | - Yerkezhan Sailaubekova
- Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Nazigul Zhumagazhiyeva
- Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Shinichiro Kobayashi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Miki Higashi
- Tissue Engineering and Regenerative Therapeutics in Gastrointestinal Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Keiichi Hashiguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Naoyuki Yamaguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masahiro Nakashima
- Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kengo Kanetaka
- Tissue Engineering and Regenerative Therapeutics in Gastrointestinal Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Chen C, Demirkhanyan L, Gondi CS. The Multifaceted Role of miR-21 in Pancreatic Cancers. Cells 2024; 13:948. [PMID: 38891080 PMCID: PMC11172074 DOI: 10.3390/cells13110948] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 05/23/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
With the lack of specific signs and symptoms, pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at late metastatic stages, resulting in poor survival outcomes. Among various biomarkers, microRNA-21 (miR-21), a small non-coding RNA, is highly expressed in PDAC. By inhibiting regulatory proteins at the 3' untranslated regions (UTR), miR-21 holds significant roles in PDAC cell proliferation, epithelial-mesenchymal transition, angiogenesis, as well as cancer invasion, metastasis, and resistance therapy. We conducted a systematic search across major databases for articles on miR-21 and pancreatic cancer mainly published within the last decade, focusing on their diagnostic, prognostic, therapeutic, and biological roles. This rigorous approach ensured a comprehensive review of miR-21's multifaceted role in pancreatic cancers. In this review, we explore the current understandings and future directions regarding the regulation, diagnostic, prognostic, and therapeutic potential of targeting miR-21 in PDAC. This exhaustive review discusses the involvement of miR-21 in proliferation, epithelial-mesenchymal transition (EMT), apoptosis modulation, angiogenesis, and its role in therapy resistance. Also discussed in the review is the interplay between various molecular pathways that contribute to tumor progression, with specific reference to pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Clare Chen
- Department of Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
| | - Lusine Demirkhanyan
- Department of Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
- Departments of Internal Medicine and Surgery, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
| | - Christopher S. Gondi
- Department of Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
- Departments of Internal Medicine and Surgery, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
- Departments of Internal Medicine, Surgery, and Health Science Education and Pathology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
- Health Care Engineering Systems Center, The Grainger College of Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
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Chen Z, Ou Y, Ye F, Li W, Jiang H, Liu S. Machine learning identifies the role of SMAD6 in the prognosis and drug susceptibility in bladder cancer. J Cancer Res Clin Oncol 2024; 150:264. [PMID: 38767747 PMCID: PMC11106122 DOI: 10.1007/s00432-024-05798-z] [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: 03/05/2024] [Accepted: 05/10/2024] [Indexed: 05/22/2024]
Abstract
BACKGROUND Bladder cancer (BCa) is among the most prevalent malignant tumors affecting the urinary system. Due to its highly recurrent nature, standard treatments such as surgery often fail to significantly improve patient prognosis. Our research aims to predict prognosis and identify precise therapeutic targets for novel treatment interventions. METHODS We collected and screened genes related to the TGF-β signaling pathway and performed unsupervised clustering analysis on TCGA-BLCA samples based on these genes. Our analysis revealed two novel subtypes of bladder cancer with completely different biological characteristics, including immune microenvironment, drug sensitivity, and more. Using machine learning classifiers, we identified SMAD6 as a hub gene contributing to these differences and further investigated the role of SMAD6 in bladder cancer in the single-cell transcriptome data. Additionally, we analyzed the relationship between SMAD6 and immune checkpoint genes. Finally, we performed a series of in vitro assays to verify the function of SMAD6 in bladder cancer cell lines. RESULTS We have revealed two novel subtypes of bladder cancer, among which C1 exhibits a worse prognosis, lower drug sensitivity, a more complex tumor microenvironment, and a 'colder' immune microenvironment compared to C2. We identified SMAD6 as a key gene responsible for the differences and further explored its impact on the molecular characteristics of bladder cancer. Through in vitro experiments, we found that SMAD6 promoted the prognosis of BCa patients by inhibiting the proliferation and migration of BCa cells. CONCLUSION Our study reveals two novel subtypes of BCa and identifies SMAD6 as a highly promising therapeutic target.
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Affiliation(s)
- Ziang Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuxi Ou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Fangdie Ye
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Weijian Li
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Haowen Jiang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
| | - Shenghua Liu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
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Saleh RO, Jasim SA, Kadhum WR, Hjazi A, Faraz A, Abid MK, Yumashev A, Alawadi A, Aiad IAZ, Alsalamy A. Exploring the detailed role of interleukins in cancer: A comprehensive review of literature. Pathol Res Pract 2024; 257:155284. [PMID: 38663179 DOI: 10.1016/j.prp.2024.155284] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 03/25/2024] [Accepted: 03/30/2024] [Indexed: 05/12/2024]
Abstract
The cancer cells that are not normal can grow into tumors, invade surrounding tissues, and travel to other parts of the body via the lymphatic or circulatory systems. Interleukins, a vital class of signaling proteins, facilitate cell-to-cell contact within the immune system. A type of non-coding RNA known as lncRNAs mediates its actions by regulating miRNA-mRNA roles (Interleukins). Because of their dual function in controlling the growth of tumors and altering the immune system's response to cancer cells, interleukins have been extensively studied concerning cancer. Understanding the complex relationships between interleukins, the immune system, the tumor microenvironment, and the components of interleukin signaling pathways that impact the miRNA-mRNA axis, including lncRNAs, has advanced significantly in cancer research. Due to the significant and all-encompassing influence of interleukins on the immune system and the development and advancement of cancers, lncRNAs play a crucial role in cancer research by modulating interleukins. Their diverse effects on immune system regulation, tumor growth encouragement, and tumor inhibition make them appealing candidates for potential cancer treatments and diagnostics. A deeper understanding of the relationship between the biology of interleukin and lncRNAs will likely result in more effective immunotherapy strategies and individualized cancer treatments.
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Affiliation(s)
- Raed Obaid Saleh
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq
| | - Saade Abdalkareem Jasim
- Pharmacy Department, Al-Huda University College, Anbar, Iraq; Biotechnology Department, College of Applied Science, Fallujah University, Anbar, Iraq.
| | - Wesam R Kadhum
- Department of Pharmacy, Kut University College, Kut, Wasit 52001, Iraq; Advanced Research Center, Kut University College, Kut, Wasit 52001, Iraq
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Ali Faraz
- Department of Basic Medical Sciences, College of Medicine, Majmaah University, Majmaah 11952, Saudi Arabia.
| | - Mohammed Kadhem Abid
- Department of Anesthesia, College of Health & Medical Technology, Al-Ayen University, Thi-Qar, Iraq
| | - Alexey Yumashev
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Ahmed Alawadi
- College of Technical Engineering, the Islamic University, Najaf, Iraq; College of Technical Engineering, the Islamic University of Al Diwaniyah, Iraq; College of Technical Engineering, the Islamic University of Babylon, Iraq
| | - Ibrahim Ahmed Zaki Aiad
- Department of Pediatrics, General Medicine Practice Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia
| | - Ali Alsalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
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Chen Y, Cheng CS, Yang P, Dong S, Chen L. Novel silicene-mesoporous silica nanoparticles conjugated gemcitabine induced cellular apoptosis via upregulating NF- κB p65 nuclear translocation suppresses pancreatic cancer growth in vitroand in vivo. NANOTECHNOLOGY 2024; 35:255101. [PMID: 38452386 DOI: 10.1088/1361-6528/ad312a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 03/07/2024] [Indexed: 03/09/2024]
Abstract
Pancreatic cancer's high fatality rates stem from its resistance to systemic drug delivery and aggressive metastasis, limiting the efficacy of conventional treatments. In this study, two-dimensional ultrathin silicene nanosheets were initially synthesized and near-infrared-responsive two-dimensional silicene-mesoporous silica nanoparticles (SMSNs) were successfully constructed to load the clinically-approved conventional pancreatic cancer chemotherapeutic drug gemcitabine. Experiments on nanoparticle characterization show that they have excellent photothermal conversion ability and stability. Then silicene-mesoporous silica nanoparticles loaded with gemcitabine nanoparticles (SMSN@G NPs) were employed in localized photothermal therapy to control pancreatic tumor growth and achieve therapeutic effects. Our research confirmed the functionality of SMSN@G NPs through immunoblotting and apoptotic assays, demonstrating its capacity to enhance the nuclear translocation of the NF-κB p65, further affect the protein levels of apoptosis-related genes, induce the apoptosis of tumor cells, and ultimately inhibit the growth of the tumor. Additionally, the study assessed the inhibitory role of SMSN@G NPs on pancreatic neoplasm growthin vivo, revealing its excellent biocompatibility. SMSN@G NPs have a nice application prospect for anti-pancreatic tumors.
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Affiliation(s)
- Yuhang Chen
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Chien-Shan Cheng
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Peiwen Yang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Shu Dong
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Lianyu Chen
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
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Cai X, Wang Z, Lin S, Chen H, Bu H. Ginsenoside Rg3 suppresses vasculogenic mimicry by impairing DVL3-maintained stemness via PAAD cell-derived exosomal miR-204 in pancreatic adenocarcinoma. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 126:155402. [PMID: 38350242 DOI: 10.1016/j.phymed.2024.155402] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 01/05/2024] [Accepted: 01/31/2024] [Indexed: 02/15/2024]
Abstract
BACKGROUND Vasculogenic mimicry (VM) is an angiogenesis-independent process that potentially contributes to the poor clinical outcome of anti-angiogenesis therapy in multiple malignant cancers, including pancreatic adenocarcinoma (PAAD). Several studies have shown that ginsenoside Rg3, a bioactive component of ginseng, holds considerable potential for cancer treatment. Our previous work has proved that Rg3 can inhibit VM formation in PAAD. However, its underlying mechanism remains unclear. PURPOSE To explore the underlying mechanism by which Rg3 affects VM formation in PAAD. METHODS We first investigated the effects of Rg3 on the cellular phenotypes of two PAAD cell lines (SW-1990 and PCI-35), and the expression of EMT- and stemness-related proteins. SW-1990 cells were adopted to construct xenograft models, and the anti-tumor effects of Rg3 in vivo were validated. Subsequently, we isolated the exosomes from the two PAAD cell lines with Rg3 treatment or not, and explored whether Rg3 regulated VM via PAAD cell-derived exosomes. MiRNA sequencing, clinical analysis, and rescue experiments were performed to investigate whether and which miRNA was involved. Subsequently, the target gene of miRNA was predicted using the miRDB website (https://mirdb.org/), and rescue experiments were further conducted to validate those in vitro and in vivo. RESULTS Rg3 indeed exhibited excellent anti-tumor effects both in vitro and in vivo, with inhibitory effects on EMT and stemness of PAAD cells. More interestingly, Rg3-treated PAAD cell-derived exosomes suppressed the tube-forming ability of HUVEC and PAAD cells, with a decrease in stemness-related protein expression, indicating that Rg3 inhibited both angiogenesis and VM processes. Subsequently, we found that Rg3 induced the up-regulation of miR-204 in PAAD cell-derived exosomes, and miR-204 alone inhibited tube and sphere formation abilities of PAAD cells like exosomes. Specifically, miR-204 down-regulated DVL3 expression, which was involved in regulating cancer cell stemness, and ultimately affected VM. The in vivo experiments further indicated that Rg3-treated SW-1990 cell-derived exosome-inhibited tumor growth, VM formation, and stemness-related protein expression can be abrogated by DVL3 overexpression. CONCLUSION Ginsenoside Rg3 increased the PAAD cell-derived exosomal miR-204 levels, which subsequently inhibited its target genes DVL3 expression in the receptor PAAD cells, and the down-regulated DVL3 broke stemness maintenance, ultimately suppressing VM formation of PAAD. Our findings revealed a novel mechanism by which Rg3 exerted its anti-tumor activity in PAAD via inhibiting VM, and provided a promising strategy to make up for the deficiency of anti-angiogenesis therapy in cancer.
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Affiliation(s)
- Xufan Cai
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People's Republic of China
| | - Zhaohong Wang
- Department of hepatobiliary and pancreatic surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Shengzhang Lin
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, #51 Huzhou Street, Gongshu District, Hangzhou, Zhejiang 310015, People's Republic of China.
| | - Hui Chen
- Department of hepatobiliary and pancreatic surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Heqi Bu
- Department of Surgery, Tongde Hospital of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang 310012, People's Republic of China
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Jasim SA, Al-Hawary SIS, Kaur I, Ahmad I, Hjazi A, Petkov I, Ali SHJ, Redhee AH, Shuhata Alubiady MH, Al-Ani AM. Critical role of exosome, exosomal non-coding RNAs and non-coding RNAs in head and neck cancer angiogenesis. Pathol Res Pract 2024; 256:155238. [PMID: 38493725 DOI: 10.1016/j.prp.2024.155238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 02/13/2024] [Accepted: 03/02/2024] [Indexed: 03/19/2024]
Abstract
Head and neck cancer (HNC) refers to the epithelial malignancies of the upper aerodigestive tract. HNCs have a constant yet slow-growing rate with an unsatisfactory overall survival rate globally. The development of new blood vessels from existing blood conduits is regarded as angiogenesis, which is implicated in the growth, progression, and metastasis of cancer. Aberrant angiogenesis is a known contributor to human cancer progression. Representing a promising therapeutic target, the blockade of angiogenesis aids in the reduction of the tumor cells oxygen and nutrient supplies. Despite the promise, the association of existing anti-angiogenic approaches with severe side effects, elevated cancer regrowth rates, and limited survival advantages is incontrovertible. Exosomes appear to have an essential contribution to the support of vascular proliferation, the regulation of tumor growth, tumor invasion, and metastasis, as they are a key mediator of information transfer between cells. In the exocrine region, various types of noncoding RNAs (ncRNAs) identified to be enriched and stable and contribute to the occurrence and progression of cancer. Mounting evidence suggest that exosome-derived ncRNAs are implicated in tumor angiogenesis. In this review, the characteristics of angiogenesis, particularly in HNC, and the impact of ncRNAs on HNC angiogenesis will be outlined. Besides, we aim to provide an insight on the regulatory role of exosomes and exosome-derived ncRNAs in angiogenesis in different types of HNC.
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Affiliation(s)
| | | | - Irwanjot Kaur
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, Karnataka 560069, India; Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
| | - Iliya Petkov
- Medical University - Sofia, Department of Neurology, Sofia, Bulgaria
| | - Saad Hayif Jasim Ali
- Department of medical laboratory, College of Health and Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | - Ahmed Huseen Redhee
- Medical laboratory technique college, the Islamic University, Najaf, Iraq; Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; Medical laboratory technique college, the Islamic University of Babylon, Babylon, Iraq
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Wu D, Wang Q, Yan S, Sun X, Qin Y, Yuan M, Wang NY, Huang XT. Extended survival with metastatic pancreatic cancer under fruquintinib treatment after failed chemotherapy: Two case reports. World J Clin Cases 2024; 12:1296-1304. [PMID: 38524525 PMCID: PMC10955531 DOI: 10.12998/wjcc.v12.i7.1296] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 01/02/2024] [Accepted: 02/05/2024] [Indexed: 02/29/2024] Open
Abstract
BACKGROUND Pancreatic cancer is a highly malignant disease. After decades of treatment progress, the current five-year survival rate for patients is still less than 10%. For later-line treatment, the treatment options are even more limited. Anti-angiogenic drugs can improve progression-free survival in patients with advanced pancreatic cancer. Preclinical data show that fruquintinib might improve the prognosis of advanced pancreatic cancer by targeting angiogenesis and lymphopoiesis, improving the abnormal vascular structure, and modulating the tumour immune microenvironment. CASE SUMMARY We present two cases of third-line fruquintinib monotherapy that brought an extraprolonged progress-free survival (PFS) of 10 months. Patient 1 took adjuvant gemcitabine-based and first-line nab-paclitaxel-based chemotherapy and then used local radiotherapy combined with programmed cell death 1 receptor (PD-1). Each line lasted approximately 7 months. Moreover, the patient took third-line fruquintinib, which was followed by stable disease for 10 months, during which no additional adverse effect was observed. The patient later refused to take fruquintinib due to difficulty urinating and lower abdominal pain after the coronavirus disease 2019 (COVID-19) infection. The patient died in February 2023. Patient 2 also took two prior lines of chemotherapy and then local radiotherapy combined with S-1. After confirmed disease progression, the patient experienced a continuous partial response after using fruquintinib monotherapy in the third line. After the patient had COVID-19 in December 2022, fruquintinib was discontinued. The patient died in January 2023 due to disease progression. CONCLUSION Both cases achieved a PFS benefit from later-line single-agent fruquintinib therapy. With its better safety profile, fruquintinib may be worth exploring and studying in more depth as a later-line treatment for pancreatic cancer patients.
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Affiliation(s)
- Dan Wu
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
| | - Qiong Wang
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
| | - Shuai Yan
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
| | - Xia Sun
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
| | - Ya Qin
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
| | - Ming Yuan
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
| | - Nan-Yao Wang
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
| | - Xian-Ting Huang
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
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Wang L, Wang G, Wang P, Nie F. Pancreatic ductal adenocarcinoma: CEUS characteristics are correlated with pathological findings and help predict early recurrence after resection. JOURNAL OF CLINICAL ULTRASOUND : JCU 2024; 52:230-240. [PMID: 38018362 DOI: 10.1002/jcu.23622] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 11/16/2023] [Accepted: 11/17/2023] [Indexed: 11/30/2023]
Abstract
OBJECTIVES To identify characteristics of preoperative contrast-enhanced ultrasound (CEUS) that could predict early recurrence after curative resection of pancreatic ductal adenocarcinoma (PDAC). METHODS From January 2017 to September 2022, a total of 110 patients with PDAC (all confirmed by samples obtained via operation) who underwent CEUS within 1 month before surgery were enrolled. We proposed five CEUS enhancement patterns (Pattern I, homogeneous enhancement; Pattern II, heterogeneous enhancement without cystic components; pattern III, ring enhancement; Pattern IV, starry enhancement; Pattern V, heterogeneous enhancement with cystic components) of PDAC. Clinical-pathologic and CEUS characteristics for predicting early recurrence (recurrence within 1 year after curative resection) were analyzed. Important CEUS characteristics were compared with the pathological findings. RESULTS Tumor size and TNM stage were closely associated with early recurrence. Incomplete-enhancement and enhancement pattern III, IV and V at CEUS imaging were more prone to early recurrence. Incomplete-enhancement lesions had higher histological tumor grades, less frequent remaining acini, and more frequent necrosis within the tumor. PDACs with pattern I and II had lower histological tumor grades, and pattern III, IV and V had higher histological tumor grades. PDACs with pattern I, II and IV had less frequent intratumoral necrosis than PDACs with pattern III and V, and PDACs with pattern IV had lower MVD values. CONCLUSIONS PDACs with incomplete enhancement and enhancement pattern III, IV and V were more prone to early recurrence after attempted curative resection, and these important CEUS characteristics were closely related to the pathological findings of PDAC.
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Affiliation(s)
- Lan Wang
- Ultrasound Medical Center, Lanzhou University Second Hospital, Lanzhou, China
| | - Guojuan Wang
- Ultrasound Medical Center, Lanzhou University Second Hospital, Lanzhou, China
| | - Peihua Wang
- Ultrasound Medical Center, Lanzhou University Second Hospital, Lanzhou, China
| | - Fang Nie
- Ultrasound Medical Center, Lanzhou University Second Hospital, Lanzhou, China
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Li Y, Zhang Y, Yu Q, He C, Yuan X. Intelligent scoring system based on dynamic optical breast imaging for early detection of breast cancer. BIOMEDICAL OPTICS EXPRESS 2024; 15:1515-1527. [PMID: 38495695 PMCID: PMC10942703 DOI: 10.1364/boe.515135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/06/2024] [Accepted: 01/31/2024] [Indexed: 03/19/2024]
Abstract
Early detection of breast cancer can significantly improve patient outcomes and five-year survival in clinical screening. Dynamic optical breast imaging (DOBI) technology reflects the blood oxygen metabolism level of tumors based on the theory of tumor neovascularization, which offers a technical possibility for early detection of breast cancer. In this paper, we propose an intelligent scoring system integrating DOBI features assessment and a malignancy score grading reporting system for early detection of breast cancer. Specifically, we build six intelligent feature definition models to depict characteristics of regions of interest (ROIs) from location, space, time and context separately. Similar to the breast imaging-reporting and data system (BI-RADS), we conclude the malignancy score grading reporting system to score and evaluate ROIs as follows: Malignant (≥ 80 score), Likely Malignant (60-80 score), Intermediate (35-60 score), Likely Benign (10-35 score), and Benign (<10 score). This system eliminates the influence of subjective physician judgments on the assessment of the malignant probability of ROIs. Extensive experiments on 352 Chinese patients demonstrate the effectiveness of the proposed system compared to state-of-the-art methods.
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Affiliation(s)
- Yaoyao Li
- Hangzhou Institute of Technology, Xidian University, Qiannong Dong Road No. 8, Hangzhou, Zhejiang, 311231, China
| | - Yipei Zhang
- Hangzhou Institute of Technology, Xidian University, Qiannong Dong Road No. 8, Hangzhou, Zhejiang, 311231, China
| | - Qiang Yu
- Hangzhou Institute of Technology, Xidian University, Qiannong Dong Road No. 8, Hangzhou, Zhejiang, 311231, China
| | - Chenglong He
- Hangzhou Institute of Technology, Xidian University, Qiannong Dong Road No. 8, Hangzhou, Zhejiang, 311231, China
| | - Xiguo Yuan
- Hangzhou Institute of Technology, Xidian University, Qiannong Dong Road No. 8, Hangzhou, Zhejiang, 311231, China
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Peña-Flores JA, Muela-Campos D, Guzmán-Medrano R, Enríquez-Espinoza D, González-Alvarado K. Functional Relevance of Extracellular Vesicle-Derived Long Non-Coding and Circular RNAs in Cancer Angiogenesis. Noncoding RNA 2024; 10:12. [PMID: 38392967 PMCID: PMC10891584 DOI: 10.3390/ncrna10010012] [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: 12/19/2023] [Revised: 02/02/2024] [Accepted: 02/04/2024] [Indexed: 02/25/2024] Open
Abstract
Extracellular vesicles (EVs) are defined as subcellular structures limited by a bilayer lipid membrane that function as important intercellular communication by transporting active biomolecules, such as proteins, amino acids, metabolites, and nucleic acids, including long non-coding RNAs (lncRNAs). These cargos can effectively be delivered to target cells and induce a highly variable response. LncRNAs are functional RNAs composed of at least 200 nucleotides that do not code for proteins. Nowadays, lncRNAs and circRNAs are known to play crucial roles in many biological processes, including a plethora of diseases including cancer. Growing evidence shows an active presence of lnc- and circRNAs in EVs, generating downstream responses that ultimately affect cancer progression by many mechanisms, including angiogenesis. Moreover, many studies have revealed that some tumor cells promote angiogenesis by secreting EVs, which endothelial cells can take up to induce new vessel formation. In this review, we aim to summarize the bioactive roles of EVs with lnc- and circRNAs as cargo and their effect on cancer angiogenesis. Also, we discuss future clinical strategies for cancer treatment based on current knowledge of circ- and lncRNA-EVs.
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Affiliation(s)
- José A. Peña-Flores
- Doctoral Program in Biomedical and Stomatological Sciences, Faculty of Dentistry, Autonomous University of Chihuahua, Chihuahua 31000, Mexico; (D.M.-C.); (R.G.-M.); (D.E.-E.); (K.G.-A.)
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46
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Hartupee C, Nagalo BM, Chabu CY, Tesfay MZ, Coleman-Barnett J, West JT, Moaven O. Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target. Front Immunol 2024; 15:1287459. [PMID: 38361931 PMCID: PMC10867137 DOI: 10.3389/fimmu.2024.1287459] [Citation(s) in RCA: 26] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 01/04/2024] [Indexed: 02/17/2024] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is projected to become the 2nd leading cause of cancer-related deaths in the United States. Limitations in early detection and treatment barriers contribute to the lack of substantial success in the treatment of this challenging-to-treat malignancy. Desmoplasia is the hallmark of PDAC microenvironment that creates a physical and immunologic barrier. Stromal support cells and immunomodulatory cells face aberrant signaling by pancreatic cancer cells that shifts the complex balance of proper repair mechanisms into a state of dysregulation. The product of this dysregulation is the desmoplastic environment that encases the malignant cells leading to a dense, hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance, and suppresses anti-tumor immune invasion. This desmoplastic environment combined with the immunoregulatory events that allow it to persist serve as the primary focus of this review. The physical barrier and immune counterbalance in the tumor microenvironment (TME) make PDAC an immunologically cold tumor. To convert PDAC into an immunologically hot tumor, tumor microenvironment could be considered alongside the tumor cells. We discuss the complex network of microenvironment molecular and cellular composition and explore how they can be targeted to overcome immuno-therapeutic challenges.
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Affiliation(s)
- Conner Hartupee
- Division of Surgical Oncology, Department of Surgery, Louisiana State University (LSU) Health, New Orleans, LA, United States
| | - Bolni Marius Nagalo
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
- The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Chiswili Y. Chabu
- Division of Biological Sciences, University of Missouri, Columbia, MO, United States
- Department of Surgery, School of Medicine, University of Missouri, Columbia, MO, United States
- Siteman Cancer Center, Washington University, St. Louis, MO, United States
| | - Mulu Z. Tesfay
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Joycelynn Coleman-Barnett
- Division of Surgical Oncology, Department of Surgery, Louisiana State University (LSU) Health, New Orleans, LA, United States
- Department of Interdisciplinary Oncology, Louisiana Cancer Research Center, Louisiana State University (LSU) Health, New Orleans, LA, United States
| | - John T. West
- Department of Interdisciplinary Oncology, Louisiana Cancer Research Center, Louisiana State University (LSU) Health, New Orleans, LA, United States
| | - Omeed Moaven
- Division of Surgical Oncology, Department of Surgery, Louisiana State University (LSU) Health, New Orleans, LA, United States
- Department of Interdisciplinary Oncology, Louisiana Cancer Research Center, Louisiana State University (LSU) Health, New Orleans, LA, United States
- Louisiana State University - Louisiana Children's Medical Center (LSU - LCMC) Cancer Center, New Orleans, LA, United States
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Zheng R, Wang S, Wang J, Zhou M, Shi Q, Liu B. Neuromedin U regulates the anti-tumor activity of CD8 + T cells and glycolysis of tumor cells in the tumor microenvironment of pancreatic ductal adenocarcinoma in an NMUR1-dependent manner. Cancer Sci 2024; 115:334-346. [PMID: 38071753 PMCID: PMC10859610 DOI: 10.1111/cas.16024] [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: 06/03/2023] [Revised: 11/01/2023] [Accepted: 11/07/2023] [Indexed: 02/13/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis, which is lethal in approximately 90% of cases despite advanced standard therapies. A typical feature of PDAC is the immunosuppressive tumor microenvironment with multiple immunosuppressive factors including neurotransmitters. Recently, neuromedin U (NMU), a highly conserved neuropeptide with many physiological functions, has attracted attention for its roles in tumorigenesis and metastasis in several types of cancers. However, whether NMU affects PDAC progression remains unclear. In this study, using an orthotopic mouse model of PDAC in combination with bioinformatics analysis, we found that NMU was upregulated in tumor tissues from the patients with PDAC and positively correlated with a poor prognosis of the disease. Interestingly, knockout of the Nmu gene in mice enhanced the anti-tumor functions of tumor-infiltrating CD8+ T cells in an NMU receptor 1-dependent manner. Additionally, NMU promoted the glycolytic metabolism of mouse PDAC tumors. The activities of pyruvate kinase (PK) and lactate dehydrogenase (LDH), pivotal enzymes involved in the regulation of lactate production, were markedly reduced in tumor tissues from NMU-knockout mice. In vitro the presence of LDHA inhibitor can reduce the production of lactic acid stimulated by NMU, which can increase the anti-tumor activity of CD8+ T cells. Moreover, treatment of the pancreatic cancer cells with a phosphoinositide 3-kinase (PI3K) inhibitor diminished NMU-induced lactate production and the activities of PK and LDH, suggesting that NMU might regulate glycolysis via the PI3K/AKT pathway.
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Affiliation(s)
- Rui Zheng
- Department of Pathogenic Microbiology, School of Basic Medical ScienceChina Medical UniversityShenyangChina
- Department of Physiology, School of Basic Medical ScienceShenyang Medical CollegeShenyangChina
| | - Si Wang
- Department of Pathogenic Microbiology, School of Basic Medical ScienceChina Medical UniversityShenyangChina
| | - Jia Wang
- Department of Pathogenic Microbiology, School of Basic Medical ScienceChina Medical UniversityShenyangChina
| | - Mengnan Zhou
- Department of Pathogenic Microbiology, School of Basic Medical ScienceChina Medical UniversityShenyangChina
| | - Qi Shi
- Department of Pathogenic Microbiology, School of Basic Medical ScienceChina Medical UniversityShenyangChina
| | - Beixing Liu
- Department of Pathogenic Microbiology, School of Basic Medical ScienceChina Medical UniversityShenyangChina
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Fan M, Deng G, Ma Y, Si H, Wang Z, Dai G. Survival outcome of different treatment sequences in patients with locally advanced and metastatic pancreatic cancer. BMC Cancer 2024; 24:67. [PMID: 38216928 PMCID: PMC10785544 DOI: 10.1186/s12885-024-11823-8] [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: 01/04/2023] [Accepted: 01/02/2024] [Indexed: 01/14/2024] Open
Abstract
BACKGROUND Despite some therapeutic advances, improvement in survival rates of unresectable and/or metastatic pancreatic ductal adenocarcinoma (PDAC) has been minimal over recent decade. We aimed to evaluate the impact of different treatment sequences on clinical outcomes of advanced PDAC at our academic institution. METHODS In this single institution retrospective analysis, we assessed characteristics and survival rates of unresectable and/or metastatic pancreatic PDAC patients who started a systemic treatment between 01/2015 and 12/2021. Survival analyses were performed by Kaplan-Meier and Cox proportional hazards model. RESULTS The number of 285 patients received at least two lines of treatment, but only 137 patients were suitable for third-line treatment. Subgroup analysis showed that thirty-seven patients received A line (gemcitabine/nab-paclitaxel or nab-paclitaxel combined therapy to FOLFIRINOX) therapy, 37 patients received B line (nab-paclitaxel combined therapy to gemcitabine combined therapy to FOLFIRINOX) therapy, 21 patients received C line (nab-paclitaxel combined therapy to gemcitabine combined therapy to oxaliplatin or irinotecan combined therapy) therapy. Survival rates for different treatment lines were significantly different and median overall survival (OS) was 14.00, 18.00, and 14.00 months, respectively (p<0.05). CONCLUSION Our study provides real-world evidence for the effectiveness of different treatment sequences and underscores the treatment sequences on survival outcome when considering the entire management in advanced PDAC.
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Affiliation(s)
- Mengjiao Fan
- Medical School of Chinese People's Liberation Army, Beijing, China
- Department of oncology, The Fifth Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China
- Department of oncology, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Guochao Deng
- Department of oncology, The Fifth Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Yue Ma
- Medical School of Chinese People's Liberation Army, Beijing, China
- Department of oncology, The Fifth Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Haiyan Si
- Department of oncology, The Fifth Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Zhikuan Wang
- Department of oncology, The Fifth Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.
| | - Guanghai Dai
- Department of oncology, The Fifth Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.
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Yang Z, Li H, Hao J, Mei H, Qiu M, Wang H, Gao M. EPYC functions as a novel prognostic biomarker for pancreatic cancer. Sci Rep 2024; 14:719. [PMID: 38184732 PMCID: PMC10771449 DOI: 10.1038/s41598-024-51478-w] [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: 10/30/2023] [Accepted: 01/05/2024] [Indexed: 01/08/2024] Open
Abstract
Pancreatic cancer (PC) has become a worldwide challenge attributed to its difficult early diagnosis and rapid progression. Treatments continue to be limited besides surgical resection. Hence, we aimed to discover novel biological signatures as clinically effective therapeutic targets for PC via the mining of public tumor databases. We found that epiphycan (EPYC) could function as an independent risk factor to predict the poor prognosis in PC based on integrated bioinformatics analysis. We downloaded associated PC data profiles from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) online websites, then applied the software Rstudio to filter out genes under the strict criteria. After the batch survival analysis using Log-rank test and univariate cox regression, we obtained 39 candidate genes. Subsequently, we narrowed the scope to 8 genes by establishing a Lasso regression model. Eventually, we focused on 2 genes (EPYC and MET) by further building a multivariate cox regression model. Given that the role of EPYC in PC remains obscure, we then performed a series of molecular functional experiments, including RT-qPCR, CCK8, EdU, colony formation, Transwell, western blot, cell live-dead staining, subcutaneous tumor formation, to enhance our insight into its underlying molecular mechanisms. The above results demonstrated that EPYC was highly expressed in PC cell lines and could promote the proliferation of PCs via PI3K-AKT signaling pathway in vivo and in vitro. We arrived at a conclusion that EPYC was expected to be a biological neo-biomarker for PC followed by being a potential therapeutic target.
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Affiliation(s)
- Zhen Yang
- Department of Clinical Laboratory, Tianjin Union Medical Center of Nankai University, Tianjin, China.
- The Institute of Translational Medicine, Tianjin Union Medical Center of Nankai University, Tianjin, China.
| | - Honglin Li
- Department of Clinical Laboratory, Dachuan District People's Hospital, Sichuan, China
| | - Jie Hao
- Department of Thyroid and Breast Surgery, Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center of Nankai University, Tianjin, China
| | - Hanwei Mei
- The Institute of Translational Medicine, Tianjin Union Medical Center of Nankai University, Tianjin, China
- Department of Oncology, Tianjin Union Medical Center of Nankai University, Tianjin, China
| | - Minghan Qiu
- The Institute of Translational Medicine, Tianjin Union Medical Center of Nankai University, Tianjin, China
- Department of Oncology, Tianjin Union Medical Center of Nankai University, Tianjin, China
| | - Huaqing Wang
- The Institute of Translational Medicine, Tianjin Union Medical Center of Nankai University, Tianjin, China.
- Department of Oncology, Tianjin Union Medical Center of Nankai University, Tianjin, China.
| | - Ming Gao
- Department of Thyroid and Breast Surgery, Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center of Nankai University, Tianjin, China.
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Maduabuchi WO, Tansi FL, Faenger B, Southern P, Pankhurst QA, Steiniger F, Westermann M, Hilger I. Local Magnetic Hyperthermia and Systemic Gemcitabine/Paclitaxel Chemotherapy Triggers Neo-Angiogenesis in Orthotopic Pancreatic Tumors without Involvement of Auto/Paracrine Tumor Cell VEGF Signaling and Hypoxia. Cancers (Basel) 2023; 16:33. [PMID: 38201461 PMCID: PMC10778317 DOI: 10.3390/cancers16010033] [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: 09/12/2023] [Revised: 10/20/2023] [Accepted: 12/12/2023] [Indexed: 01/12/2024] Open
Abstract
There is a growing interest in exploring the therapeutically mediated modulation of tumor vascularization of pancreatic cancer, which is known for its poorly perfused tumor microenvironment limiting the delivery of therapeutic agents to the tumor site. Here, we assessed how magnetic hyperthermia in combination with chemotherapy selectively affects growth, the vascular compartment of tumors, and the presence of tumor cells expressing key regulators of angiogenesis. To that purpose, a orthotopic PANC-1 (fluorescent human pancreatic adenocarcinoma) mouse tumor model (Rj:Athym-Foxn1nu/nu) was used. Magnetic hyperthermia was applied alone or in combination with systemic chemotherapy (gemcitabine 50 mg per kg body weight, nab-pacitaxel 30 mg/kg body weight) on days 1 and 7 following magnetic nanoparticle application (dose: 1 mg per 100 mm3 of tumor). We used ultrasound imaging, immunohistochemistry, multi-spectral optoacoustic tomography (MSOT), and hematology to assess the biological parameters mentioned above. We found that magnetic hyperthermia in combination with gemcitabine/paclitaxel chemotherapy was able to impact tumor growth (decreased volumes and Ki67 expression) and to trigger neo-angiogenesis (increased small vessel diameter) as a result of the therapeutically mediated cell damages/stress in tumors. The applied stressors activated specific pro-angiogenic mechanisms, which differed from those seen in hypoxic conditions involving HIF-1α, since (a) treated tumors showed a significant decrease of cells expressing VEGF, CD31, HIF-1α, and neuropilin-1; and (b) the relative tumor blood volume and oxygen level remained unchanged. Neo-angiogenesis seems to be the result of the activation of cell stress pathways, like MAPK pathways (high number of pERK-expressing tumor cells). In the long term, the combination of magnetic hyperthermia and chemotherapy could potentially be applied to transiently modulate tumor angiogenesis and to improve drug accessibility during oncologic therapies of pancreatic cancer.
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Affiliation(s)
- Wisdom O. Maduabuchi
- Department of Experimental Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany (F.L.T.); (B.F.)
| | - Felista L. Tansi
- Department of Experimental Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany (F.L.T.); (B.F.)
| | - Bernd Faenger
- Department of Experimental Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany (F.L.T.); (B.F.)
| | - Paul Southern
- Resonant Circuits Limited, 21 Albemarle Street, London W1S 4BS, UK; (P.S.); (Q.A.P.)
- Healthcare Biomagnetics Laboratory, University College London, 21 Albemarle St., London W1S 4BS, UK
| | - Quentin A. Pankhurst
- Resonant Circuits Limited, 21 Albemarle Street, London W1S 4BS, UK; (P.S.); (Q.A.P.)
- Healthcare Biomagnetics Laboratory, University College London, 21 Albemarle St., London W1S 4BS, UK
| | - Frank Steiniger
- Center for Electron Microscopy, Jena University Hospital, Friedrich Schiller University Jena, Ziegelmuehlenweg 1, 07743 Jena, Germany; (F.S.); (M.W.)
| | - Martin Westermann
- Center for Electron Microscopy, Jena University Hospital, Friedrich Schiller University Jena, Ziegelmuehlenweg 1, 07743 Jena, Germany; (F.S.); (M.W.)
| | - Ingrid Hilger
- Department of Experimental Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany (F.L.T.); (B.F.)
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