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Wan LH, Mao BJ, Wang B. Relationship between skeletal muscle mass and prognosis in patients with liver cancer receiving targeted therapy: A meta-analysis. World J Clin Oncol 2025; 16:102611. [DOI: 10.5306/wjco.v16.i5.102611] [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: 10/23/2024] [Revised: 02/01/2025] [Accepted: 04/01/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Many studies have found that sarcopenia is related to the survival of patients with liver cancer, which may lead to worse prognosis.
AIM To investigate the relationship between skeletal muscle mass and prognosis in patients with liver cancer receiving targeted therapy by meta-analysis.
METHODS PubMed, Embase, Cochrane Library, and Web of Science were searched for clinical studies on the relationship between skeletal muscle index (SMI) and the prognosis of patients with liver cancer receiving targeted therapy from inception to March 1, 2022. Meta-analysis and sensitivity analysis of the data were performed using Stata 16.0 software.
RESULTS A total of 6877 studies were searched, and finally 12 articles with 1715 cases were included. Meta-analysis result of 8 articles showed that compared with non-low SMI group, the overall survival (OS) of patients with liver cancer in the low SMI group was significantly shorter (hazard ratio = 1.60, 95% confidence interval: 1.44-1.77, P = 0.000). Meta-analysis result of 4 articles showed that, compared with low SMI group, patients in the non-low SMI group had longer OS (hazard ratio = 0.59, 95% confidence interval: 0.38-0.91, P = 0.018).
CONCLUSION Skeletal muscle mass is positively correlated with OS in patients with liver cancer receiving targeted therapy.
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Affiliation(s)
- Ling-Hong Wan
- Department of Gastroenterology, Daping Hospital, Army Medical University, Third Military Medical University, Chongqing 400042, China
| | - Bi-Jing Mao
- Department of Oncology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Bin Wang
- Department of Oncology, The Seventh People’s Hospital of Chongqing, Affiliated Central Hospital of Chongqing University of Technology, Chongqing 400054, China
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Cui H, Li Z, Liu Y, Yang Y, Huangfu L, Kong J, Sun X, Gao S, Yang D, Zheng Y. Integrated analysis of single-cell RNA-seq and bulk RNA-seq unravels the molecular feature of tumor-associated neutrophils of head and neck squamous cell carcinoma. BMC Cancer 2025; 25:821. [PMID: 40312694 PMCID: PMC12046871 DOI: 10.1186/s12885-025-14179-9] [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: 11/12/2024] [Accepted: 04/17/2025] [Indexed: 05/03/2025] Open
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is a lethal malignancy with a high recurrence and distant metastasis rate, posing significant challenges to patient prognosis. Recent studies suggest that tumor-associated neutrophils (TANs) can modulate immune cell infiltration and influence tumor initiation and progression. However, the potential clinical significance of TANs in HNSCC remains insufficiently explored. METHODS TANs-specific marker genes were identified via single-cell sequencing data from HNSCC. Based on data from The Cancer Genome Atlas (TCGA), a prognostic risk model was constructed using TANs cell marker genes, and the model was validated with data from the Gene Expression Omnibus (GEO) database. The associations between the TANs signature and clinical characteristics, functional pathways, immune cell infiltration, immune checkpoint expression, and responses to immunotherapy and chemotherapy, were then investigated. Cell counting kit-8(CCK-8), Transwell, and wound healing assays were conducted to assess the functional role of TANs marker molecules. RESULTS TANs characteristic genes were identified from single-cell sequencing data from HNSCC patients. On the basis of these characteristic genes, a tumor-associated neutrophils-associated signature (NRS) was developed and validated across internal and external cross-platform cohorts through comprehensive procedures. The NRS demonstrated robust and reliable performance in predicting overall survival. Additionally, patients with a low NRS showed enhanced immune cell infiltration, active lipid metabolism, and increased sensitivity to immunotherapy. In contrast, patients with a high NRS exhibited poor prognostic outcomes, advanced clinical stages, and significant associations with HNSCC metastasis and progression. Furthermore, we identified a TANs-associated biomarker, OLR1, and validated that OLR1 promotes HNSCC proliferation, invasion, and migration through CCK-8, Transwell invasion, and wound healing assays. CONCLUSION This study has developed a promising TANs-based tool that may aid in personalized treatment and prognostic management for patients with HNSCC.
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Affiliation(s)
- Haiyang Cui
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Zhikai Li
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yukun Liu
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yuchuan Yang
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Linkuan Huangfu
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Jinglin Kong
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xiaocong Sun
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Shibo Gao
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Daoke Yang
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Yingjuan Zheng
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
- Department of Hyperthermia and Photodynamic Therapy, the First Affiliated Hospital of Zhengzhou University, Henan Province, Zhengzhou, People's Republic of China.
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Lin GS, Zheng RQ, Xu ZW, Xing SP, Wu HF, Xie Y, Huang H, Liu YQ. Proteomic screening identifies brusatol targets TGFβRII to suppresses non-small cell lung cancer metastasis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 139:156468. [PMID: 39978271 DOI: 10.1016/j.phymed.2025.156468] [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: 09/14/2024] [Revised: 01/25/2025] [Accepted: 02/03/2025] [Indexed: 02/22/2025]
Abstract
BACKGROUND Metastasis remains the leading cause of cancer mortality. The natural product brusatol (Bru) has exhibited promising anticancer activity; however, the target proteins of Bru and the underlying mechanisms in suppressing tumor metastasis remain unclear. PURPOSE We aim to identify the target of Bru and examine its role in suppressing tumor metastasis. METHODS The human proteome microarrays and biotin-labelled Bru were employed to identify the direct targets of Bru. To evaluate the anti-migration properties of Bru, TGF-β1 overexpressing NSCLC cells were constructed, wound-healing and transwell assays were performed. The anti-metastatic effects of Bru were assessed using A549-luciferase cell orthotopic xenografts. RESULTS We identified that Bru has a high binding affinity for the TGF-β receptor type-II (TGFβRII) protein by probing biotin-labelled Bru on human proteome microarrays. Bru can directly interact with TGFβRII and then effectively suppress recombinant TGF-β1- or TGF-β1 overexpression-induced phosphorylation of Smad2 and Smad3, leading to reduced expression of epithelial-mesenchymal transition (EMT)-associated proteins and the suppression of NSCLC cell migration and invasion. Furthermore, Bru suppressed TGF-β signaling and exerted anti-metastatic activity in the orthotopic xenografts using A549-luciferase cells overexpressing TGF-β1. CONCLUSION Our findings identified that Bru functions as a novel TGFβRII inhibitor, leading to the abrogation of TGF-β signaling activation and the suppression of NSCLC metastasis.
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MESH Headings
- Humans
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/metabolism
- Lung Neoplasms/drug therapy
- Lung Neoplasms/pathology
- Lung Neoplasms/metabolism
- Receptor, Transforming Growth Factor-beta Type II/metabolism
- Animals
- Proteomics
- A549 Cells
- Epithelial-Mesenchymal Transition/drug effects
- Quassins/pharmacology
- Transforming Growth Factor beta1/metabolism
- Cell Movement/drug effects
- Mice
- Cell Line, Tumor
- Mice, Nude
- Smad2 Protein/metabolism
- Neoplasm Metastasis
- Xenograft Model Antitumor Assays
- Smad3 Protein/metabolism
- Phosphorylation/drug effects
- Receptors, Transforming Growth Factor beta/metabolism
- Receptors, Transforming Growth Factor beta/antagonists & inhibitors
- Mice, Inbred BALB C
- Antineoplastic Agents, Phytogenic/pharmacology
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Affiliation(s)
- Guo-Sheng Lin
- Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China
| | - Rou-Qiao Zheng
- Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China
| | - Zi-Wei Xu
- Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China
| | - Shang-Ping Xing
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, China
| | - Hui-Fei Wu
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan 528400, China
| | - Youliang Xie
- Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
| | - Huicai Huang
- Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China.
| | - Yong-Qiang Liu
- Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China.
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Li S, Yan L, Li C, Lou L, Cui F, Yang X, He F, Jiang Y. NPC1 controls TGFBR1 stability in a cholesterol transport-independent manner and promotes hepatocellular carcinoma progression. Nat Commun 2025; 16:439. [PMID: 39762312 PMCID: PMC11704005 DOI: 10.1038/s41467-024-55788-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 12/27/2024] [Indexed: 01/11/2025] Open
Abstract
Niemann-Pick disease type C protein 1 (NPC1), classically associated with cholesterol transport and viral entry, has an emerging role in cancer biology. Here, we demonstrate that knockout of Npc1 in hepatocytes attenuates hepatocellular carcinoma (HCC) progression in both DEN (diethylnitrosamine)-CCl4 induced and MYC-driven HCC mouse models. Mechanistically, NPC1 significantly promotes HCC progression by modulating the TGF-β pathway, independent of its traditional role in cholesterol transport. We identify that the 692-854 amino acid region of NPC1's transmembrane domain is critical for its interaction with TGF-β receptor type-1 (TGFBR1). This interaction prevents the binding of SMAD7 and SMAD ubiquitylation regulatory factors (SMURFs) to TGFBR1, reducing TGFBR1 ubiquitylation and degradation, thus enhancing its stability. Notably, the NPC1 (P691S) mutant, which is defective in cholesterol transport, still binds TGFBR1, underscoring a cholesterol-independent mechanism. These findings highlight a cholesterol transport-independent mechanism by which NPC1 contributes to the stability of TGFBR1 in HCC and suggest potential therapeutic strategies targeting NPC1 for HCC treatment.
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Affiliation(s)
- Shuangyan Li
- School of Life Sciences, Tsinghua University, Beijing, China
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Lishan Yan
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Chaoying Li
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Lijuan Lou
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Fengjiao Cui
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xiao Yang
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Fuchu He
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China.
- Research Unit of Proteomics Dirven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing, China.
- Anhui Medical University, Hefei, China.
| | - Ying Jiang
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China.
- Anhui Medical University, Hefei, China.
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5
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Lv K, He T. Cancer-associated fibroblasts: heterogeneity, tumorigenicity and therapeutic targets. MOLECULAR BIOMEDICINE 2024; 5:70. [PMID: 39680287 PMCID: PMC11649616 DOI: 10.1186/s43556-024-00233-8] [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: 07/24/2024] [Revised: 11/04/2024] [Accepted: 11/19/2024] [Indexed: 12/17/2024] Open
Abstract
Cancer, characterized by its immune evasion, active metabolism, and heightened proliferation, comprises both stroma and cells. Although the research has always focused on parenchymal cells, the non-parenchymal components must not be overlooked. Targeting cancer parenchymal cells has proven to be a formidable challenge, yielding limited success on a broad scale. The tumor microenvironment(TME), a critical niche for cancer cell survival, presents a novel way for cancer treatment. Cancer-associated fibroblast (CAF), as a main component of TME, is a dynamically evolving, dual-functioning stromal cell. Furthermore, their biological activities span the entire spectrum of tumor development, metastasis, drug resistance, and prognosis. A thorough understanding of CAFs functions and therapeutic advances holds significant clinical implications. In this review, we underscore the heterogeneity of CAFs by elaborating on their origins, types and function. Most importantly, by elucidating the direct or indirect crosstalk between CAFs and immune cells, the extracellular matrix, and cancer cells, we emphasize the tumorigenicity of CAFs in cancer. Finally, we highlight the challenges encountered in the exploration of CAFs and list targeted therapies for CAF, which have implications for clinical treatment.
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Affiliation(s)
- Keke Lv
- Department of Hepatopanreatobiliary Surgery, Changhai Hospital, 168 Changhai Road, Yangpu District, Shanghai, 200433, China
| | - Tianlin He
- Department of Hepatopanreatobiliary Surgery, Changhai Hospital, 168 Changhai Road, Yangpu District, Shanghai, 200433, China.
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6
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Zelisko N, Lesyk R, Stoika R. Structure, unique biological properties, and mechanisms of action of transforming growth factor β. Bioorg Chem 2024; 150:107611. [PMID: 38964148 DOI: 10.1016/j.bioorg.2024.107611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 06/07/2024] [Accepted: 06/30/2024] [Indexed: 07/06/2024]
Abstract
Transforming growth factor β (TGF-β) is a ubiquitous molecule that is extremely conserved structurally and plays a systemic role in human organism. TGF-β is a homodimeric molecule consisting of two subunits joined through a disulphide bond. In mammals, three genes code for TGF-β1, TGF-β2, and TGF-β3 isoforms of this cytokine with a dominating expression of TGF-β1. Virtually, all normal cells contain TGF-β and its specific receptors. Considering the exceptional role of fine balance played by the TGF-β in anumber of physiological and pathological processes in human body, this cytokine may be proposed for use in medicine as an immunosuppressant in transplantology, wound healing and bone repair. TGFb itself is an important target in oncology. Strategies for blocking members of TGF-β signaling pathway as therapeutic targets have been considered. In this review, signalling mechanisms of TGF-β1 action are addressed, and their role in physiology and pathology with main focus on carcinogenesis are described.
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Affiliation(s)
- Nataliya Zelisko
- Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, 79010 Lviv, Ukraine
| | - Roman Lesyk
- Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, 79010 Lviv, Ukraine.
| | - Rostyslav Stoika
- Department of Regulation of Cell Proliferation and Apoptosis, Institute of Cell Biology of National Academy of Sciences of Ukraine, Drahomanov 14/16, 79005 Lviv, Ukraine
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7
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de Haan LR, van Golen RF, Heger M. Molecular Pathways Governing the Termination of Liver Regeneration. Pharmacol Rev 2024; 76:500-558. [PMID: 38697856 DOI: 10.1124/pharmrev.123.000955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/24/2024] [Accepted: 02/08/2024] [Indexed: 05/05/2024] Open
Abstract
The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.
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Affiliation(s)
- Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Rowan F van Golen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
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8
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Gao X, Zuo S. Immune landscape and immunotherapy of hepatocellular carcinoma: focus on innate and adaptive immune cells. Clin Exp Med 2023; 23:1881-1899. [PMID: 36773210 PMCID: PMC10543580 DOI: 10.1007/s10238-023-01015-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 01/27/2023] [Indexed: 02/12/2023]
Abstract
Hepatocellular carcinoma (HCC) is responsible for roughly 90% of all cases of primary liver cancer, and the cases are on the rise. The treatment of advanced HCC is a serious challenge. Immune checkpoint inhibitor (ICI) therapy has marked a watershed moment in the history of HCC systemic treatment. Atezolizumab in combination with bevacizumab has been approved as a first-line treatment for advanced HCC since 2020; however, the combination therapy is only effective in a limited percentage of patients. Considering that the tumor immune microenvironment (TIME) has a great impact on immunotherapies for HCC, an in-depth understanding of the immune landscape in tumors and the current immunotherapeutic approaches is extremely necessary. We elaborate on the features, functions, and cross talk of the innate and adaptive immune cells in HCC and highlight the benefits and drawbacks of various immunotherapies for advanced HCC, as well as future projections. HCC consists of a heterogeneous group of cancers with distinct etiologies and immune microenvironments. Almost all the components of innate and adaptive immune cells in HCC have altered, showing a decreasing trend in the number of tumor suppressor cells and an increasing trend in the pro-cancer cells, and there is also cross talk between various cell types. Various immunotherapies for HCC have also shown promising efficacy and application prospect. There are multilayered interwoven webs among various immune cell types in HCC, and emerging evidence demonstrates the promising prospect of immunotherapeutic approaches for HCC.
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Affiliation(s)
- Xiaoqiang Gao
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, No. 28, Guiyi Street, Guiyang, 550000, Guizhou, China
- Guizhou Medical University, Guiyang, Guizhou, China
| | - Shi Zuo
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, No. 28, Guiyi Street, Guiyang, 550000, Guizhou, China.
- Guizhou Medical University, Guiyang, Guizhou, China.
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9
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Nixon BG, Gao S, Wang X, Li MO. TGFβ control of immune responses in cancer: a holistic immuno-oncology perspective. Nat Rev Immunol 2023; 23:346-362. [PMID: 36380023 PMCID: PMC10634249 DOI: 10.1038/s41577-022-00796-z] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/10/2022] [Indexed: 11/16/2022]
Abstract
The immune system responds to cancer in two main ways. First, there are prewired responses involving myeloid cells, innate lymphocytes and innate-like adaptive lymphocytes that either reside in premalignant tissues or migrate directly to tumours, and second, there are antigen priming-dependent responses, in which adaptive lymphocytes are primed in secondary lymphoid organs before homing to tumours. Transforming growth factor-β (TGFβ) - one of the most potent and pleiotropic regulatory cytokines - controls almost every stage of the tumour-elicited immune response, from leukocyte development in primary lymphoid organs to their priming in secondary lymphoid organs and their effector functions in the tumour itself. The complexity of TGFβ-regulated immune cell circuitries, as well as the contextual roles of TGFβ signalling in cancer cells and tumour stromal cells, necessitates the use of rigorous experimental systems that closely recapitulate human cancer, such as autochthonous tumour models, to uncover the underlying immunobiology. The diverse functions of TGFβ in healthy tissues further complicate the search for effective and safe cancer therapeutics targeting the TGFβ pathway. Here we discuss the contextual complexity of TGFβ signalling in tumour-elicited immune responses and explain how understanding this may guide the development of mechanism-based cancer immunotherapy.
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Affiliation(s)
- Briana G Nixon
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Immunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School of Biomedical Sciences, Cornell University, New York, NY, USA
| | - Shengyu Gao
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Xinxin Wang
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Immunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School of Biomedical Sciences, Cornell University, New York, NY, USA
| | - Ming O Li
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Immunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School of Biomedical Sciences, Cornell University, New York, NY, USA.
- Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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10
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Goenka A, Khan F, Verma B, Sinha P, Dmello CC, Jogalekar MP, Gangadaran P, Ahn B. Tumor microenvironment signaling and therapeutics in cancer progression. Cancer Commun (Lond) 2023; 43:525-561. [PMID: 37005490 PMCID: PMC10174093 DOI: 10.1002/cac2.12416] [Citation(s) in RCA: 109] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 02/22/2023] [Accepted: 03/20/2023] [Indexed: 04/04/2023] Open
Abstract
Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME, the immune checkpoints and immunosuppressive chemokines, and currently used inhibitors targeting these pathways. These include both intrinsic and non-autonomous tumor cell signaling pathways in the TME: protein kinase C (PKC) signaling, Notch, and transforming growth factor (TGF-β) signaling, Endoplasmic Reticulum (ER) stress response, lactate signaling, Metabolic reprogramming, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and Siglec signaling pathways. We also discuss the recent advances in Programmed Cell Death Protein 1 (PD-1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), T-cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte Activating Gene 3 (LAG3) immune checkpoint inhibitors along with the C-C chemokine receptor 4 (CCR4)- C-C class chemokines 22 (CCL22)/ and 17 (CCL17), C-C chemokine receptor type 2 (CCR2)- chemokine (C-C motif) ligand 2 (CCL2), C-C chemokine receptor type 5 (CCR5)- chemokine (C-C motif) ligand 3 (CCL3) chemokine signaling axis in the TME. In addition, this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME, which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer therapies. We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response. Overall, this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME, highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology. We highlight the importance of the most recent technologies of microfluidics and lab-on-chip models for TME research and also present an overview of extrinsic factors, such as the inhabitant human microbiome, which have the potential to modulate TME biology and drug responses.
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Affiliation(s)
- Anshika Goenka
- The Ken & Ruth Davee Department of NeurologyThe Robert H. Lurie Comprehensive Cancer CenterNorthwestern University Feinberg School of MedicineChicago, 60611ILUSA
| | - Fatima Khan
- Department of Neurological SurgeryFeinberg School of MedicineNorthwestern UniversityChicago, 60611ILUSA
| | - Bhupender Verma
- Department of OphthalmologySchepens Eye Research InstituteMassachusetts Eye and Ear InfirmaryHarvard Medical SchoolBoston, 02114MAUSA
| | - Priyanka Sinha
- Department of NeurologyMassGeneral Institute for Neurodegenerative DiseaseMassachusetts General Hospital, Harvard Medical SchoolCharlestown, 02129MAUSA
| | - Crismita C. Dmello
- Department of Neurological SurgeryFeinberg School of MedicineNorthwestern UniversityChicago, 60611ILUSA
| | - Manasi P. Jogalekar
- Helen Diller Family Comprehensive Cancer CenterUniversity of California San FranciscoSan Francisco, 94143CAUSA
| | - Prakash Gangadaran
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future TalentsDepartment of Biomedical Science, School of MedicineKyungpook National UniversityDaegu, 41944South Korea
- Department of Nuclear MedicineSchool of Medicine, Kyungpook National University, Kyungpook National University HospitalDaegu, 41944South Korea
| | - Byeong‐Cheol Ahn
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future TalentsDepartment of Biomedical Science, School of MedicineKyungpook National UniversityDaegu, 41944South Korea
- Department of Nuclear MedicineSchool of Medicine, Kyungpook National University, Kyungpook National University HospitalDaegu, 41944South Korea
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11
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Acitelli E, Maiorca C, Grani G, Maranghi M. Metabolic adverse events of multitarget kinase inhibitors: a systematic review. Endocrine 2023:10.1007/s12020-023-03362-2. [PMID: 37067769 PMCID: PMC10239378 DOI: 10.1007/s12020-023-03362-2] [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: 03/05/2023] [Accepted: 03/31/2023] [Indexed: 04/18/2023]
Abstract
PURPOSE Multitargeted kinase inhibitors (MKIs) are used for the treatment of several cancers. By targeting multiple signaling pathways, MKIs have become cornerstones of the oncologic treatment. Although their use leads to important results in terms of survival, treatment with MKIs can determine important side effects the clinician must be aware of. Among those, arterial hypertension, mucositis and skin lesions are universally reported, while data about metabolic alterations are scarce. In our review, we focused on glucose and lipid alterations in MKI-treated patients. METHODS We searched for articles, published between January 2012 and December 2022, evaluating the effects on lipid and glucose metabolism of four MKIs (Cabozantinib, Lenvatinib, Sorafenib, and Vandetanib) in adult patients with cancer. We focused on drugs approved for thyroid malignancies, since a worse metabolic control may potentially impact life expectancy, due to their better overall survival rate. RESULTS As for glucose metabolism, the majority of the studies reported elevation of glucose levels (prevalence: 1-17%) with different grades of severity, including death. As for cholesterol, 12 studies reported worsening or new-onset hypercholesterolemia (prevalence: 4-40%). Finally, 19 studies reported different grades of hypertriglyceridemia (prevalence: 1-86%), sometimes leading to life-threatening events. CONCLUSIONS Despite some inherent limitations, our analysis may cast light upon some of the MKIs metabolic disorders that can impact on patients' health, especially when long-term survival is expected. Future clinical trials should consider routine assessment of glucose and lipid levels, because underdetection and underreporting of alterations can lead to the overlooking of important adverse events.
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Affiliation(s)
- Elisa Acitelli
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Carlo Maiorca
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Giorgio Grani
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
| | - Marianna Maranghi
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
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12
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Sounbuli K, Mironova N, Alekseeva L. Diverse Neutrophil Functions in Cancer and Promising Neutrophil-Based Cancer Therapies. Int J Mol Sci 2022; 23:ijms232415827. [PMID: 36555469 PMCID: PMC9779721 DOI: 10.3390/ijms232415827] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/09/2022] [Accepted: 12/11/2022] [Indexed: 12/15/2022] Open
Abstract
Neutrophils represent the most abundant cell type of leukocytes in the human blood and have been considered a vital player in the innate immune system and the first line of defense against invading pathogens. Recently, several studies showed that neutrophils play an active role in the immune response during cancer development. They exhibited both pro-oncogenic and anti-tumor activities under the influence of various mediators in the tumor microenvironment. Neutrophils can be divided into several subpopulations, thus contradicting the traditional concept of neutrophils as a homogeneous population with a specific function in the innate immunity and opening new horizons for cancer therapy. Despite the promising achievements in this field, a full understanding of tumor-neutrophil interplay is currently lacking. In this review, we try to summarize the current view on neutrophil heterogeneity in cancer, discuss the different communication pathways between tumors and neutrophils, and focus on the implementation of these new findings to develop promising neutrophil-based cancer therapies.
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Affiliation(s)
- Khetam Sounbuli
- Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev Ave., 8, Novosibirsk 630090, Russia
- Faculty of Natural Sciences, Novosibirsk State University, Novosibirsk 630090, Russia
| | - Nadezhda Mironova
- Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev Ave., 8, Novosibirsk 630090, Russia
- Correspondence: ; Tel.: +7-383-363-51-61
| | - Ludmila Alekseeva
- Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev Ave., 8, Novosibirsk 630090, Russia
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13
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Harkus U, Wankell M, Palamuthusingam P, McFarlane C, Hebbard L. Immune checkpoint inhibitors in HCC: Cellular, molecular and systemic data. Semin Cancer Biol 2022; 86:799-815. [PMID: 35065242 DOI: 10.1016/j.semcancer.2022.01.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/12/2022] [Accepted: 01/17/2022] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related deaths in the world, and for patients with advanced disease there are few therapeutic options available. The complex immunological microenvironment of HCC and the success of immunotherapy in several types of tumours, has raised the prospect of potential benefit for immune based therapies, such as immune checkpoint inhibitors (ICIs), in HCC. This has led to significant breakthrough research, numerous clinical trials and the rapid approval of multiple systemic drugs for HCC by regulatory bodies worldwide. Although some patients responded well to ICIs, many have failed to achieve significant benefit, while others showed unexpected and paradoxical deterioration. The aim of this review is to discuss the pathophysiology of HCC, the tumour microenvironment, key clinical trials evaluating ICIs in HCC, various resistance mechanisms to ICIs, and possible ways to overcome these impediments to improve patient outcomes.
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Affiliation(s)
- Uasim Harkus
- Townsville University Hospital, Townsville, Queensland 4811, Australia
| | - Miriam Wankell
- Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Medicine and Health, James Cook University, Townsville, Queensland 4811, Australia
| | - Pranavan Palamuthusingam
- College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia; Townsville University Hospital, Townsville, Queensland 4811, Australia; Mater Hospital, Townsville, Queensland 4811, Australia
| | - Craig McFarlane
- Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Medicine and Health, James Cook University, Townsville, Queensland 4811, Australia
| | - Lionel Hebbard
- Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Medicine and Health, James Cook University, Townsville, Queensland 4811, Australia; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales 2145, Australia.
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14
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Jiang W, Zhao T, Zhen X, Jin C, Li H, Ha J. Rapid Determination of 9 Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma in Human Plasma by QuEChERS-UPLC-MS/MS. Front Pharmacol 2022; 13:920436. [PMID: 35800447 PMCID: PMC9253689 DOI: 10.3389/fphar.2022.920436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 05/11/2022] [Indexed: 11/13/2022] Open
Abstract
A reliable and rapid method employing QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) pretreatment coupled with ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) was successfully developed and validated for the analysis of nine tyrosine kinase inhibitors (TKIs) in human plasma. Biological samples were extracted with acetonitrile and salted out with 350 mg of anhydrous magnesium sulfate (MgSO4), followed by purification with 40 mg of ethyl enediamine-N-propylsilane (PSA) adsorbents. All analytes and internal standards (IS) were separated on the Hypersil GOLD VANQUISH C18 (2.1 mm × 100 mm, 1.9 μM) column using the mobile phases composed of acetonitrile (phase A) and 0.1% formic acid in water (phase B) for 8.0 min. Detection was performed by selection reaction monitoring (SRM) in the positive ion electrospray mode. Lenvatinib, sorafenib, cabozantinib, apatinib, gefitinib, regorafenib, and anlotinib rendered good linearity over the range of 0.1–10 ng/ml, and 1–100 ng/ml for tivantinib and galunisertib. All linear correlation coefficients for all standard curves were ≥ 0.9966. The limits of detection (LOD) and the limits of quantitation (LOQ) ranged from 0.003 to 0.11 ng/ml and 0.01–0.37 ng/ml, respectively. The method was deemed satisfactory with an accuracy of -7.34–6.64%, selectivity, matrix effect (ME) of 90.48–107.77%, recovery, and stability. The proposed method is simple, efficient, reliable, and applicable for the detection of TKIs in human plasma samples as well as for providing a reference for the clinical adjustment of drug administration regimen by monitoring the drug concentrations in the plasma of patients.
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Affiliation(s)
- Wen Jiang
- College of Chemistry and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, China
| | - Tingting Zhao
- College of Pharmacy, Hebei Medical University, Shijiazhuang, China
| | - Xiaolan Zhen
- Hebei Institute of Drug and Medical Device Inspection, Shijiazhuang, China
| | - Chengcheng Jin
- College of Chemistry and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, China
| | - Hui Li
- Hebei Institute of Drug and Medical Device Inspection, Shijiazhuang, China
- *Correspondence: Hui Li, ; Jing Ha,
| | - Jing Ha
- College of Chemistry and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, China
- *Correspondence: Hui Li, ; Jing Ha,
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15
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Galunisertib Exerts Antifibrotic Effects on TGF-β-Induced Fibroproliferative Dermal Fibroblasts. Int J Mol Sci 2022; 23:ijms23126689. [PMID: 35743131 PMCID: PMC9223605 DOI: 10.3390/ijms23126689] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 06/10/2022] [Accepted: 06/11/2022] [Indexed: 02/06/2023] Open
Abstract
Dermal fibroblasts in pathological scars secrete constitutively elevated levels of TGF-β, signaling the transcription of fibrotic genes via activin-like kinase 5 (ALK5). In the present study, we examine the antifibrotic effects of galunisertib, a small-molecule inhibitor of ALK5, on fibroproliferative dermal fibroblasts in an in vitro model of wound healing. We induced fibrosis in human dermal fibroblasts with exogenous TGF-β and performed cellular proliferation assays after treatment with varying concentrations of galunisertib. Dermal fibroblast proliferation was diminished to homeostatic levels without cytotoxicity at concentrations as high as 10 μM. An in vitro scratch assay revealed that galunisertib significantly enhanced cellular migration and in vitro wound closure beginning 24 h post-injury. A gene expression analysis demonstrated a significant attenuation of fibrotic gene expression, including collagen-1a, alpha-smooth muscle actin, fibronectin, and connective tissue growth factor, with increased expression of the antifibrotic genes MMP1 and decorin. Protein synthesis assays confirmed drug activity and corroborated the transcription findings. In summary, galunisertib simultaneously exerts antifibrotic effects on dermal fibroblasts while enhancing rates of in vitro wound closure. Galunisertib has already completed phase II clinical trials for cancer therapy with minimal adverse effects and is a promising candidate for the treatment and prevention of pathological cutaneous scars.
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16
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Geh D, Leslie J, Rumney R, Reeves HL, Bird TG, Mann DA. Neutrophils as potential therapeutic targets in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2022; 19:257-273. [PMID: 35022608 DOI: 10.1038/s41575-021-00568-5] [Citation(s) in RCA: 126] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/06/2021] [Indexed: 12/13/2022]
Abstract
The success of atezolizumab plus bevacizumab treatment contributed to a shift in systemic therapies for hepatocellular carcinoma (HCC) towards combinations that include cancer immunotherapeutic agents. Thus far, the principal focus of cancer immunotherapy has been on interrupting immune checkpoints that suppress antitumour lymphocytes. As well as lymphocytes, the HCC environment includes numerous other immune cell types, among which neutrophils are emerging as an important contributor to the pathogenesis of HCC. A growing body of evidence supports neutrophils as key mediators of the immunosuppressive environment in which some cancers develop, as well as drivers of tumour progression. If neutrophils have a similar role in HCC, approaches that target or manipulate neutrophils might have therapeutic benefits, potentially including sensitization of tumours to conventional immunotherapy. Several neutrophil-directed therapies for patients with HCC (and other cancers) are now entering clinical trials. This Review outlines the evidence in support of neutrophils as drivers of HCC and details their mechanistic roles in development, progression and metastasis, highlighting the reasons that neutrophils are well worth investigating despite the challenges associated with studying them. Neutrophil-modulating anticancer therapies entering clinical trials are also summarized.
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Affiliation(s)
- Daniel Geh
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Rob Rumney
- School of Pharmacy, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Helen L Reeves
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
- Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - Thomas G Bird
- Cancer Research UK Beatson Institute, Glasgow, UK
- MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
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17
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Baba AB, Rah B, Bhat GR, Mushtaq I, Parveen S, Hassan R, Hameed Zargar M, Afroze D. Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within. Front Pharmacol 2022; 13:791272. [PMID: 35295334 PMCID: PMC8918694 DOI: 10.3389/fphar.2022.791272] [Citation(s) in RCA: 110] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 02/09/2022] [Indexed: 12/11/2022] Open
Abstract
A ubiquitously expressed cytokine, transforming growth factor-beta (TGF-β) plays a significant role in various ongoing cellular mechanisms. The gain or loss-of-function of TGF-β and its downstream mediators could lead to a plethora of diseases includes tumorigenesis. Specifically, at the early onset of malignancy TGF-β act as tumour suppressor and plays a key role in clearing malignant cells by reducing the cellular proliferation and differentiation thus triggers the process of apoptosis. Subsequently, TGF-β at an advanced stage of malignancy promotes tumorigenesis by augmenting cellular transformation, epithelial-mesenchymal-transition invasion, and metastasis. Besides playing the dual roles, depending upon the stage of malignancy, TGF-β also regulates cell fate through immune and stroma components. This oscillatory role of TGF-β to fight against cancer or act as a traitor to collaborate and crosstalk with other tumorigenic signaling pathways and its betrayal within the cell depends upon the cellular context. Therefore, the current review highlights and understands the dual role of TGF-β under different cellular conditions and its crosstalk with other signaling pathways in modulating cell fate.
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18
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Zhao GS, Liu S, Liu Y, Li C, Wang RY, Bian J, Zhu RP, Zhou J, Zhang YW. Clinical application of gelatin sponge microparticles-transcatheter arterial chemoembolization combined with synchronous antigen-presenting dendritic cell sequential reinfusion for treatment of advanced large liver cancer: A single-center, prospective, non-randomized, controlled trial. Medicine (Baltimore) 2022; 101:e28803. [PMID: 35212274 PMCID: PMC8878883 DOI: 10.1097/md.0000000000028803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 01/24/2022] [Indexed: 01/04/2023] Open
Abstract
To assess the clinical efficacy and safety of gelatin sponge microparticles-transcatheter arterial chemoembolization (GSMs-TACE) plus synchronous antigen-presenting dendritic cell (DC) sequential reinfusion for advanced large liver cancer (LC).Patients with large LC were assigned to the experimental (combined sequential DC therapy) or control group. All patients received standardized GSMs-TACE. In the experimental group, 60 mL of peripheral blood was collected for in vitro culture of DCs (10-14 days). Then, intravenous reinfusion was conducted 3 times within 10, 20, and 30 days after surgery. Adverse reactions during the treatment were recorded and evaluated. The overall survival, transcatheter arterial chemoembolization frequency, and physical score (PS) were calculated.The median survival time of the experimental group was significantly longer than that of the control group. There were significant differences in median progression-free survival between the 2 groups (P < .05) and the objective effective rate at 1 and 6 months and 1 year (P < .05), but not 2 years (P > .05). The PSs of 2 groups were significantly improved at 1 month after GSMs-TACE, with more obvious improvement in the experimental group (P < .05).GSMs-TACE plus synchronous DC sequential reinfusion significantly prolonged the median survival time, improved the tumor response rate and PS, prolonged progression-free survival, and reduced intervention frequency. GSMs-TACE plus synchronous DC sequential reinfusion treatment is suitable for comprehensive treatment of patients with advanced larger LC in China.
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Affiliation(s)
- Guang Sheng Zhao
- Interventional Medicine Center, Affiliated Zhongshan Hospital of Dalian University, No.6 Jie Fang Street, Dalian, Liaoning Province, China
| | - Song Liu
- Interventional Medicine Center, Linyi Cancer Hospital, 6 East Lingyuan Street, Linyi, Shandong Province, China
| | - Ying Liu
- Hepatobiliary and Pancreatic Center, Beijing Tsinghua Changgung Hospital, 168 Litang Road, Changping District, Beijing, China
| | - Chuang Li
- Interventional Medicine Center, Affiliated Zhongshan Hospital of Dalian University, No.6 Jie Fang Street, Dalian, Liaoning Province, China
| | - Ruo Yu Wang
- Cancer Treatment Center, Affiliated Zhongshan Hospital of Dalian University, No.6 Jiefang Street, Dalian, Liaoning Province, China
| | - Jie Bian
- Department of Radiology, The Second Affiliated Hospital of Dalian Medical University, No.467 Zhongshan Road, Shahekou District, Dalian 116027, Liaoning Province, China
| | - Rui Ping Zhu
- Department of Pathology, Affiliated Zhongshan Hospital of Dalian University, No.6 Jie Fang Street, Dalian, Liaoning Province, China
| | - Jun Zhou
- Interventional Medicine Center, Affiliated Zhongshan Hospital of Dalian University, No.6 Jie Fang Street, Dalian, Liaoning Province, China
| | - Yue Wei Zhang
- Hepatobiliary and Pancreatic Center, Beijing Tsinghua Changgung Hospital, 168 Litang Road, Changping District, Beijing, China
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19
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Neutrophils: Driving inflammation during the development of hepatocellular carcinoma. Cancer Lett 2021; 522:22-31. [PMID: 34517084 DOI: 10.1016/j.canlet.2021.09.011] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 09/05/2021] [Accepted: 09/07/2021] [Indexed: 12/13/2022]
Abstract
The relationship between immune and inflammatory responses in hepatocellular carcinoma (HCC) has garnered significant interest. In the peripheral blood and tumour microenvironment (TME), neutrophils, which are innate immune cells, crucially respond to various inflammatory factors, leading to tumour progression. To some extent, they affect the clinical treatment strategy and survival among HCC patients. A high circulating neutrophil-to-lymphocyte ratio is a reliable factor that can be used to predict poor outcomes in HCC patients. However, the mechanisms underlying the protumoural effects of circulating neutrophils remain poorly understood. Besides, the distinct role and function of neutrophils at the site of HCC remain relatively unclear, which is partially attributed to their substantial heterogeneity compared with other immune cells. In this review, we firstly discuss the current information available, detailing distinct subsets, functional phenotypes, and the impact of circulating and tumour-infiltrating neutrophils on tumourigenesis in HCC. Furthermore, we describe recent pre-clinical and clinical studies concerning neutrophils for evaluating the feasibility of targeting diverse protumoural aspects to improve therapeutic efficacy, thus paving the way for neutrophil-based treatment, especially in combination with immunotherapy.
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20
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Benjamin DJ, Lyou Y. Advances in Immunotherapy and the TGF-β Resistance Pathway in Metastatic Bladder Cancer. Cancers (Basel) 2021; 13:cancers13225724. [PMID: 34830879 PMCID: PMC8616345 DOI: 10.3390/cancers13225724] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/12/2021] [Accepted: 11/14/2021] [Indexed: 12/31/2022] Open
Abstract
Simple Summary Bladder cancer accounts for a significant burden to global public health. Despite advances in therapeutics with the advent of immunotherapy, only a small subset of patients benefit from immunotherapy. In this review, we examine the evidence that suggests that the TGF-β pathway may present a resistance mechanism to immunotherapy. In addition, we present possible therapies that may overcome the TGF-β resistance pathway in the treatment of bladder cancer. Abstract Bladder cancer accounts for nearly 200,000 deaths worldwide yearly. Urothelial carcinoma (UC) accounts for nearly 90% of cases of bladder cancer. Cisplatin-based chemotherapy has remained the mainstay of treatment in the first-line setting for locally advanced or metastatic UC. More recently, the treatment paradigm in the second-line setting was drastically altered with the approval of several immune checkpoint inhibitors (ICIs). Given that only a small subset of patients respond to ICI, further studies have been undertaken to understand potential resistance mechanisms to ICI. One potential resistance mechanism that has been identified in the setting of metastatic UC is the TGF-β signaling pathway. Several pre-clinical and ongoing clinical trials in multiple advanced tumor types have evaluated several therapies that target the TGF-β pathway. In addition, there are ongoing and planned clinical trials combining TGF-β inhibition with ICI, which may provide a promising therapeutic approach for patients with advanced and metastatic UC.
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Affiliation(s)
- David J. Benjamin
- Chao Family Comprehensive Cancer Center, Division of Hematology/Oncology, Department of Medicine, UC Irvine Medical Center, Orange, CA 92868, USA;
| | - Yung Lyou
- Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
- Correspondence: ; Tel.: +1-626-256-2805; Fax: +1-625-301-8233
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21
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Yang Y, Ye WL, Zhang RN, He XS, Wang JR, Liu YX, Wang Y, Yang XM, Zhang YJ, Gan WJ. The Role of TGF- β Signaling Pathways in Cancer and Its Potential as a Therapeutic Target. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:6675208. [PMID: 34335834 PMCID: PMC8321733 DOI: 10.1155/2021/6675208] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 06/22/2021] [Indexed: 02/08/2023]
Abstract
The transforming growth factor-β (TGF-β) signaling pathway mediates various biological functions, and its dysregulation is closely related to the occurrence of malignant tumors. However, the role of TGF-β signaling in tumorigenesis and development is complex and contradictory. On the one hand, TGF-β signaling can exert antitumor effects by inhibiting proliferation or inducing apoptosis of cancer cells. On the other hand, TGF-β signaling may mediate oncogene effects by promoting metastasis, angiogenesis, and immune escape. This review summarizes the recent findings on molecular mechanisms of TGF-β signaling. Specifically, this review evaluates TGF-β's therapeutic potential as a target by the following perspectives: ligands, receptors, and downstream signaling. We hope this review can trigger new ideas to improve the current clinical strategies to treat tumors related to the TGF-β signaling pathway.
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Affiliation(s)
- Yun Yang
- Department of Pathology, Medical College of Soochow University, Soochow University, Suzhou 215123, China
| | - Wen-Long Ye
- Department of Pathology, Medical College of Soochow University, Soochow University, Suzhou 215123, China
| | - Ruo-Nan Zhang
- Department of Pathology, Medical College of Soochow University, Soochow University, Suzhou 215123, China
- Department of Pathology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China
| | - Xiao-Shun He
- Department of Pathology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China
| | - Jing-Ru Wang
- Department of Pathology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China
| | - Yu-Xuan Liu
- Department of Pathology, Medical College of Soochow University, Soochow University, Suzhou 215123, China
| | - Yi Wang
- Department of Pathology, Medical College of Soochow University, Soochow University, Suzhou 215123, China
| | - Xue-Mei Yang
- Department of Pathology, Medical College of Soochow University, Soochow University, Suzhou 215123, China
- Department of Pathology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China
| | - Yu-Juan Zhang
- Department of Pathology, Medical College of Soochow University, Soochow University, Suzhou 215123, China
| | - Wen-Juan Gan
- Department of Pathology, Dushu Lake Hospital Affiliated of Soochow University, Soochow University, Suzhou 215124, China
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22
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The TGF-β Pathway: A Pharmacological Target in Hepatocellular Carcinoma? Cancers (Basel) 2021; 13:cancers13133248. [PMID: 34209646 PMCID: PMC8268320 DOI: 10.3390/cancers13133248] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 02/07/2023] Open
Abstract
Transforming Growth Factor-beta (TGF-β) superfamily members are essential for tissue homeostasis and consequently, dysregulation of their signaling pathways contributes to the development of human diseases. In the liver, TGF-β signaling participates in all the stages of disease progression from initial liver injury to hepatocellular carcinoma (HCC). During liver carcinogenesis, TGF-β plays a dual role on the malignant cell, behaving as a suppressor factor at early stages, but contributing to later tumor progression once cells escape from its cytostatic effects. Moreover, TGF-β can modulate the response of the cells forming the tumor microenvironment that may also contribute to HCC progression, and drive immune evasion of cancer cells. Thus, targeting the TGF-β pathway may constitute an effective therapeutic option for HCC treatment. However, it is crucial to identify biomarkers that allow to predict the response of the tumors and appropriately select the patients that could benefit from TGF-β inhibitory therapies. Here we review the functions of TGF-β on HCC malignant and tumor microenvironment cells, and the current strategies targeting TGF-β signaling for cancer therapy. We also summarize the clinical impact of TGF-β inhibitors in HCC patients and provide a perspective on its future use alone or in combinatorial strategies for HCC treatment.
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Liu ZL, Liu JH, Staiculescu D, Chen J. Combination of molecularly targeted therapies and immune checkpoint inhibitors in the new era of unresectable hepatocellular carcinoma treatment. Ther Adv Med Oncol 2021; 13:17588359211018026. [PMID: 34104226 PMCID: PMC8150670 DOI: 10.1177/17588359211018026] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Multikinase inhibitors (MKIs) have been the only first-line treatment for advanced hepatocellular carcinoma (HCC) for more than a decade, until the approval of immune checkpoint inhibitors (ICIs). Moreover, the combination regimen of atezolizumab (anti-programmed cell death protein ligand 1 antibody) plus bevacizumab (anti-vascular endothelial growth factor monoclonal antibody) has recently been demonstrated to have superior efficacy when compared with sorafenib monotherapy. The remarkable efficacy has made this combination therapy the new standard treatment for advanced HCC. In addition to MKIs, many other molecularly targeted therapies are under investigation, some of which have shown promising results. Therefore, in the era of immuno-oncology, there is a significant rationale for testing the combinations of molecularly targeted therapies and ICIs. Indeed, numerous preclinical and clinical studies have shown the synergic antitumor efficacy of such combinations. In this review, we aim to summarize the current knowledge on the combination of molecularly targeted therapies and immune checkpoint therapies for HCC from both preclinical and clinical perspectives.
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Affiliation(s)
- Ze-Long Liu
- Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jing-Hua Liu
- Department of Hepatobiliary Surgery and Professor Cai’s Laboratory, Linyi People’s Hospital, Linyi, Shandong Province, China
| | - Daniel Staiculescu
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jiang Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, No. 3, East Qingchun Road, Hangzhou, Zhejiang Province, 310016, China
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
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Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8 + T Cell Response in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13081922. [PMID: 33923463 PMCID: PMC8073815 DOI: 10.3390/cancers13081922] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/22/2021] [Accepted: 04/14/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary The cytotoxic T cell response against hepatocellular carcinoma antigens is exhausted and fails in its task of deleting tumoral cells. These cells are featured by the expression of negative immune checkpoints that can be modulated to restore T cell function. The blockade of the PD-1/PD-L1 pathway has shown promising results in rescuing hepatocellular carcinoma-specific CD8 T cells but only a reduced group of cases is sensitive to this treatment and the effect is usually temporary. Therefore, new anti-PD-1 based combinatory strategies are underway to increase the response by adding the effect of blocking neo-angiogenesis and other negative immune checkpoints, boosting positive immune checkpoints, blocking suppressive cytokines, or inducing the expression of tumoral neoantigens. The restoration of T cell responses with these anti-PD-1 based combinatory therapies will change the outcome of advanced hepatocellular carcinoma. Abstract Thirty to fifty percent of hepatocellular carcinomas (HCC) display an immune class genetic signature. In this type of tumor, HCC-specific CD8 T cells carry out a key role in HCC control. Those potential reactive HCC-specific CD8 T cells recognize either HCC immunogenic neoantigens or aberrantly expressed host’s antigens, but they become progressively exhausted or deleted. These cells express the negative immunoregulatory checkpoint programmed cell death protein 1 (PD-1) which impairs T cell receptor signaling by blocking the CD28 positive co-stimulatory signal. The pool of CD8 cells sensitive to anti-PD-1/PD-L1 treatment is the PD-1dim memory-like precursor pool that gives rise to the effector subset involved in HCC control. Due to the epigenetic imprints that are transmitted to the next generation, the effect of PD-1 blockade is transient, and repeated treatments lead to tumor resistance. During long-lasting disease, besides the TCR signaling impairment, T cells develop other failures that should be also set-up to increase T cell reactivity. Therefore, several PD-1 blockade-based combinatory therapies are currently under investigation such as adding antiangiogenics, anti-TGFβ1, blockade of other negative immune checkpoints, or increasing HCC antigen presentation. The effect of these combinations on CD8+ T cells is discussed in this review.
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Liu S, Ren J, Ten Dijke P. Targeting TGFβ signal transduction for cancer therapy. Signal Transduct Target Ther 2021; 6:8. [PMID: 33414388 PMCID: PMC7791126 DOI: 10.1038/s41392-020-00436-9] [Citation(s) in RCA: 227] [Impact Index Per Article: 56.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 12/04/2020] [Accepted: 12/05/2020] [Indexed: 12/19/2022] Open
Abstract
Transforming growth factor-β (TGFβ) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis. Dysregulation of TGFβ family signaling can lead to a plethora of developmental disorders and diseases, including cancer, immune dysfunction, and fibrosis. In this review, we focus on TGFβ, a well-characterized family member that has a dichotomous role in cancer progression, acting in early stages as a tumor suppressor and in late stages as a tumor promoter. The functions of TGFβ are not limited to the regulation of proliferation, differentiation, apoptosis, epithelial-mesenchymal transition, and metastasis of cancer cells. Recent reports have related TGFβ to effects on cells that are present in the tumor microenvironment through the stimulation of extracellular matrix deposition, promotion of angiogenesis, and suppression of the anti-tumor immune reaction. The pro-oncogenic roles of TGFβ have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients. However, the critical function of TGFβ in maintaining tissue homeostasis makes targeting TGFβ a challenge. Here, we review the pleiotropic functions of TGFβ in cancer initiation and progression, summarize the recent clinical advancements regarding TGFβ signaling interventions for cancer treatment, and discuss the remaining challenges and opportunities related to targeting this pathway. We provide a perspective on synergistic therapies that combine anti-TGFβ therapy with cytotoxic chemotherapy, targeted therapy, radiotherapy, or immunotherapy.
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Affiliation(s)
- Sijia Liu
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands
| | - Jiang Ren
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands
| | - Peter Ten Dijke
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands.
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26
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Goulet CR, Pouliot F. TGFβ Signaling in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1270:89-105. [PMID: 33123995 DOI: 10.1007/978-3-030-47189-7_6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Transforming growth factor beta (TGFβ) is a pleiotropic growth factor. Under normal physiological conditions, TGFβ maintains homeostasis in mammalian tissues by restraining the growth of cells and stimulating apoptosis. However, the role of TGFβ signaling in the carcinogenesis is complex. TGFβ acts as a tumor suppressor in the early stages of disease and as a tumor promoter in its later stages where cancer cells have been relieved from TGFβ growth controls. Overproduction of TGFβ by cancer cells lead to a local fibrotic and immune-suppressive microenvironment that fosters tumor growth and correlates with invasive and metastatic behavior of the cancer cells. Here, we present an overview of the complex biology of the TGFβ family, and we discuss the roles of TGFβ signaling in carcinogenesis and how this knowledge is being leveraged to develop TGFβ inhibition therapies against the tumor.
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Affiliation(s)
- Cassandra Ringuette Goulet
- Oncology Division, CHU de Québec Research Center, Quebec, QC, Canada
- Department of Surgery, Faculty of Medicine, Laval University, Quebec, QC, Canada
| | - Frédéric Pouliot
- Oncology Division, CHU de Québec Research Center, Quebec, QC, Canada.
- Department of Surgery, Faculty of Medicine, Laval University, Quebec, QC, Canada.
- Department of surgery, CHU de Québec Research Center - Laval University, Quebec City, QC, Canada.
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27
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Derynck R, Turley SJ, Akhurst RJ. TGFβ biology in cancer progression and immunotherapy. Nat Rev Clin Oncol 2020; 18:9-34. [DOI: 10.1038/s41571-020-0403-1] [Citation(s) in RCA: 560] [Impact Index Per Article: 112.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2020] [Indexed: 02/07/2023]
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Ciardiello D, Elez E, Tabernero J, Seoane J. Clinical development of therapies targeting TGFβ: current knowledge and future perspectives. Ann Oncol 2020; 31:1336-1349. [PMID: 32710930 DOI: 10.1016/j.annonc.2020.07.009] [Citation(s) in RCA: 184] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/22/2020] [Accepted: 07/14/2020] [Indexed: 01/06/2023] Open
Abstract
Transforming growth factor beta (TGFβ) is a pleiotropic cytokine that plays a key role in both physiologic and pathologic conditions, including cancer. Importantly, TGFβ can exhibit both tumor-suppressive and oncogenic functions. In normal epithelial cells TGFβ acts as an antiproliferative and differentiating factor, whereas in advanced tumors TGFβ can act as an oncogenic factor by creating an immune-suppressive tumor microenvironment, and inducing cancer cell proliferation, angiogenesis, invasion, tumor progression, and metastatic spread. A wealth of preclinical findings have demonstrated that targeting TGFβ is a promising means of exerting antitumor activity. Based on this rationale, several classes of TGFβ inhibitors have been developed and tested in clinical trials, namely, monoclonal, neutralizing, and bifunctional antibodies; antisense oligonucleotides; TGFβ-related vaccines; and receptor kinase inhibitors. It is now >15 years since the first clinical trial testing an anti-TGFβ agent was engaged. Despite the promising preclinical studies, translation of the basic understanding of the TGFβ oncogenic response into the clinical setting has been slow and challenging. Here, we review the conclusions and status of all the completed and ongoing clinical trials that test compounds that inhibit the TGFβ pathway, and discuss the challenges that have arisen during their clinical development. With none of the TGFβ inhibitors evaluated in clinical trials approved for cancer therapy, clinical development for TGFβ blockade therapy is primarily oriented toward TGFβ inhibitor combinations. Immune checkpoint inhibitors are considered candidates, albeit with efficacy anticipated to be restricted to specific populations. In this context, we describe current efforts in the search for biomarkers for selecting the appropriate cancer patients who are likely to benefit from anti-TGFβ therapies. The knowledge accumulated during the last 15 years of clinical research in the context of the TGFβ pathway is crucial to design better, innovative, and more successful trials.
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Affiliation(s)
- D Ciardiello
- Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain; Department of Medicina di Precisione, Università degli studi della Campania, Luigi Vanvitelli, Naples, Italy
| | - E Elez
- Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - J Tabernero
- Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain; Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain; CIBERONC, Barcelona, Spain
| | - J Seoane
- Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain; Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain; CIBERONC, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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29
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Masuda A, Nakamura T, Abe M, Iwamoto H, Sakaue T, Tanaka T, Suzuki H, Koga H, Torimura T. Promotion of liver regeneration and anti‑fibrotic effects of the TGF‑β receptor kinase inhibitor galunisertib in CCl4‑treated mice. Int J Mol Med 2020; 46:427-438. [PMID: 32377696 DOI: 10.3892/ijmm.2020.4594] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 03/30/2020] [Indexed: 11/05/2022] Open
Abstract
The cytokine transforming growth factor‑β (TGF‑β) serves a key role in hepatic fibrosis and has cytostatic effects on hepatocytes. The present study investigated the anti‑fibrogenic and regenerative effects of the TGF‑β receptor type I kinase inhibitor galunisertib (LY2157299) in mice with carbon tetrachloride (CCl4)‑induced liver cirrhosis and in vitro. Mice were intraperitoneally treated with CCl4 for 8 weeks. At week 5, the mice were divided randomly into four treatment groups: Vehicle‑treated; and treated with low‑; middle‑; and high‑dose galunisertib, which was administered from weeks 5‑8. The mice were sacrificed after 8 weeks of CCl4 treatment. Liver fibrosis, as evaluated by histology and determination of hydroxyproline content, progressed during week 4‑8 of CCl4 treatment in the vehicle‑treated mice. Galunisertib treatment dose‑dependently prevented liver fibrosis, as demonstrated by the direct inhibition of α‑smooth muscle actin‑positive activated hepatic stellate cells (HSCs) after 8 weeks of CCl4 treatment. The levels of active matrix metalloproteinase (MMP)‑9 in galunisertib‑treated livers were significantly increased compared with the vehicle‑treated livers. In the high‑dose group, the number of PCNA‑positive hepatocytes and endothelial cells markedly increased compared with the vehicle group. Reverse transcription‑quantitative PCR analysis verified that interleukin‑6 and epiregulin expression levels were significantly increased in livers from the group treated with high‑dose galunisertib compared with the vehicle‑treated group. Galunisertib inhibited the proliferation of activated HSCs and collagen synthesis in addition to restoring MMP activity. Moreover, galunisertib promoted liver remodeling by proliferating hepatocytes and vascular endothelial cells, while significantly increasing liver weight. These results are consistent with the cytostatic action of TGF‑β that negatively regulates liver regeneration, and demonstrated that galunisertib inhibited TGF‑β signaling, halted liver fibrosis progression and promoted hepatic regeneration. The results of the present study suggest that galunisertib may be an effective treatment for liver cirrhosis.
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Affiliation(s)
- Atsutaka Masuda
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Toru Nakamura
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Mitsuhiko Abe
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Takahiko Sakaue
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Toshimitsu Tanaka
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Hiroyuki Suzuki
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
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30
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Faivre S, Rimassa L, Finn RS. Molecular therapies for HCC: Looking outside the box. J Hepatol 2020; 72:342-352. [PMID: 31954496 DOI: 10.1016/j.jhep.2019.09.010] [Citation(s) in RCA: 261] [Impact Index Per Article: 52.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Revised: 08/29/2019] [Accepted: 09/10/2019] [Indexed: 12/12/2022]
Abstract
Over the past decade, sorafenib has been the only systemic agent with proven clinical efficacy for patients with unresectable hepatocellular carcinoma (HCC). Recently, lenvatinib was shown to be non-inferior to sorafenib, while regorafenib, cabozantinib, and ramucirumab were shown to be superior to placebo in patients failing sorafenib. In addition, trials of immune checkpoint inhibitors reported encouraging efficacy signals. However, apart from alpha-fetoprotein, which is used to select patients for ramucirumab, no biomarkers are available to identify patients that may respond to a specific treatment. Different synergisms have been postulated based on the potential interplay between antiangiogenic drugs and immunotherapy, with several clinical trials currently testing this hypothesis. Indeed, encouraging preliminary results of phase I studies of bevacizumab plus atezolizumab and lenvatinib plus pembrolizumab have led to the design of ongoing phase III trials, including both antiangiogenics and immune checkpoint inhibitors in the front-line setting. Other important phase II studies have tested molecular therapies directed against different novel targets, such as transforming growth factor-beta, MET (hepatocyte growth factor receptor), and fibroblast growth factor receptor 4. These studies integrated translational research with the aim of better defining the biological tumour profile and identifying tumour and blood biomarkers that select patients who may really benefit from a specific molecular therapy. Importantly, good safety profiles make these drugs suitable for future combinations. In this review, we discuss the most recent data on novel combination strategies and targets, as well as looking ahead to the future role of molecular therapies in the treatment of patients with advanced HCC.
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Affiliation(s)
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center IRCCS, Rozzano (Milan), Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy.
| | - Richard S Finn
- Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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31
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Farah M, Nelson KC, Tetzlaff MT, Nagarajan P, Torres-Cabala CA, Prieto VG, Curry JL, Aung PP. Lichen planus related to transforming growth factor beta inhibitor in a patient with metastatic chondrosarcoma: a case report. J Cutan Pathol 2020; 47:490-493. [PMID: 31930527 DOI: 10.1111/cup.13645] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 12/22/2019] [Accepted: 01/07/2020] [Indexed: 01/10/2023]
Abstract
Transforming growth factor-beta1 (TGF-β1) is expressed in normal epidermis. TGF-β1 potently inhibits keratinocyte proliferation and immunomodulatory properties, mainly by suppressing immune responses to self-antigens. Lichen planus (LP) is a form of dermatitis caused by cell-mediated immune dysfunction, but the exact pathogenic pathways are unknown, which poses therapeutic challenges. We report on a 68-year-old man who developed multiple pruritic, discrete, and well-demarcated, flat-topped red-purple papules and macules on the back and upper arms following 4 cycles of treatment with TGF-β receptor I (TGFBR-I) inhibitor, ly3200882, for metastatic chondrosarcoma. The biopsy showed hyperkeratosis, wedge-shaped hypergranulosis, elongation of the rete ridges, and a dense band-like lymphohistiocytic infiltrate admixed with colloid bodies and pigment incontinence, consistent with LP. Temporal correlation suggested that the TGFBR-I inhibitor might be a trigger. Treatment with topical clobetasol and oral metronidazole led to partial resolution of the lesions with postinflammatory hyperpigmentation. We believe this is the first reported case of LP related to TGFBR-I inhibitor therapy. This report expands the list of cutaneous adverse events associated with this novel class of targeted therapy. More importantly, this report supports emerging evidence that failure of TGF-β1 activation/signal transduction is an important mechanism in the pathogenesis of LP and suggests the TGF-β1 pathway as a potential therapeutic target in this disease.
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Affiliation(s)
- Maya Farah
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kelly C Nelson
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael T Tetzlaff
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Carlos A Torres-Cabala
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Victor G Prieto
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jonathan L Curry
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Phyu P Aung
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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32
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Zhang CH, Li M, Lin YP, Gao Q. Systemic Therapy for Hepatocellular Carcinoma: Advances and Hopes. Curr Gene Ther 2020; 20:84-99. [PMID: 32600231 DOI: 10.2174/1566523220666200628014530] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 12/24/2022]
Abstract
The majority of patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage that can only benefit from systemic treatments. Although HCC is highly treatmentresistant, significant achievements have been made in the molecular targeted therapy and immunotherapy of HCC. In addition to regorafenib, cabozantinib and ramucirumab were approved for the second- line targeted treatment by the FDA after disease progression on sorafenib. Nivolumab failed to demonstrate remarkable benefit in overall survival (OS) as first-line therapy, while pembrolizumab did not achieve pre-specified statistical significance in both OS and progression-free survival (PFS) as second-line treatment. Combinations of targeted agents, immune checkpoint inhibitors and other interventions showed favorable results. In this review, we summarized the progress of systemic therapy in HCC and discussed the future directions of the treatment of HCC.
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Affiliation(s)
- Chen-Hao Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Ming Li
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - You-Pei Lin
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
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33
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In vivo imaging of TGFβ signalling components using positron emission tomography. Drug Discov Today 2019; 24:2258-2272. [DOI: 10.1016/j.drudis.2019.08.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 08/01/2019] [Accepted: 08/28/2019] [Indexed: 12/21/2022]
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34
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Collery P, Desmaele D, Vijaykumar V. Design of Rhenium Compounds in Targeted Anticancer Therapeutics. Curr Pharm Des 2019; 25:3306-3322. [DOI: 10.2174/1381612825666190902161400] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 08/30/2019] [Indexed: 12/25/2022]
Abstract
Background:
Many rhenium (Re) complexes with potential anticancer properties have been synthesized
in the recent years with the aim to overcome the clinical limitations of platinum agents. Re(I) tricarbonyl
complexes are the most common but Re compounds with higher oxidation states have also been investigated, as
well as hetero-metallic complexes and Re-loaded self-assembling devices. Many of these compounds display
promising cytotoxic and phototoxic properties against malignant cells but all Re compounds are still at the stage
of preclinical studies.
Methods:
The present review focused on the rhenium based cancer drugs that were in preclinical and clinical
trials were examined critically. The detailed targeted interactions and experimental evidences of Re compounds
reported by the patentable and non-patentable research findings used to write this review.
Results:
In the present review, we described the most recent and promising rhenium compounds focusing on their
potential mechanism of action including, phototoxicity, DNA binding, mitochondrial effects, oxidative stress
regulation or enzyme inhibition. Many ligands have been described that modulating the lipophilicity, the luminescent
properties, the cellular uptake, the biodistribution, and the cytotoxicity, the pharmacological and toxicological
profile.
Conclusion:
Re-based anticancer drugs can also be used in targeted therapies by coupling to a variety of biologically
relevant targeting molecules. On the other hand, combination with conventional cytotoxic molecules, such
as doxorubicin, allowed to take into profit the targeting properties of Re for example toward mitochondria.
Through the example of the diseleno-Re complex, we showed that the main target could be the oxidative status,
with a down-stream regulation of signaling pathways, and further on selective cell death of cancer cells versus
normal cells.
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Affiliation(s)
- Philippe Collery
- Society for the Coordination of Therapeutic Researches, 20220 Algajola, France
| | - Didier Desmaele
- Institut Galien, Universite Paris-Saclay, 92296 Chatenay-Malabry, France
| | - Veena Vijaykumar
- Biotechnology Department, REVA University, Bangalore, 560064, India
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Noonan A, Pawlik TM. Hepatocellular carcinoma: an update on investigational drugs in phase I and II clinical trials. Expert Opin Investig Drugs 2019; 28:941-949. [DOI: 10.1080/13543784.2019.1677606] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Anne Noonan
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, The James Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Timothy M. Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, The James Comprehensive Cancer Center, Columbus, Ohio, USA
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