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Grillo E, Romani C, Ettorre VM, Santin AD, Mitola S. The VEGF/VEGFR2 system in ovarian cancer: From functional to pharmacological significance. Biochim Biophys Acta Rev Cancer 2025; 1880:189374. [PMID: 40516635 DOI: 10.1016/j.bbcan.2025.189374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 06/10/2025] [Accepted: 06/10/2025] [Indexed: 06/16/2025]
Abstract
The vascular endothelial growth factor receptor 2 (VEGFR2) is a tyrosine kinase receptor regulating a variety of biological processes, including embryonic development, angiogenesis, tissue homeostasis and cancer. VEGFR2 is activated by canonical VEGFs and non-canonical ligands, triggering intracellular signaling cascades that mediate its biological activity. Preclinical studies show that VEGFR2 plays a complex yet pivotal role in the progression of ovarian cancer (OC), a deadly disease with a global burden of more than 320,000 women in 2022. Several inhibitors of the VEGF/VEGFR2 axis have been developed and are currently approved or included in clinical trials/preclinical studies for the therapy of different types of OC. Originally developed as anti-angiogenics, anti-VEGF/VEGFR2 drugs are now well-known to also affect tumor cells, immune cells and cancer-associated fibroblasts (CAFs), also in OC. In this review we address the specific role of the VEGF/VEGFR2 axis in OC cells, and, from this perspective, we discuss the therapeutic significance of VEGFR2 targeting. Dissection of the molecular landscape modulated by the VEGF/VEGFR2 system in tumor cells in addition to stromal ones will facilitate ongoing translational efforts directed toward OC therapy. SIGNIFICANCE STATEMENT: Anti-angiogenics blocking the VEGF/VEGFR2 axis are widely used to treat ovarian cancer, although resistance and poor response occur. Recent advances reveal that anti-VEGF/VEGFR2 drugs act on multiple compartments, including ovarian cancer cells. This review discusses the functional and pharmacological significance of the VEGF/VEGFR2 axis in ovarian cancer cells highlighting insights from preclinical and clinical studies. A deeper understanding of this pathway is essential for a safe/efficacious usage of anti-angiogenics targeting the VEGFR2 pathway in ovarian cancer.
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Affiliation(s)
- Elisabetta Grillo
- Department of Molecular and Translational Medicine, University of Brescia, Via Branze 39, 25123 Brescia, Italy.
| | - Chiara Romani
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Victoria M Ettorre
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, Yale University School of Medicine, New Haven, CT 06520, United States of America
| | - Alessandro D Santin
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, Yale University School of Medicine, New Haven, CT 06520, United States of America
| | - Stefania Mitola
- Department of Molecular and Translational Medicine, University of Brescia, Via Branze 39, 25123 Brescia, Italy.
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Nie Z, Liu Y, Xu L, Wang Y, Wang M, Zhou W, Zhu H, Zhao M, Wang S, Zhang H, Geng M, Peng M, Zeng H, Zhang Y, Zhu P, Shen W. Selenium nanoparticles attenuate retinal pathological angiogenesis by disrupting cell cycle distribution. Nanomedicine (Lond) 2025; 20:803-816. [PMID: 40114604 PMCID: PMC11988272 DOI: 10.1080/17435889.2025.2480046] [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: 09/30/2024] [Accepted: 03/12/2025] [Indexed: 03/22/2025] Open
Abstract
AIM This study aims to explore the mechanism by which selenium nanoparticles (SeNPs) inhibit retinal neovascularization (RNV) and to identify a more effective treatment for pathological RNV. MATERIALS & METHODS The characterization and identification of the synthesized selenium nanoparticles (SeNPs) were conducted to investigate their effects on the function of human umbilical vein endothelial cells (HUVECs), retinal blood vessel development in mice, and the impact on oxygen-induced retinopathy. Tritium-labeled thymine was utilized to label newly synthesized DNA both in vivo and in vitro, allowing for the observation of SeNPs' effects on cell proliferation. Additionally, flow cytometry, immunofluorescence, and western blotting techniques were employed to elucidate the mechanisms by which SeNPs inhibit retinal neovascularization. RESULTS SeNPs can significantly inhibit the functions of vascular endothelial cells, particularly their proliferation, both in vivo and in vitro. The SeNPs achieve this by modulating the expression of cell cycle-related proteins through the regulation of the PI3K-AKT-p21 axis, which in turn inhibits the transition of the cell cycle from the G1 phase to the S phase. CONCLUSION SeNPs may be a novel treatment for the interference of retinal neovascularization.
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Affiliation(s)
- Zheng Nie
- Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yongxuan Liu
- Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Li Xu
- Department of Laboratory Diagnosis, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yang Wang
- Department of Reproductive Medicine Center, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Mengzhu Wang
- Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Wen Zhou
- Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Huimin Zhu
- Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Min Zhao
- Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Shikun Wang
- Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Hongjian Zhang
- Oriental Pan-Vascular Devices Innovation College, University of Shanghai for Science and Technology, Shanghai, China
| | - Meijing Geng
- Oriental Pan-Vascular Devices Innovation College, University of Shanghai for Science and Technology, Shanghai, China
| | - Mai Peng
- Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Hao Zeng
- Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yuan Zhang
- Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Pengxi Zhu
- Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Wei Shen
- Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
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Zeng W, Liu F, Liu Y, Zhang Z, Hu H, Ning S, Zhang H, Chen X, Liao Z, Zhang Z. Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma. Clin Mol Hepatol 2025; 31:489-508. [PMID: 39736265 PMCID: PMC12016601 DOI: 10.3350/cmh.2024.0934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/18/2024] [Accepted: 12/26/2024] [Indexed: 01/01/2025] Open
Abstract
BACKGROUND/AIMS Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. METHODS TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. RESULTS TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. CONCLUSION Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.
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Affiliation(s)
- Weifeng Zeng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Furong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Yachong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Ze Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Haofan Hu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Shangwu Ning
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Hongwei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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Yuan CR, Lee TKW. TM4SF1 - A new immune target for treatment of hepatocellular carcinoma: Editorial on "Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma". Clin Mol Hepatol 2025; 31:646-649. [PMID: 39924999 PMCID: PMC12016624 DOI: 10.3350/cmh.2025.0102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 02/06/2025] [Indexed: 02/11/2025] Open
Affiliation(s)
- Chen Rui Yuan
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
| | - Terence Kin Wah Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
- State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong
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Jiao J, Wu Y, Wu S, Jiang J. Enhancing Colorectal Cancer Treatment Through VEGF/VEGFR Inhibitors and Immunotherapy. Curr Treat Options Oncol 2025; 26:213-225. [PMID: 40045029 DOI: 10.1007/s11864-025-01306-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2025] [Indexed: 03/20/2025]
Abstract
OPINION STATEMENT Colorectal cancer, ranking as the third most prevalent malignancy globally, substantially benefits from both immunotherapy and VEGF/VEGFR inhibitors. Nevertheless, the use of monotherapy proves inadequate in effectively tackling the heterogeneity of tumors and the intricacies of their microenvironment, frequently leading to drug resistance and immune evasion. This situation underscores the pressing need for innovative strategies aimed at augmenting the effectiveness and durability of treatments. Clinical research demonstrates that the combination of VEGF/VEGFR inhibitors (primarily including VEGF/VEGFR-targeted drugs and multi-kinase inhibitors) with immune checkpoint inhibitors creates a synergistic effect in the treatment of colorectal cancer. Our analysis explores how VEGF/VEGFR inhibitors recalibrate the tumor microenvironment, modulate immune cell functions, and influence the expression of immune checkpoints and cytokines. Furthermore, we critically evaluate the preclinical and clinical feasibility of these combined therapeutic approaches. Despite the potential for toxicity, the significant benefits and prospective applications of these strategies warrant thorough exploration. Exploring the synergistic mechanisms of these combined treatments has the potential to inaugurate a new paradigm in oncology, enabling more personalized and efficacious treatment modalities. Additionally, the synergy between VEGF/VEGFR inhibitors and nascent immunotherapies emerges as a promising field of inquiry.
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Affiliation(s)
- Jing Jiao
- Nanjing Medical University, Nanjing, 211166, Jiangsu, China
- Department of Tumor Biological Treatment, Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University Jiangsu Engineering Research Center for Tumor Immunotherapy, Soochow University, Juqian Road №185, Changzhou, 213003, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - You Wu
- Department of Tumor Biological Treatment, Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University Jiangsu Engineering Research Center for Tumor Immunotherapy, Soochow University, Juqian Road №185, Changzhou, 213003, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Shaoxian Wu
- Department of Tumor Biological Treatment, Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University Jiangsu Engineering Research Center for Tumor Immunotherapy, Soochow University, Juqian Road №185, Changzhou, 213003, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Jingting Jiang
- Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
- Department of Tumor Biological Treatment, Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University Jiangsu Engineering Research Center for Tumor Immunotherapy, Soochow University, Juqian Road №185, Changzhou, 213003, China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
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Ma J, Yang G, Qin X, Mo L, Xiong X, Xiong Y, He H, Lan D, Fu W, Li J, Yin S. Molecular characterization of MSX2 gene and its role in regulating steroidogenesis in yak (Bos grunniens) cumulus granulosa cells. Theriogenology 2025; 231:101-110. [PMID: 39427591 DOI: 10.1016/j.theriogenology.2024.10.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 10/13/2024] [Accepted: 10/16/2024] [Indexed: 10/22/2024]
Abstract
Cumulus granulosa cells (CGCs) are somatic cells surrounding the oocyte that play an important role in oocyte growth, meiotic maturation, ovulation, and fertilization in mammals. Therefore, revealing the molecular mechanisms related to the development and function of CGCs is essential for further understanding the regulatory network in female reproduction. MSX2 belongs to the highly conserved msh homeobox gene family and plays diverse roles in different biological processes. This study cloned the coding sequence (CDS) of the yak MSX2 gene and detected the abundance and localization of MSX2 in the major female reproductive organs. The results indicated that the CDS of this gene included 747 base pairs and encoded 248 amino acids. The abundance of MSX2 mRNA was highly expressed in the luteal phase of the yak ovary during the estrous cycle, and MSX2 protein was widely expressed in different female reproductive organs, including the ovary, corpus luteum, uterus, and oviduct. Repressing MSX2 abundance in yak CGCs declined the cell viability and defective steroidogenesis. Several genes abundances related to cell proliferation, apoptosis, and sterogenesis also changed after MSX2 knockdown. MSX2 overexpression had the opposite effect on cell viability in yak CGCs. These results reveal the specific mechanism by which MSX2 regulates the development and function of yak CGCs and give novel and valuable insights into the mechanisms involved in yak reproduction.
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Affiliation(s)
- Jun Ma
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, Sichuan, 610041, China
| | - Gan Yang
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, Sichuan, 610041, China
| | - Xuan Qin
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, Sichuan, 610041, China
| | - Luoyu Mo
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, Sichuan, 610041, China
| | - Xianrong Xiong
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, Sichuan, 610041, China; Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province, Ministry of Education, Chengdu, Sichuan, 610041, China
| | - Yan Xiong
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, Sichuan, 610041, China; Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province, Ministry of Education, Chengdu, Sichuan, 610041, China
| | - Honghong He
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, Sichuan, 610041, China; Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province, Ministry of Education, Chengdu, Sichuan, 610041, China
| | - Daoliang Lan
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, Sichuan, 610041, China; Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province, Ministry of Education, Chengdu, Sichuan, 610041, China
| | - Wei Fu
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, Sichuan, 610041, China; Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province, Ministry of Education, Chengdu, Sichuan, 610041, China
| | - Jian Li
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, Sichuan, 610041, China; Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province, Ministry of Education, Chengdu, Sichuan, 610041, China
| | - Shi Yin
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, Sichuan, 610041, China; Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province, Ministry of Education, Chengdu, Sichuan, 610041, China; Key Laboratory of Modem Technology (Southwest Minzu University), State Ethnic Affairs Commission, Chengdu, Sichuan, 610041, China.
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Jiang B, Zhang W, Zhang X, Sun Y. Targeting senescent cells to reshape the tumor microenvironment and improve anticancer efficacy. Semin Cancer Biol 2024; 101:58-73. [PMID: 38810814 DOI: 10.1016/j.semcancer.2024.05.002] [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: 01/17/2024] [Revised: 05/09/2024] [Accepted: 05/12/2024] [Indexed: 05/31/2024]
Abstract
Cancer is daunting pathology with remarkable breadth and scope, spanning genetics, epigenetics, proteomics, metalobomics and cell biology. Cellular senescence represents a stress-induced and essentially irreversible cell fate associated with aging and various age-related diseases, including malignancies. Senescent cells are characterized of morphologic alterations and metabolic reprogramming, and develop a highly active secretome termed as the senescence-associated secretory phenotype (SASP). Since the first discovery, senescence has been understood as an important barrier to tumor progression, as its induction in pre-neoplastic cells limits carcinogenesis. Paradoxically, senescent cells arising in the tumor microenvironment (TME) contribute to tumor progression, including augmented therapeutic resistance. In this article, we define typical forms of senescent cells commonly observed within the TME and how senescent cells functionally remodel their surrounding niche, affect immune responses and promote cancer evolution. Furthermore, we highlight the recently emerging pipelines of senotherapies particularly senolytics, which can selectively deplete senescent cells from affected organs in vivo and impede tumor progression by restoring therapeutic responses and securing anticancer efficacies. Together, co-targeting cancer cells and their normal but senescent counterparts in the TME holds the potential to achieve increased therapeutic benefits and restrained disease relapse in future clinical oncology.
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Affiliation(s)
- Birong Jiang
- School of Pharmacy, Institute of Aging Medicine, Binzhou Medical University, Yantai, Shandong 264003, China
| | - Wei Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xuguang Zhang
- Mengniu Institute of Nutrition Science, Global R&D Innovation Center, Shanghai 200124, China
| | - Yu Sun
- School of Pharmacy, Institute of Aging Medicine, Binzhou Medical University, Yantai, Shandong 264003, China; CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China; Department of Medicine and VAPSHCS, University of Washington, Seattle, WA 98195, USA.
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Guo M, Zhang J, Han J, Hu Y, Ni H, Yuan J, Sun Y, Liu M, Gao L, Liao W, Ma C, Liu Y, Li S, Li N. VEGFR2 blockade inhibits glioblastoma cell proliferation by enhancing mitochondrial biogenesis. J Transl Med 2024; 22:419. [PMID: 38702818 PMCID: PMC11067099 DOI: 10.1186/s12967-024-05155-1] [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: 12/06/2023] [Accepted: 04/02/2024] [Indexed: 05/06/2024] Open
Abstract
BACKGROUND Glioblastoma is an aggressive brain tumor linked to significant angiogenesis and poor prognosis. Anti-angiogenic therapies with vascular endothelial growth factor receptor 2 (VEGFR2) inhibition have been investigated as an alternative glioblastoma treatment. However, little is known about the effect of VEGFR2 blockade on glioblastoma cells per se. METHODS VEGFR2 expression data in glioma patients were retrieved from the public database TCGA. VEGFR2 intervention was implemented by using its selective inhibitor Ki8751 or shRNA. Mitochondrial biogenesis of glioblastoma cells was assessed by immunofluorescence imaging, mass spectrometry, and western blot analysis. RESULTS VEGFR2 expression was higher in glioma patients with higher malignancy (grade III and IV). VEGFR2 inhibition hampered glioblastoma cell proliferation and induced cell apoptosis. Mass spectrometry and immunofluorescence imaging showed that the anti-glioblastoma effects of VEGFR2 blockade involved mitochondrial biogenesis, as evidenced by the increases of mitochondrial protein expression, mitochondria mass, mitochondrial oxidative phosphorylation (OXPHOS), and reactive oxygen species (ROS) production, all of which play important roles in tumor cell apoptosis, growth inhibition, cell cycle arrest and cell senescence. Furthermore, VEGFR2 inhibition exaggerated mitochondrial biogenesis by decreased phosphorylation of AKT and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which mobilized PGC1α into the nucleus, increased mitochondrial transcription factor A (TFAM) expression, and subsequently enhanced mitochondrial biogenesis. CONCLUSIONS VEGFR2 blockade inhibits glioblastoma progression via AKT-PGC1α-TFAM-mitochondria biogenesis signaling cascade, suggesting that VEGFR2 intervention might bring additive therapeutic values to anti-glioblastoma therapy.
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Affiliation(s)
- Min Guo
- Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
| | - Junhao Zhang
- Department of Medicine-Solna, Division of Cardiovascular Medicine, Karolinska University Hospital, Solna, 171 76, Stockholm, Sweden
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiang Han
- Department of Biopharmaceutical Sciences and National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Yingyue Hu
- Department of Biopharmaceutical Sciences and National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Hao Ni
- Department of Medicine-Solna, Division of Cardiovascular Medicine, Karolinska University Hospital, Solna, 171 76, Stockholm, Sweden
- Department of Gynaecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Juan Yuan
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Yang Sun
- Department of Immunology and Shandong University-Karolinska Institutet Collaborative Laboratory, Shandong University Cheeloo Medical College, School of Basic Medicine, Jinan, China
| | - Meijuan Liu
- Department of Biopharmaceutical Sciences and National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Lifen Gao
- Department of Immunology and Shandong University-Karolinska Institutet Collaborative Laboratory, Shandong University Cheeloo Medical College, School of Basic Medicine, Jinan, China
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chunhong Ma
- Department of Immunology and Shandong University-Karolinska Institutet Collaborative Laboratory, Shandong University Cheeloo Medical College, School of Basic Medicine, Jinan, China
| | - Yaou Liu
- Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Shuijie Li
- Department of Biopharmaceutical Sciences and National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), College of Pharmacy, Harbin Medical University, Harbin, China.
| | - Nailin Li
- Department of Medicine-Solna, Division of Cardiovascular Medicine, Karolinska University Hospital, Solna, 171 76, Stockholm, Sweden.
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Li Q, Li Y, Qiao Q, Zhao N, Yang Y, Wang L, Wang Y, Guo C, Guo Y. Oral administration of Bifidobacterium breve improves anti-angiogenic drugs-derived oral mucosal wound healing impairment via upregulation of interleukin-10. Int J Oral Sci 2023; 15:56. [PMID: 38072973 PMCID: PMC10711028 DOI: 10.1038/s41368-023-00263-y] [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: 06/23/2023] [Revised: 10/31/2023] [Accepted: 11/20/2023] [Indexed: 12/18/2023] Open
Abstract
Recent studies have suggested that long-term application of anti-angiogenic drugs may impair oral mucosal wound healing. This study investigated the effect of sunitinib on oral mucosal healing impairment in mice and the therapeutic potential of Bifidobacterium breve (B. breve). A mouse hard palate mucosal defect model was used to investigate the influence of sunitinib and/or zoledronate on wound healing. The volume and density of the bone under the mucosal defect were assessed by micro-computed tomography (micro-CT). Inflammatory factors were detected by protein microarray analysis and enzyme-linked immunosorbent assay (ELISA). The senescence and biological functions were tested in oral mucosal stem cells (OMSCs) treated with sunitinib. Ligated loop experiments were used to investigate the effect of oral B. breve. Neutralizing antibody for interleukin-10 (IL-10) was used to prove the critical role of IL-10 in the pro-healing process derived from B. breve. Results showed that sunitinib caused oral mucosal wound healing impairment in mice. In vitro, sunitinib induced cellular senescence in OMSCs and affected biological functions such as proliferation, migration, and differentiation. Oral administration of B. breve reduced oral mucosal inflammation and promoted wound healing via intestinal dendritic cells (DCs)-derived IL-10. IL-10 reversed cellular senescence caused by sunitinib in OMSCs, and IL-10 neutralizing antibody blocked the ameliorative effect of B. breve on oral mucosal wound healing under sunitinib treatment conditions. In conclusion, sunitinib induces cellular senescence in OMSCs and causes oral mucosal wound healing impairment and oral administration of B. breve could improve wound healing impairment via intestinal DCs-derived IL-10.
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Affiliation(s)
- Qingxiang Li
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Yuke Li
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Qiao Qiao
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Ning Zhao
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Yuanning Yang
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Lin Wang
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Yifei Wang
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Chuanbin Guo
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China.
| | - Yuxing Guo
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China.
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10
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Kellers F. [Tumor-immune cell interaction and senescence-associated molecules in colorectal carcinoma]. PATHOLOGIE (HEIDELBERG, GERMANY) 2023; 44:113-120. [PMID: 38038733 DOI: 10.1007/s00292-023-01267-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/19/2023] [Indexed: 12/02/2023]
Abstract
BACKGROUND Cellular senescence permanently arrests the cell cycle of premalignant cells following protumorigenic stimuli, counteracting tumor progression. Senescence induction leads to phenotypic and metabolic changes and alters the interaction with the cells' microenvironment. This mediates tumor immunosurveillance but bears promalignant potential and may contribute to disease progression. OBJECTIVES Our study aims to investigate the prognostic potential of senescence markers in colorectal carcinoma (CRC) and to understand the interaction of senescent tumor cells and immune cells. MATERIALS AND METHODS Immunohistochemical markers were studied on a tissue microarray (TMA) containing tumor tissue of n = 598 CRC patients and were evaluated using digital image analysis. Results were correlated with disease-specific survival (DSS) and progression-free survival (PFS). Consecutive TMA sections were stained for senescence markers and immune cell markers to analyze the spatial relation of those cell populations. Senescence was induced in CRC cell lines in vitro and co-cultures with various immune cell lines were established to study the interactions. RESULTS Expression of different senescent-associated markers is associated with increased or decreased DSS and PFS. Close proximity of p21+ senescent tumor cells and CD8+ immune cells correlates with increased DSS and PFS. In vitro, senescent cells were dose-dependently eliminated by immune cells, which is facilitated via direct cell-cell contact and induction of apoptosis. CONCLUSIONS Depicting the initiation of this important anti-tumor mechanism, markers of cellular senescence are of significant prognostic relevance in CRC. Moreover, our results show the pleiotropic effect of senescence in vivo. Absence as well as exceeding expression of senescence markers are associated with a negative prognosis in CRC. The impact of cellular senescence depends on the tumor microenvironment and the immunosurveillance of senescent cells. Proximity analyses of senescent cells and tumor-infiltrating immune cells have significant prognostic relevance and reflect this.
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Affiliation(s)
- Franziska Kellers
- Institut für Pathologie, Universitätsmedizin Mainz, Mainz, Deutschland.
- Institut für Pathologie, Universitätsklinikum Schleswig-Holstein, Kiel, Deutschland.
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11
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Kashyap MK, Mangrulkar SV, Kushwaha S, Ved A, Kale MB, Wankhede NL, Taksande BG, Upaganlawar AB, Umekar MJ, Koppula S, Kopalli SR. Recent Perspectives on Cardiovascular Toxicity Associated with Colorectal Cancer Drug Therapy. Pharmaceuticals (Basel) 2023; 16:1441. [PMID: 37895912 PMCID: PMC10610064 DOI: 10.3390/ph16101441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/06/2023] [Accepted: 10/08/2023] [Indexed: 10/29/2023] Open
Abstract
Cardiotoxicity is a well-known adverse effect of cancer-related therapy that has a significant influence on patient outcomes and quality of life. The use of antineoplastic drugs to treat colorectal cancers (CRCs) is associated with a number of undesirable side effects including cardiac complications. For both sexes, CRC ranks second and accounts for four out of every ten cancer deaths. According to the reports, almost 39% of patients with colorectal cancer who underwent first-line chemotherapy suffered cardiovascular impairment. Although 5-fluorouracil is still the backbone of chemotherapy regimen for colorectal, gastric, and breast cancers, cardiotoxicity caused by 5-fluorouracil might affect anywhere from 1.5% to 18% of patients. The precise mechanisms underlying cardiotoxicity associated with CRC treatment are complex and may involve the modulation of various signaling pathways crucial for maintaining cardiac health including TKI ErbB2 or NRG-1, VEGF, PDGF, BRAF/Ras/Raf/MEK/ERK, and the PI3/ERK/AMPK/mTOR pathway, resulting in oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis, ultimately damaging cardiac tissue. Thus, the identification and management of cardiotoxicity associated with CRC drug therapy while minimizing the negative impact have become increasingly important. The purpose of this review is to catalog the potential cardiotoxicities caused by anticancer drugs and targeted therapy used to treat colorectal cancer as well as strategies focused on early diagnosing, prevention, and treatment of cardiotoxicity associated with anticancer drugs used in CRC therapy.
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Affiliation(s)
- Monu Kumar Kashyap
- Goel Institute of Pharmaceutical Sciences, Faizabad Road, Lucknow 226028, Uttar Pradesh, India;
- Dr. A. P. J. Abdul Kalam Technical University, Lucknow 222001, Uttar Pradesh, India;
| | - Shubhada V. Mangrulkar
- Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India; (S.V.M.); (M.B.K.); (N.L.W.)
| | - Sapana Kushwaha
- National Institute of Pharmaceutical Education and Research, Raebareli 229010, Uttar Pradesh, India
| | - Akash Ved
- Dr. A. P. J. Abdul Kalam Technical University, Lucknow 222001, Uttar Pradesh, India;
| | - Mayur B. Kale
- Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India; (S.V.M.); (M.B.K.); (N.L.W.)
| | - Nitu L. Wankhede
- Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India; (S.V.M.); (M.B.K.); (N.L.W.)
| | - Brijesh G. Taksande
- Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India; (S.V.M.); (M.B.K.); (N.L.W.)
| | - Aman B. Upaganlawar
- SNJB’s Shriman Sureshdada Jain Collge of Pharmacy, Neminagar, Chandwad, Nadik 423101, Maharashtra, India;
| | - Milind J. Umekar
- Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India; (S.V.M.); (M.B.K.); (N.L.W.)
| | - Sushruta Koppula
- College of Biomedical and Health Sciences, Konkuk University, Chungju-Si 27478, Chungcheongbuk Do, Republic of Korea
| | - Spandana Rajendra Kopalli
- Department of Bioscience and Biotechnology, Sejong University, Gwangjin-gu, Seoul 05006, Republic of Korea
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12
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Fettucciari K, Fruganti A, Stracci F, Spaterna A, Marconi P, Bassotti G. Clostridioides difficile Toxin B Induced Senescence: A New Pathologic Player for Colorectal Cancer? Int J Mol Sci 2023; 24:8155. [PMID: 37175861 PMCID: PMC10179142 DOI: 10.3390/ijms24098155] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/26/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Clostridioides difficile (C. difficile) is responsible for a high percentage of gastrointestinal infections and its pathological activity is due to toxins A and B. C. difficile infection (CDI) is increasing worldwide due to the unstoppable spread of C. difficile in the anthropized environment and the progressive human colonization. The ability of C. difficile toxin B to induce senescent cells and the direct correlation between CDI, irritable bowel syndrome (IBS), and inflammatory bowel diseases (IBD) could cause an accumulation of senescent cells with important functional consequences. Furthermore, these senescent cells characterized by long survival could push pre-neoplastic cells originating in the colon towards the complete neoplastic transformation in colorectal cancer (CRC) by the senescence-associated secretory phenotype (SASP). Pre-neoplastic cells could appear as a result of various pro-carcinogenic events, among which, are infections with bacteria that produce genotoxins that generate cells with high genetic instability. Therefore, subjects who develop IBS and/or IBD after CDI should be monitored, especially if they then have further CDI relapses, waiting for the availability of senolytic and anti-SASP therapies to resolve the pro-carcinogenic risk due to accumulation of senescent cells after CDI followed by IBS and/or IBD.
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Affiliation(s)
- Katia Fettucciari
- Biosciences & Medical Embryology Section, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy;
| | - Alessandro Fruganti
- School of Biosciences and Veterinary Medicine, University of Camerino, 62024 Matelica, Italy
| | - Fabrizio Stracci
- Public Health Section, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy;
| | - Andrea Spaterna
- School of Biosciences and Veterinary Medicine, University of Camerino, 62024 Matelica, Italy
| | - Pierfrancesco Marconi
- Biosciences & Medical Embryology Section, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy;
| | - Gabrio Bassotti
- Gastroenterology, Hepatology & Digestive Endoscopy Section, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy;
- Gastroenterology & Hepatology Unit, Santa Maria Della Misericordia Hospital, 06129 Perugia, Italy
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13
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Bhukdee D, Nuwongsri P, Israsena N, Sriswasdi S. Improved Delineation of Colorectal Cancer Molecular Subtypes and Functional Profiles with a 62-Gene Panel. Mol Cancer Res 2023; 21:240-252. [PMID: 36490322 DOI: 10.1158/1541-7786.mcr-22-0476] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 11/01/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022]
Abstract
Since its establishment in 2015, the transcriptomics-based consensus molecular subtype (CMS) classification has unified our understanding of colorectal cancer. Each of the four CMS exhibited distinctive high-level molecular signatures that correlated well with prognosis and treatment response. Nonetheless, many key aspects of colorectal cancer progression and intra-subtype heterogeneity remain unresolved. This is partly because the bulk transcriptomic data used to define CMS contain substantial interference from non-tumor cells. Here, we propose a concise panel of 62 genes that not only accurately recapitulates all key characteristics of the four original CMS but also identifies three additional subpopulations with unique molecular signatures. Validation on independent cohorts confirms that the new CMS4 intra-subtypes coincide with single-cell-derived intrinsic subtypes and that the panel consists of many immune cell-type markers that can capture the status of tumor microenvironment. Furthermore, a 2D embedding of CMS structure based on the proposed gene panel provides a high-resolution view of the functional pathways and cell-type markers that underlie each CMS intra-subtype and the continuous progression from CMS2 to CMS4 subtypes. Our gene panel and 2D visualization refined the delineation of colorectal cancer subtypes and could aid further discovery of molecular mechanisms in colorectal cancer. IMPLICATIONS : Well-selected gene panel and representation can capture both the continuum of cancer cell states and tumor microenvironment status.
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Affiliation(s)
- Dhup Bhukdee
- Science Division, Mahidol University International College, Nakhon Pathom, Thailand.,Center of Excellence in Computational Molecular Biology, Faculty of Medicine, Chulalongkorn University, Pathum Wan, Bangkok, Thailand
| | - Pattarin Nuwongsri
- Center of Excellence in Computational Molecular Biology, Faculty of Medicine, Chulalongkorn University, Pathum Wan, Bangkok, Thailand.,Center of Excellence in Stem Cell and Cell Therapy, Faculty of Medicine, Chulalongkorn University, Pathum Wan, Bangkok, Thailand
| | - Nipan Israsena
- Center of Excellence in Stem Cell and Cell Therapy, Faculty of Medicine, Chulalongkorn University, Pathum Wan, Bangkok, Thailand.,Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Pathum Wan, Bangkok, Thailand
| | - Sira Sriswasdi
- Center of Excellence in Computational Molecular Biology, Faculty of Medicine, Chulalongkorn University, Pathum Wan, Bangkok, Thailand.,Center for Artificial Intelligence in Medicine, Research Affairs, Faculty of Medicine, Chulalongkorn University, Pathum Wan, Bangkok, Thailand
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14
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Domen A, Deben C, Verswyvel J, Flieswasser T, Prenen H, Peeters M, Lardon F, Wouters A. Cellular senescence in cancer: clinical detection and prognostic implications. J Exp Clin Cancer Res 2022; 41:360. [PMID: 36575462 PMCID: PMC9793681 DOI: 10.1186/s13046-022-02555-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/30/2022] [Indexed: 12/28/2022] Open
Abstract
Cellular senescence is a state of stable cell-cycle arrest with secretory features in response to cellular stress. Historically, it has been considered as an endogenous evolutionary homeostatic mechanism to eliminate damaged cells, including damaged cells which are at risk of malignant transformation, thereby protecting against cancer. However, accumulation of senescent cells can cause long-term detrimental effects, mainly through the senescence-associated secretory phenotype, and paradoxically contribute to age-related diseases including cancer. Besides its role as tumor suppressor, cellular senescence is increasingly being recognized as an in vivo response in cancer patients to various anticancer therapies. Its role in cancer is ambiguous and even controversial, and senescence has recently been promoted as an emerging hallmark of cancer because of its hallmark-promoting capabilities. In addition, the prognostic implications of cellular senescence have been underappreciated due to the challenging detection and sparse in and ex vivo evidence of cellular senescence in cancer patients, which is only now catching up. In this review, we highlight the approaches and current challenges of in and ex vivo detection of cellular senescence in cancer patients, and we discuss the prognostic implications of cellular senescence based on in and ex vivo evidence in cancer patients.
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Affiliation(s)
- Andreas Domen
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium.
- Department of Oncology, Antwerp University Hospital (UZA), 2650, Edegem (Antwerp), Belgium.
| | - Christophe Deben
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium
| | - Jasper Verswyvel
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium
| | - Tal Flieswasser
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium
| | - Hans Prenen
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium
- Department of Oncology, Antwerp University Hospital (UZA), 2650, Edegem (Antwerp), Belgium
| | - Marc Peeters
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium
- Department of Oncology, Antwerp University Hospital (UZA), 2650, Edegem (Antwerp), Belgium
| | - Filip Lardon
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium
| | - An Wouters
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium
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15
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Bousset L, Gil J. Targeting senescence as an anticancer therapy. Mol Oncol 2022; 16:3855-3880. [PMID: 36065138 PMCID: PMC9627790 DOI: 10.1002/1878-0261.13312] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/12/2022] [Accepted: 08/21/2022] [Indexed: 01/10/2023] Open
Abstract
Cellular senescence is a stress response elicited by different molecular insults. Senescence results in cell cycle exit and is characterised by multiple phenotypic changes such as the production of a bioactive secretome. Senescent cells accumulate during ageing and are present in cancerous and fibrotic lesions. Drugs that selectively kill senescent cells (senolytics) have shown great promise for the treatment of age-related diseases. Senescence plays paradoxical roles in cancer. Induction of senescence limits cancer progression and contributes to therapy success, but lingering senescent cells fuel progression, recurrence, and metastasis. In this review, we describe the intricate relation between senescence and cancer. Moreover, we enumerate how current anticancer therapies induce senescence in tumour cells and how senolytic agents could be deployed to complement anticancer therapies. "One-two punch" therapies aim to first induce senescence in the tumour followed by senolytic treatment to target newly exposed vulnerabilities in senescent tumour cells. "One-two punch" represents an emerging and promising new strategy in cancer treatment. Future challenges of "one-two punch" approaches include how to best monitor senescence in cancer patients to effectively survey their efficacy.
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Affiliation(s)
- Laura Bousset
- MRC London Institute of Medical Sciences (LMS)UK
- Faculty of Medicine, Institute of Clinical Sciences (ICS)Imperial College LondonUK
| | - Jesús Gil
- MRC London Institute of Medical Sciences (LMS)UK
- Faculty of Medicine, Institute of Clinical Sciences (ICS)Imperial College LondonUK
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16
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Saoudi Gonzalez N, López D, Gómez D, Ros J, Baraibar I, Salva F, Tabernero J, Élez E. Pharmacokinetics and pharmacodynamics of approved monoclonal antibody therapy for colorectal cancer. Expert Opin Drug Metab Toxicol 2022; 18:755-767. [PMID: 36582117 DOI: 10.1080/17425255.2022.2160316] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION The introduction of monoclonal antibodies to the chemotherapy backbone treatment has challenged the paradigm of metastatic colorectal cancer (mCRC) treatment. Their mechanism of action and pharmacokinetics are complex but important to understand in order to improve patient selection and treatment outcomes for mCRC population. AREAS COVERED This review examines the scientific data, pharmacodynamics, and pharmacokinetics of approved monoclonal antibodies used to treat mCRC patients, including agents targeting signaling via VEGFR (bevacizumab and ramucirumab), EGFR (cetuximab and panitumumab), HER2/3 target therapy, and immunotherapy agents such as pembrolizumab or nivolumab. Efficacy and mechanism of action of bispecific antibodies are also covered. EXPERT OPINION mCRC is a heterogeneous disease and the optimal selection and sequence of treatments is challenging. Monoclonal antibodies have complex pharmacokinetics and pharmacodynamics, with important interactions between them. The arrival of bioequivalent molecules to the market increases the need for the characterization of pharmacokinetics and pharmacodynamics of classic monoclonal antibodies to reach bioequivalent novel molecules.
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Affiliation(s)
- Nadia Saoudi Gonzalez
- Medical Oncology Department, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.,Medical Oncology Department, Vall d'Hebron Institute of Oncology, Vhio Barcelona, Spain
| | - Daniel López
- Medical Oncology Department, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Diego Gómez
- Medical Oncology Department, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Javier Ros
- Medical Oncology Department, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.,Medical Oncology Department, Vall d'Hebron Institute of Oncology, Vhio Barcelona, Spain
| | - Iosune Baraibar
- Medical Oncology Department, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.,Medical Oncology Department, Vall d'Hebron Institute of Oncology, Vhio Barcelona, Spain
| | - Francesc Salva
- Medical Oncology Department, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.,Medical Oncology Department, Vall d'Hebron Institute of Oncology, Vhio Barcelona, Spain
| | - Josep Tabernero
- Medical Oncology Department, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.,Medical Oncology Department, Vall d'Hebron Institute of Oncology, Vhio Barcelona, Spain
| | - Elena Élez
- Medical Oncology Department, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.,Medical Oncology Department, Vall d'Hebron Institute of Oncology, Vhio Barcelona, Spain
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17
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Wu Y, Xie M, Sun JH, Li CC, Dong GH, Zhang QS, Cui PL. Cellular senescence: a promising therapeutic target in colorectal cancer. Future Oncol 2022; 18:3463-3470. [PMID: 36069254 DOI: 10.2217/fon-2021-0661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Colorectal cancer is one of the most malignant cancers worldwide, and efforts have been made to elucidate the mechanism of colorectal carcinogenesis. Cellular senescence is a physiological process in cell life, but it is also found in cancer initiation and progression. Lines of evidence show that senescence may influence the development and progression of colorectal carcinogenesis. Here, the authors review the characteristics of senescence and the recent findings of a relationship between senescence and colorectal cancer.
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Affiliation(s)
- Yue Wu
- International Medical Services (IMS), Beijing Tiantan Hospital of Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Min Xie
- International Medical Services (IMS), Beijing Tiantan Hospital of Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Jia-Huan Sun
- International Medical Services (IMS), Beijing Tiantan Hospital of Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Cong-Cong Li
- International Medical Services (IMS), Beijing Tiantan Hospital of Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Ge-Hong Dong
- Department of Pathology, Beijing Tiantan Hospital of Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Qin-Sheng Zhang
- Department of Gastroenterology, Henan Province Hospital of Traditional Chinese Medicine, Henan University of Chinese Medicine, No. 6 Dongfeng Road, Jinshui District, Zhengzhou, Henan, 450002, China
| | - Pei-Lin Cui
- International Medical Services (IMS), Beijing Tiantan Hospital of Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
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18
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Kellers F, Fernandez A, Konukiewitz B, Schindeldecker M, Tagscherer KE, Heintz A, Jesinghaus M, Roth W, Foersch S. Senescence-Associated Molecules and Tumor-Immune-Interactions as Prognostic Biomarkers in Colorectal Cancer. Front Med (Lausanne) 2022; 9:865230. [PMID: 35492321 PMCID: PMC9039237 DOI: 10.3389/fmed.2022.865230] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 03/08/2022] [Indexed: 11/20/2022] Open
Abstract
Background and Aims The initiation of cellular senescence in response to protumorigenic stimuli counteracts malignant progression in (pre)malignant cells. Besides arresting proliferation, cells entering this terminal differentiation state adopt a characteristic senescence-associated secretory phenotype (SASP) which initiates alterations to their microenvironment and effects immunosurveillance of tumorous lesions. However, some effects mediated by senescent cells contribute to disease progression. Currently, the exploration of senescent cells' impact on the tumor microenvironment and the evaluation of senescence as possible target in colorectal cancer (CRC) therapy demand reliable detection of cellular senescence in vivo. Therefore, specific immunohistochemical biomarkers are required. Our aim is to analyze the clinical implications of senescence detection in colorectal carcinoma and to investigate the interactions of senescent tumor cells and their immune microenvironment in vitro and in vivo. Methods Senescence was induced in CRC cell lines by low-dose-etoposide treatment and confirmed by Senescence-associated β-galactosidase (SA-β-GAL) staining and fluorescence activated cell sorting (FACS) analysis. Co-cultures of senescent cells and immune cells were established. Multiple cell viability assays, electron microscopy and live cell imaging were conducted. Immunohistochemical (IHC) markers of senescence and immune cell subtypes were studied in a cohort of CRC patients by analyzing a tissue micro array (TMA) and performing digital image analysis. Results were compared to disease-specific survival (DSS) and progression-free survival (PFS). Results Varying expression of senescence markers in tumor cells was associated with in- or decreased survival of CRC patients. Proximity analysis of p21-positive senescent tumor cells and cytotoxic T cells revealed a significantly better prognosis for patients in which these cell types have the possibility to directly interact. In vitro, NK-92 cells (mimicking natural killer T cells) or TALL-104 cells (mimicking both cytotoxic T cells and natural killer T cells) led to dose-dependent specific cytotoxicity in >75 % of the senescent CRC cells but <20 % of the proliferating control CRC cells. This immune cell-mediated senolysis seems to be facilitated via direct cell-cell contact inducing apoptosis and granule exocytosis. Conclusion Counteracting tumorigenesis, cellular senescence is of significant relevance in CRC. We show the dual role of senescence bearing both beneficial and malignancy-promoting potential in vivo. Absence as well as exceeding expression of senescence markers are associated with bad prognosis in CRC. The antitumorigenic potential of senescence induction is determined by tumor micromilieu and immune cell-mediated elimination of senescent cells.
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Affiliation(s)
- Franziska Kellers
- Institute of Pathology, University Medical Center Mainz, Mainz, Germany
| | - Aurélie Fernandez
- Institute of Pathology, University Medical Center Mainz, Mainz, Germany
| | - Björn Konukiewitz
- Institute of Pathology, Christian-Albrecht University of Kiel, Kiel, Germany
| | | | | | - Achim Heintz
- Department of General, Visceral and Vascular Surgery, Catholic Hospital Mainz, Mainz, Germany
| | - Moritz Jesinghaus
- Department of Pathology, University Hospital Marburg, Marburg, Germany
| | - Wilfried Roth
- Institute of Pathology, University Medical Center Mainz, Mainz, Germany
| | - Sebastian Foersch
- Institute of Pathology, University Medical Center Mainz, Mainz, Germany
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Alhazzani K, Venkatesan T, Natarajan U, Algahtani M, Alaseem A, Alobid S, Rathinavelu A. Evaluation of antitumor effects of VEGFR-2 inhibitor F16 in a colorectal xenograft model. Biotechnol Lett 2022; 44:787-801. [PMID: 35501620 DOI: 10.1007/s10529-022-03243-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 03/04/2022] [Indexed: 11/02/2022]
Abstract
OBJECTIVES Colorectal cancer (CRC) is the third most prevalent type of cancer in the United States. The treatment options for cancer include surgery, chemotherapy, radiation, and/or targeted therapy, which show significant improvement in overall survival. Among the various available treatments, antagonizing VEGF/VEGFR-2 pathways have shown effectiveness in limiting colorectal cancer growth and improving clinical outcomes. In this regard, we hypothesized that F16, a novel VEGFR-2 inhibitor, would control colorectal cancer growth by blocking the VEGFR-2 singling pathway in both in vitro and in vivo conditions. Therefore, the current study was aimed to analyze the efficacy of F16 on the growth of Colo 320DM cells under in vitro and in vivo conditions. RESULTS Human RT2 profiler PCR array analysis results clearly showed that angiogenesis and anti-apoptosis-related gene expressions were significantly reduced in HUVEC cells after F16 (5 μM) treatment. In addition, Western blot results revealed that F16 attenuated the downstream signaling of the VEGFR-2 pathway in HUVEC cells by up-regulating the p53 and p21 levels and down-regulating the p-AKT and p-FAK levels. Accordingly, F16 confirmed potent cytotoxic effects against the cell viability of Colo 320DM tumors, with an IC50 value of 9.52 ± 1.49 µM. Furthermore, treatment of mice implanted with Colo 320DM xenograft tumors showed a significant reduction in tumor growth and increases in survival rate compared to controls. Immunohistochemistry analysis of tumor tissues showed a reduction in CD31 levels also in F16 treated groups. CONCLUSIONS These results justify further evaluation of F16 as a potential new therapeutic agent for treating colorectal cancers.
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Affiliation(s)
- Khalid Alhazzani
- Pharmacology and Toxicology Department, College of Pharmacy, King Saud University, Riyadh, 12371, Saudi Arabia
| | - Thiagarajan Venkatesan
- Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, 3321 College Ave., Fort Lauderdale, FL, 33314, USA
| | - Umamaheswari Natarajan
- Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, 3321 College Ave., Fort Lauderdale, FL, 33314, USA
| | - Mohammad Algahtani
- Pharmacology and Toxicology Department, College of Pharmacy, King Saud University, Riyadh, 12371, Saudi Arabia
| | - Ali Alaseem
- College of Medicine, Al-Imam Mohammad Ibn Saud Islamic University, Riyadh, 13317, Saudi Arabia
| | - Saad Alobid
- Pharmacology and Toxicology Department, College of Pharmacy, King Saud University, Riyadh, 12371, Saudi Arabia
| | - Appu Rathinavelu
- Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, 3321 College Ave., Fort Lauderdale, FL, 33314, USA. .,College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, 33314, USA.
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20
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Fakhri S, Zachariah Moradi S, DeLiberto LK, Bishayee A. Cellular senescence signaling in cancer: A novel therapeutic target to combat human malignancies. Biochem Pharmacol 2022; 199:114989. [DOI: 10.1016/j.bcp.2022.114989] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/05/2022] [Accepted: 03/07/2022] [Indexed: 12/26/2022]
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21
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Kido Y, Ando T, Iga T, Ema M, Kubota Y, Tai-Nagara I. Genetic Deletion of Vascular Endothelial Growth Factor Receptor 2 in Endothelial Cells Leads to Immediate Disruption of Tumor Vessels and Aggravation of Hypoxia. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:379-388. [PMID: 34861214 DOI: 10.1016/j.ajpath.2021.11.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/27/2021] [Accepted: 11/04/2021] [Indexed: 06/13/2023]
Abstract
Vascular endothelial growth factor (VEGF) blockers are used widely in clinics to target various types of human cancer. Although VEGF blockers exert marked tumor suppressive effects, the therapeutic effects can be limited. Moreover, accumulating evidence shows that VEGF acts not just on endothelial cells but also on various nonendothelial cells, including tumor and immune cells, suggesting a need to revisit the bona fide action of VEGF on endothelial cells using specific genetic mouse models. Herein, tamoxifen-inducible endothelial-specific knockout mice lacking VEGF receptor 2 (Vegfr2), the major signal transducer for VEGF, were used. The initial event resulting from cessation of endothelial Vegfr2 signaling was vascular truncation and fragmentation, rather than maturation of abnormalized vessels. Although deletion of endothelial Vegfr2 suppressed intratumor hemorrhage, it enhanced hypoxia in tumor cells and reduced the number of infiltrating cytotoxic T cells, suggesting a profound reduction in intratumor blood flow. In various tissues, deletion of endothelial Vegfr2 induced regression of healthy capillaries in intestinal villi, substantiating intestinal perforation, which is one of the most common adverse effects of VEGF blockade in humans. Overall, the data suggest that some of the known effects of VEGF blockers on tumor vessels are caused by partial cessation of VEGF signaling, or by actions on nonendothelial cells. The results increase the understanding of the mechanisms underlying anti-angiogenic therapy.
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Affiliation(s)
- Yasuaki Kido
- Department of Anatomy, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Tomofumi Ando
- Department of Anatomy, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan; Department of Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Takahito Iga
- Department of Anatomy, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan; Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Masatsugu Ema
- Department of Stem Cells and Human Disease Models, Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Yoshiaki Kubota
- Department of Anatomy, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
| | - Ikue Tai-Nagara
- Department of Anatomy, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
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22
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Transient Activation of Hedgehog Signaling Inhibits Cellular Senescence and Inflammation in Radiated Swine Salivary Glands through Preserving Resident Macrophages. Int J Mol Sci 2021; 22:ijms222413493. [PMID: 34948290 PMCID: PMC8708934 DOI: 10.3390/ijms222413493] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/12/2021] [Accepted: 12/14/2021] [Indexed: 12/11/2022] Open
Abstract
Salivary gland function is commonly and irreversibly damaged by radiation therapy for head and neck cancer. This damage greatly decreases the patient’s quality of life and is difficult to remedy. Previously, we found that the transient activation of Hedgehog signaling alleviated salivary hypofunction after radiation in both mouse and pig models through the inhibition of radiation-induced cellular senescence that is mediated by resident macrophages in mouse submandibular glands. Here we report that in swine parotid glands sharing many features with humans, the Hedgehog receptor PTCH1 is mainly expressed in macrophages, and levels of PTCH1 and multiple macrophage markers are significantly decreased by radiation but recovered by transient Hedgehog activation. These parotid macrophages mainly express the M2 macrophage marker ARG1, while radiation promotes expression of pro-inflammatory cytokine that is reversed by transient Hedgehog activation. Hedgehog activation likely preserves parotid macrophages after radiation through inhibition of P53 signaling and consequent cellular senescence. Consistently, VEGF, an essential anti-senescence cytokine downstream of Hedgehog signaling, is significantly decreased by radiation but recovered by transient Hedgehog activation. These findings indicate that in the clinically-relevant swine model, transient Hedgehog activation restores the function of irradiated salivary glands through the recovery of resident macrophages and the consequent inhibition of cellular senescence and inflammation.
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23
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Wang G, Wang Y, Yang X, Zhang Y, Lu Y, Li Y. The expression and diagnostic value of serum levels of EphA2 and VEGF-A in patients with colorectal cancer. Cancer Biomark 2021; 31:399-408. [PMID: 34092605 DOI: 10.3233/cbm-201745] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Several molecules are highly expressed in the serum of cancer patients, and can be used as serological markers. This approach has become one of the important auxiliary diagnostic methods for cancer. AIM To investigate the correlation between the serum levels of EphA2 and VEGF-A and the pathogenesis of colorectal cancer (CRC) as well as the potential value of these molecules in the diagnosis of CRC. METHODS ELISA was used to detect the levels of EphA2 and VEGF-A in the peripheral venous serum of 106 newly diagnosed patients with CRC and 69 normal controls. The relationship between the serum EphA2 and VEGF-A levels and the clinicopathological characteristics of CRC patients was analyzed. ROC analysis was used to investigate the diagnostic value of the serum EphA2 and VEGF-A levels in CRC, and the optimal cutoff value was calculated. RESULTS The serum levels of EphA2 and VEGF-A in the CRC group were higher than those in the control as well as CEA, the serum level of EphA2 was positively correlated with the VEGF-A levels, but neither was significantly associated with the clinicopathological parameters of CRC. The ROC curve showed that the single index AUC was < 0.7 except for VEGF-A, and the accuracy of the combined diagnosis was higher than that of any other single index. The diagnosis scheme involving all three markers was the best (the sensitivity was 60.40%, the specificity was 92.8%, and the accuracy was 53.1%). The best critical values calculated were EphA2 > 297.92 ng/ml, EphA2 > 183.92 pg/ml and CEA > 5.19 ng/ml. CONCLUSION The serum levels of EphA2 and VEGF-A are high in CRC patients, and the combine detection of CEA, EphA2 and VEGF-A can significantly improve the diagnostic accuracy of CRC.
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Affiliation(s)
- Ganbiao Wang
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.,Department of General Surgery, Guzhen County Traditional Chinese Medicine Hospital, Guzhen, Bengbu, Anhui, China.,Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yigao Wang
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.,Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xiaodong Yang
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yaqin Zhang
- Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yida Lu
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yongxiang Li
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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24
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Meng X, Li D, Chen L, He H, Wang Q, Hong C, He J, Gao X, Yang Y, Jiang B, Nie G, Yan X, Gao L, Fan K. High-Performance Self-Cascade Pyrite Nanozymes for Apoptosis-Ferroptosis Synergistic Tumor Therapy. ACS NANO 2021; 15:5735-5751. [PMID: 33705663 DOI: 10.1021/acsnano.1c01248] [Citation(s) in RCA: 235] [Impact Index Per Article: 58.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
As next-generation artificial enzymes, nanozymes have shown great promise for tumor catalytic therapy. In particular, their peroxidase-like activity has been employed to catalyze hydrogen peroxide (H2O2) to produce highly toxic hydroxyl radicals (•OH) to kill tumor cells. However, limited by the low affinity between nanozymes with H2O2 and the low level of H2O2 in the tumor microenvironment, peroxidase nanozymes usually produced insufficient •OH to kill tumor cells for therapeutic purposes. Herein, we present a pyrite peroxidase nanozyme with ultrahigh H2O2 affinity, resulting in a 4144- and 3086-fold increase of catalytic activity compared with that of classical Fe3O4 nanozyme and natural horseradish peroxidase, respectively. We found that the pyrite nanozyme also possesses intrinsic glutathione oxidase-like activity, which catalyzes the oxidation of reduced glutathione accompanied by H2O2 generation. Thus, the dual-activity pyrite nanozyme constitutes a self-cascade platform to generate abundant •OH and deplete reduced glutathione, which induces apoptosis as well as ferroptosis of tumor cells. Consequently, it killed apoptosis-resistant tumor cells harboring KRAS mutation by inducing ferroptosis. The pyrite nanozyme also exhibited favorable tumor-specific cytotoxicity and biodegradability to ensure its biosafety. These results indicate that the high-performance pyrite nanozyme is an effective therapeutic reagent and may aid the development of nanozyme-based tumor catalytic therapy.
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Affiliation(s)
- Xiangqin Meng
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- School of Future Technology, University of Chinese Academy of Sciences, Beijing 101408, China
| | - Dandan Li
- Department of Pharmacology, School of Medicine, Institute of Translational Medicine, Yangzhou University, Yangzhou 225001, Jiangsu, China
| | - Lei Chen
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- Department of Pharmacology, School of Medicine, Institute of Translational Medicine, Yangzhou University, Yangzhou 225001, Jiangsu, China
| | - Helen He
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Qian Wang
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Chaoyi Hong
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Jiuyang He
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Xingfa Gao
- Laboratory of Theoretical and Computational Nanoscience, National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing 100190, China
| | - Yili Yang
- Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medicine Sciences, Suzhou 215123, Jiangsu, China
| | - Bing Jiang
- Nanozyme Medical Center, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Guohui Nie
- Department of Otolaryngology and Institute of Translational Medicine, Shenzhen Second People's Hospital/The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen 518035, Guangdong, China
| | - Xiyun Yan
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- School of Future Technology, University of Chinese Academy of Sciences, Beijing 101408, China
- Nanozyme Medical Center, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Lizeng Gao
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- Nanozyme Medical Center, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Kelong Fan
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- Nanozyme Medical Center, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China
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25
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Patel NH, Bloukh S, Alwohosh E, Alhesa A, Saleh T, Gewirtz DA. Autophagy and senescence in cancer therapy. Adv Cancer Res 2021; 150:1-74. [PMID: 33858594 DOI: 10.1016/bs.acr.2021.01.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Tumor cells can undergo diverse responses to cancer therapy. While apoptosis represents the most desirable outcome, tumor cells can alternatively undergo autophagy and senescence. Both autophagy and senescence have the potential to make complex contributions to tumor cell survival via both cell autonomous and cell non-autonomous pathways. The induction of autophagy and senescence in tumor cells, preclinically and clinically, either individually or concomitantly, has generated interest in the utilization of autophagy modulating and senolytic therapies to target autophagy and senescence, respectively. This chapter summarizes the current evidence for the promotion of autophagy and senescence as fundamental responses to cancer therapy and discusses the complexity of their functional contributions to cell survival and disease outcomes. We also highlight current modalities designed to exploit autophagy and senescence in efforts to improve the efficacy of cancer therapy.
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Affiliation(s)
- Nipa H Patel
- Department of Pharmacology and Toxicology and Medicine, Virginia Commonwealth University, Richmond, VA, United States; Massey Cancer Center, Goodwin Research Laboratories, Virginia Commonwealth University, Richmond, VA, United States
| | - Sarah Bloukh
- Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | - Enas Alwohosh
- Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | - Ahmad Alhesa
- Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | - Tareq Saleh
- Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | - David A Gewirtz
- Department of Pharmacology and Toxicology and Medicine, Virginia Commonwealth University, Richmond, VA, United States; Massey Cancer Center, Goodwin Research Laboratories, Virginia Commonwealth University, Richmond, VA, United States.
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26
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Detection of Vascular Reactive Oxygen Species in Experimental Atherosclerosis by High-Resolution Near-Infrared Fluorescence Imaging Using VCAM-1-Targeted Liposomes Entrapping a Fluorogenic Redox-Sensitive Probe. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6685612. [PMID: 33763173 PMCID: PMC7963910 DOI: 10.1155/2021/6685612] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/28/2021] [Accepted: 02/05/2021] [Indexed: 01/06/2023]
Abstract
Excessive production of reactive oxygen species (ROS) and the ensuing oxidative stress are instrumental in all phases of atherosclerosis. Despite the major achievements in understanding the regulatory pathways and molecular sources of ROS in the vasculature, the specific detection and quantification of ROS in experimental models of disease remain a challenge. We aimed to develop a reliable and straightforward imaging procedure to interrogate the ROS overproduction in the vasculature and in various organs/tissues in atherosclerosis. To this purpose, the cell-impermeant ROS Brite™ 700 (RB700) probe that produces bright near-infrared fluorescence upon ROS oxidation was encapsulated into VCAM-1-targeted, sterically stabilized liposomes (VLp). Cultured human endothelial cells (EC) and macrophages (Mac) were used for in vitro experiments. C57BL6/J and ApoE-/- mice were randomized to receive normal or high-fat, cholesterol-rich diet for 10 or 32 weeks. The mice received a retroorbital injection with fluorescent tagged VLp incorporating RB700 (VLp-RB700). After two hours, the specific signals of the oxidized RB700 and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(7-nitro-2-1,3-benzoxadiazol-4-yl) (NBD-DSPE), inserted into liposome bilayers, were measured ex vivo in the mouse aorta and various organs by high-resolution fluorescent imaging. VLp-RB700 was efficiently taken up by cultured human EC and Mac, as confirmed by fluorescence microscopy and spectrofluorimetry. After systemic administration in atherosclerotic ApoE-/- mice, VLp-RB700 were efficiently concentrated at the sites of aortic lesions, as indicated by the augmented NBD fluorescence. Significant increases in oxidized RB700 signal were detected in the aorta and in the liver and kidney of atherosclerotic ApoE-/- mice. RB700 encapsulation into sterically stabilized VCAM-1-sensitive Lp could be a novel strategy for the qualitative and quantitative detection of ROS in the vasculature and various organs and tissues in animal models of disease. The accurate and precise detection of ROS in experimental models of disease could ease the translation of the results to human pathologies.
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Hwang K, Yoon JH, Lee JH, Lee S. Recent Advances in Monoclonal Antibody Therapy for Colorectal Cancers. Biomedicines 2021; 9:39. [PMID: 33466394 PMCID: PMC7824816 DOI: 10.3390/biomedicines9010039] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/31/2020] [Accepted: 12/31/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer deaths worldwide. Recent advances in recombinant DNA technology have led to the development of numerous therapeutic antibodies as major sources of blockbuster drugs for CRC therapy. Simultaneously, increasing numbers of therapeutic targets in CRC have been identified. In this review, we first highlight the physiological and pathophysiological roles and signaling mechanisms of currently known and emerging therapeutic targets, including growth factors and their receptors as well as immune checkpoint proteins, in CRC. Additionally, we discuss the current status of monoclonal antibodies in clinical development and approved by US Food and Drug Administration for CRC therapy.
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Affiliation(s)
| | | | | | - Sukmook Lee
- Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, Seoul 02707, Korea; (K.H.); (J.H.Y.); (J.H.L.)
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28
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Lokesh R, Jeyakanthan J, Kannabiran K. Targeting VEGFR2 protein by marine Streptomyces globosus VITLGK011-derived compound BECA: An in vitro and in silico analysis. J Basic Microbiol 2020; 60:983-993. [PMID: 33103250 DOI: 10.1002/jobm.202000461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/29/2020] [Accepted: 10/05/2020] [Indexed: 11/08/2022]
Abstract
This study investigates the anticancer cytotoxic mechanism of action of benzoyloxy-ethyl-carbamic acid (BECA) produced by Streptomyces globosus VITLGK011. Flow cytometry analysis confirmed that BECA (at IC50 : 3.12 µg/ml) treatment for 24 h induced apoptosis in 60% of cells. Schrodinger Maestro tools such as QikProp and DFT were used to confirm that BECA is an eligible drug-like molecule, with suitable physiochemical properties. Glide XP tool was used to perform induced-fit docking between BECA and 30 cancer drug target proteins. The highest significance was observed for VEGFR2 protein (-6.7 kcal/mol). GROMACS tool was used to perform molecular dynamic simulation between BECA and VEGFR2 protein for 40 ns. Root mean square deviation, root mean square fluctuation, H-bond, and trajectory analysis, confirmed that BECA is a suitable inhibitor of VEGFR2 protein. Results conclude that BECA is a valid VEGFR2 inhibitor, and it thus exerts the observed anticancer cytotoxicity against MCF-7 cells.
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Affiliation(s)
- Ravi Lokesh
- Department of Botany, St. Joseph's College (Autonomous), Bengaluru, India
| | | | - Krishnan Kannabiran
- Department of Biomedical Sciences, Vellore Institute of Technology, Vellore, India
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29
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Chen J, Sun ZH, Chen LY, Xu F, Zhao YP, Li GQ, Tang M, Li Y, Zheng QY, Wang SF, Yang XH, Wu YZ, Xu GL. C5aR deficiency attenuates the breast cancer development via the p38/p21 axis. Aging (Albany NY) 2020; 12:14285-14299. [PMID: 32669478 PMCID: PMC7425439 DOI: 10.18632/aging.103468] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 05/01/2020] [Indexed: 11/25/2022]
Abstract
Emerging evidence has shown activation of the complement component C5 to C5a in cancer tissues and C5aR expression in breast cancer cells relates to the tumor development and poor prognosis, suggesting the involvement of complement C5a/C5aR pathway in the breast cancer pathogenesis. In this study, we found that as compared to the non-tumoral tissues, both C5aR and MAPK/p38 showed an elevated expression, but p21/p-p21 showed lower expression, in the tumoral tissues of breast cancer patients. Mice deficient in C5aR or mice treated with the C5aR antagonist exhibited attenuation of breast cancer growth and reduction in the p38/p-p38 expression, but increase in p21/p-p21 expression, in the tumor tissues. Pre-treatment of the breast cancer cells with recombinant C5a resulted in reduced p21 expression, and MAPK/p38 inhibitors prevented C5a-induced reduction in p21 expression, suggesting the involvement of the MAPK/p38 signaling pathway in the C5a/C5aR-mediated suppression of p21/p-p21 expression. These results provide evidence that breast cancer development may rely on C5a/C5aR interaction, for which MAPK/p38 pathway participate in down-regulating the p21 expression. Inhibition of C5a/C5aR pathway is expected to be helpful for the treatment of patients with breast cancer.
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Affiliation(s)
- Jian Chen
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Zi-Han Sun
- Breast Disease Center, Guiqian International General Hospital, Guiyang 550000, China
| | - Li-Ying Chen
- Institute of Cancer, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China
| | - Feng Xu
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Yun-Pei Zhao
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Gui-Qing Li
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Ming Tang
- Urinary Nephropathy Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400065, China
| | - You Li
- Department of ICU, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Quan-You Zheng
- Department of Urology, 958 Hospital, Army Medical University (Third Military Medical University), Chongqing 400020, China
| | - Shu-Feng Wang
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Xin-Hua Yang
- Breast Disease Center, Guiqian International General Hospital, Guiyang 550000, China
| | - Yu-Zhang Wu
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Gui-Lian Xu
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing 400038, China
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30
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Shear stress activates ATOH8 via autocrine VEGF promoting glycolysis dependent-survival of colorectal cancer cells in the circulation. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:25. [PMID: 32000836 PMCID: PMC6993408 DOI: 10.1186/s13046-020-1533-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 01/23/2020] [Indexed: 02/07/2023]
Abstract
Background Metastasis and recurrence, wherein circulating tumour cells (CTCs) play an important role, are the leading causes of death in colorectal cancer (CRC). Metastasis-initiating CTCs manage to maintain intravascular survival under anoikis, immune attack, and importantly shear stress; however, the underlying mechanisms remain poorly understood. Methods In view of the scarcity of CTCs in the bloodstream, suspended colorectal cancer cells were flowed into the cyclic laminar shear stress (LSS) according to previous studies. Then, we detected these suspended cells with a CK8+/CD45−/DAPI+ phenotype and named them mimic circulating tumour cells (m-CTCs) for subsequent CTCs related researches. Quantitative polymerase chain reaction, western blotting, and immunofluorescence were utilised to analyse gene expression change of m-CTCs sensitive to LSS stimulation. Additionally, we examined atonal bHLH transcription factor 8 (ATOH8) expressions in CTCs among 156 CRC patients and mice by fluorescence in situ hybridisation and flow cytometry. The pro-metabolic and pro-survival functions of ATOH8 were determined by glycolysis assay, live/dead cell vitality assay, anoikis assay, and immunohistochemistry. Further, the concrete up-and-down mechanisms of m-CTC survival promotion by ATOH8 were explored. Results The m-CTCs actively responded to LSS by triggering the expression of ATOH8, a fluid mechanosensor, with executive roles in intravascular survival and metabolism plasticity. Specifically, ATOH8 was upregulated via activation of VEGFR2/AKT signalling pathway mediated by LSS induced VEGF release. ATOH8 then transcriptionally activated HK2-mediated glycolysis, thus promoting the intravascular survival of colorectal cancer cells in the circulation. Conclusions This study elucidates a novel mechanism that an LSS triggered VEGF-VEGFR2-AKT-ATOH8 signal axis mediates m-CTCs survival, thus providing a potential target for the prevention and treatment of hematogenous metastasis in CRC.
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31
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Cheng Q, Ouyang X, Zhang R, Zhu L, Song X. Senescence-associated genes and non-coding RNAs function in pancreatic cancer progression. RNA Biol 2020; 17:1693-1706. [PMID: 31997706 DOI: 10.1080/15476286.2020.1719752] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
Pancreatic cancer is a major cause of mortality with a poor diagnosis and prognosis that most often occurs in elderly patients. Few studies, however, focus on the interplay of age and pancreatic cancer at the transcriptional level. Here we evaluated the possible roles of age-dependent, differentially expressed genes (DEGs) in pancreatic cancer. These DEGs were used to construct a correlation network and clustered in six gene modules, among which two modules were highly correlated with patients' survival time. Integrating different datasets, including ATAC-Seq and ChIP-Seq, we performed multi-parallel analyses and identified eight age-dependent protein coding genes and two non-coding RNAs as potential candidates. These candidates, together with KLF5, a potent functional transcription factor in pancreatic cancer, are likely to be key elements linking cellular senescence and pancreatic cancer, providing insights on the balance between them, as well as on diagnosis and subsequent prognosis of pancreatic cancer.
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Affiliation(s)
- Qingyu Cheng
- Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China , Hefei, Anhui, China
| | - Xuan Ouyang
- Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China , Hefei, Anhui, China
| | - Ran Zhang
- Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China , Hefei, Anhui, China
| | - Lianbang Zhu
- The First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China , Hefei, Anhui, China
| | - Xiaoyuan Song
- Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China , Hefei, Anhui, China
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32
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A Transient Pseudosenescent Secretome Promotes Tumor Growth after Antiangiogenic Therapy Withdrawal. Cell Rep 2019; 25:3706-3720.e8. [PMID: 30590043 DOI: 10.1016/j.celrep.2018.12.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 10/21/2018] [Accepted: 12/05/2018] [Indexed: 01/07/2023] Open
Abstract
VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) approved to treat multiple cancer types can promote metastatic disease in certain limited preclinical settings. Here, we show that stopping VEGFR TKI treatment after resistance can lead to rebound tumor growth that is driven by cellular changes resembling senescence-associated secretory phenotypes (SASPs) known to promote cancer progression. A SASP-mimicking antiangiogenic therapy-induced secretome (ATIS) was found to persist during short withdrawal periods, and blockade of known SASP regulators, including mTOR and IL-6, could blunt rebound effects. Critically, senescence hallmarks ultimately reversed after long drug withdrawal periods, suggesting that the transition to a permanent growth-arrested senescent state was incomplete and the hijacking of SASP machinery ultimately transient. These findings may account for the highly diverse and reversible cytokine changes observed in VEGF inhibitor-treated patients, and suggest senescence-targeted therapies ("senotherapeutics")-particularly those that block SASP regulation-may improve outcomes in patients after VEGFR TKI failure.
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33
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Dai G, Ding K, Cao Q, Xu T, He F, Liu S, Ju W. Emodin suppresses growth and invasion of colorectal cancer cells by inhibiting VEGFR2. Eur J Pharmacol 2019; 859:172525. [PMID: 31288005 DOI: 10.1016/j.ejphar.2019.172525] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 06/30/2019] [Accepted: 07/04/2019] [Indexed: 01/01/2023]
Abstract
Emodin can effectively inhibit colorectal cancer cells, but the mechanism remains elusive. This study analyzed the changes of VEGFR2 signaling pathways in patients with colorectal cancer and the effects of emodin on HCT116 cells and xenograft tumor model. The expression levels of VEGFR2, PI3K, and p-AKT in colorectal cancer tissue samples were significantly higher than those in adjacent normal ones. Docking simulation confirmed that emodin bound the hydrophobic pocket and partially overlapped with the binding sites of VEGFR2, thus disrupting VEGFR2 dimerization. Western blotting further confirmed that emodin significantly inhibited the expression of VEGFR2, and reduced the expressions of PI3K and p-AKT in HCT116 cells. Furthermore, it suppressed the growth, adhesion and migration of HCT116 cells. In addition, emodin inhibited the tumor growth in xenograft model and the expressions of VEGFR2, PI3K and p-AKT in vivo. In conclusion, emodin suppressed the growth of colorectal cancer cells by inhibiting VEGFR2, as a potential candidate for therapy.
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Affiliation(s)
- Guoliang Dai
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, PR China
| | - Kang Ding
- National Center of Colorectal Surgery, Jiangsu Integrate Colorectal Oncology Center, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210001, PR China
| | - Qianyu Cao
- The First Clinical College, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China
| | - Tian Xu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, PR China
| | - Fan He
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, PR China
| | - Shijia Liu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, PR China
| | - Wenzheng Ju
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, PR China.
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34
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Guha Majumdar A, Subramanian M. Hydroxychavicol from Piper betle induces apoptosis, cell cycle arrest, and inhibits epithelial-mesenchymal transition in pancreatic cancer cells. Biochem Pharmacol 2019; 166:274-291. [PMID: 31154000 DOI: 10.1016/j.bcp.2019.05.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 05/28/2019] [Indexed: 12/30/2022]
Abstract
Pancreatic cancer is a major cause of cancer-related mortality around the world. Currently, options for diagnosis and treatment are extremely limited, which culminates in a very high mortality rate. Intensive research spanning more than four decades has met several roadblocks in terms of improvement in overall survival. In this study, we have evaluated the effect of Hydroxychavicol (HC), a naturally occurring and abundantly isolatable allylarene from Piper betle leaves on pancreatic cancer cells. Our investigation reveals that HC inhibits proliferation and epithelial-mesenchymal transition (EMT) in pancreatic cancer cells. HC induces DNA damage, as evidenced by γ-H2AX, 53BP1 induction and comet assay, which further results in mitotic catastrophe and apoptosis. The apoptosis induced by HC is JNK pathway-dependent and caspase-mediated. HC also inhibits migration and invasion of pancreatic cancer cells via a generalized repression of genes involved in EMT. A quantitative real time PCR-based array revealed at least 14 different genes to be differentially expressed upon HC treatment in pancreatic cancer cells. These results show significant potential of HC as an anticancer agent against pancreatic cancer.
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Affiliation(s)
- Ananda Guha Majumdar
- Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085, India
| | - Mahesh Subramanian
- Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400 094, India.
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35
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Mioc M, Avram S, Bercean V, Kurunczi L, Ghiulai RM, Oprean C, Coricovac DE, Dehelean C, Mioc A, Balan-Porcarasu M, Tatu C, Soica C. Design, Synthesis and Biological Activity Evaluation of S-Substituted 1 H-5-Mercapto-1,2,4-Triazole Derivatives as Antiproliferative Agents in Colorectal Cancer. Front Chem 2018; 6:373. [PMID: 30234098 PMCID: PMC6134806 DOI: 10.3389/fchem.2018.00373] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 08/02/2018] [Indexed: 12/11/2022] Open
Abstract
Colon cancer is a widespread pathology with complex biochemical etiology based on a significant number of intracellular signaling pathways that play important roles in carcinogenesis, tumor proliferation and metastasis. These pathways function due to the action of key enzymes that can be used as targets for new anticancer drug development. Herein we report the synthesis and biological antiproliferative evaluation of a series of novel S-substituted 1H-3-R-5-mercapto-1,2,4-triazoles, on a colorectal cancer cell line, HT-29. Synthesized compounds were designed by docking based virtual screening (DBVS) of a previous constructed compound library against protein targets, known for their important role in colorectal cancer signaling: MEK1, ERK2, PDK1, VEGFR2. Among all synthesized structures, TZ55.7, which was retained as a possible PDK1 (phospholipid-dependent kinase 1) inhibitor, exhibited the most significant cytotoxic activity against HT-29 tumor cell line. The same compound alongside other two, TZ53.7 and TZ3a.7, led to a significant cell cycle arrest in both sub G0/G1 and G0/G1 phase. This study provides future perspectives for the development of new agents containing the 1,2,4-mercapto triazole scaffold with antiproliferative activities in colorectal cancer.
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Affiliation(s)
- Marius Mioc
- Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
| | - Sorin Avram
- Department of Computational Chemistry, Institute of Chemistry Timisoara of the Romanian Academy, Timisoara, Romania
| | | | - Ludovic Kurunczi
- Department of Computational Chemistry, Institute of Chemistry Timisoara of the Romanian Academy, Timisoara, Romania
| | - Roxana M Ghiulai
- Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
| | - Camelia Oprean
- Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania.,"Pius Brinzeu" Timisoara County Emergency Clinical Hospital, Oncogen Institute, Timisoara, Romania
| | - Dorina E Coricovac
- Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
| | - Cristina Dehelean
- Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
| | - Alexandra Mioc
- Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
| | | | - Calin Tatu
- "Pius Brinzeu" Timisoara County Emergency Clinical Hospital, Oncogen Institute, Timisoara, Romania
| | - Codruta Soica
- Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
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36
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Saleh T, Tyutynuk-Massey L, Cudjoe EK, Idowu MO, Landry JW, Gewirtz DA. Non-Cell Autonomous Effects of the Senescence-Associated Secretory Phenotype in Cancer Therapy. Front Oncol 2018; 8:164. [PMID: 29868482 PMCID: PMC5968105 DOI: 10.3389/fonc.2018.00164] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 04/30/2018] [Indexed: 12/24/2022] Open
Abstract
In addition to promoting various forms of cell death, most conventional anti-tumor therapies also promote senescence. There is now extensive evidence that therapy-induced senescence (TIS) might be transient, raising the concern that TIS could represent an undesirable outcome of therapy by providing a mechanism for tumor dormancy and eventual disease recurrence. The senescence-associated secretory phenotype (SASP) is a hallmark of TIS and may contribute to aberrant effects of cancer therapy. Here, we propose that the SASP may also serve as a major driver of escape from senescence and the re-emergence of proliferating tumor cells, wherein factors secreted from the senescent cells contribute to the restoration of tumor growth in a non-cell autonomous fashion. Accordingly, anti-SASP therapies might serve to mitigate the deleterious outcomes of TIS. In addition to providing an overview of the putative actions of the SASP, we discuss recent efforts to identify and eliminate senescent tumor cells.
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Affiliation(s)
- Tareq Saleh
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States.,Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Liliya Tyutynuk-Massey
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States.,Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Emmanuel K Cudjoe
- Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA, United States
| | - Michael O Idowu
- Department of Pathology, Virginia Commonwealth University, Richmond, VA, United States
| | - Joseph W Landry
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States.,Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States
| | - David A Gewirtz
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States.,Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
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37
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Jiang H, Dong L, Gong F, Gu Y, Zhang H, Fan D, Sun Z. Inflammatory genes are novel prognostic biomarkers for colorectal cancer. Int J Mol Med 2018; 42:368-380. [PMID: 29693170 PMCID: PMC5979867 DOI: 10.3892/ijmm.2018.3631] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 03/27/2018] [Indexed: 02/06/2023] Open
Abstract
Inflammatory genes serve a crucial role in the pathogenesis of inflammation-associated tumors. However, as recent studies have mainly focused on the effects of single inflammatory genes on colorectal cancer (CRC), but not on the global interactions between genes, the underlying mechanisms between inflammatory genes and CRC remain unclear. In the current study, two inflammation-associated networks were constructed based on inflammatory genes, differentially expressed genes (DEGs) in CRC vs. normal samples, and protein-protein interactions (PPIs). These networks included an inflammation-related neighbor network (IRNN) and an inflammation-related DEG network (IRDN). Notably, the results indicated that the inflammatory genes served as important CRC-associated genes in the IRNN. Certain inflammatory genes were more likely to be network hubs and exhibited higher betweenness centralities, indicating that these inflammatory hub genes had central roles in the communication between genes in the IRNN. By contrast, in the IRDN, functional enrichment analysis revealed that genes were enriched in numerous cancer-associated functions and pathways. Subsequently, 14 genes in a module were identified in the IRDN as the potential biomarkers associated with disease-free survival (DFS) in CRC patients in the GSE24550 dataset, the prognosis of which was further validated using three independent datasets (GSE24549, GSE34551 and GSE103479). All 14 genes (including BCAR1, CRK, FYN, GRB2, LCP2, PIK3R1, PLCG1, PTK2, PTPN11, PTPN6, SHC1, SOS1, SRC and SYK) in this module were inflammatory genes, emphasizing the critical role of inflammation in CRC. In conclusion, these findings based on integrated inflammation-associated networks provided a novel insight that may help elucidate the inflammation-mediated mechanisms involved in CRC.
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Affiliation(s)
- Hao Jiang
- Department of General Surgery, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Li Dong
- Department of General Surgery, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Fangyan Gong
- Clinical Laboratory, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Yuping Gu
- Department of General Surgery, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Henghun Zhang
- Department of General Surgery, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Dong Fan
- Department of General Surgery, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Zhiguo Sun
- Department of General Surgery, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
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38
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Fang X, Xie H, Luo M, Chen Z, Wang F, Li Q, Wang X, Ding J, Fu L. PBA2 exhibits potent anti-tumor activity via suppression of VEGFR2 mediated-cell proliferation and angiogenesis. Biochem Pharmacol 2018; 150:131-140. [DOI: 10.1016/j.bcp.2018.01.051] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Accepted: 01/31/2018] [Indexed: 11/26/2022]
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Abstract
Senescence is a durable cell cycle arrest that can be induced in response to various stress factors, such as telomere erosion, DNA damage or the aberrant activation of oncogenes. In addition to its well-established role as a stress response programme, research has revealed important physiological roles of senescence in nondisease settings, such as embryonic development, wound healing, tissue repair and ageing. Senescent cells secrete various cytokines, chemokines, matrix remodelling proteases and growth factors, a phenotype collectively referred to as the senescence-associated secretory phenotype. These factors evoke immune responses that, depending on the pathophysiological context, can either prevent or even fuel disease and tumorigenesis. Remarkably, even the gut microbiota can influence senescence in various organs. In this Review, we provide an introduction to cellular senescence, addressed particularly to gastroenterologists and hepatologists, and discuss the implications of senescence for the pathogenesis of malignant and nonmalignant gastrointestinal and hepatobiliary diseases. We conclude with an outlook on how modulation of cellular senescence might be used for therapeutic purposes.
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40
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Chen J, Li GQ, Zhang L, Tang M, Cao X, Xu GL, Wu YZ. Complement C5a/C5aR pathway potentiates the pathogenesis of gastric cancer by down-regulating p21 expression. Cancer Lett 2017; 412:30-36. [PMID: 29031586 DOI: 10.1016/j.canlet.2017.10.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 09/14/2017] [Accepted: 10/04/2017] [Indexed: 12/31/2022]
Abstract
Although the complement C5a/C5aR pathway is suggested to play a critical role in tumor pathogenesis, the underlying mechanism has yet to be fully elucidated. In the present study, we found that in patients with gastric cancer in different clinical stages (from stageⅠto stage Ⅳ), both C5aR and p-PI3K/AKT levels were significantly higher in tumoral tissues than in adjacent non-tumoral tissues. In contrast, p21/p-p21 levels were significantly lower in tumoral tissues than in adjacent non-tumoral tissues. In vitro recombinant C5a administration remarkably promoted p-PI3K/p-AKT expression, but inhibited p21/p-p21 expression. Blockage of C5a/C5aR signaling with a C5aR antagonist reversed the C5a-induced inhibitory effect on p21/p-p21 expression. C5a administration to cells pre-treated with a PI3K inhibitor also prevented this inhibitory effect, suggesting the involvement of the PI3K/AKT signaling pathway in C5a/C5aR-mediated suppression of p21/p-p21 expression. In vivo C5aR antagonist treatment caused significant reduction in tumor growth in mice, accompanied by a remarkable elevation in p21/p-p21 expression and reduction in p-PI3K/AKT activation. These results indicate that the C5a/C5aR pathway promotes gastric cancer pathogenesis by suppressing p21/p-p21 expression via activation of PI3K/AKT signaling.
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Affiliation(s)
- Jian Chen
- Department of Immunology, Third Military Medical University, Chongqing 400038, PR China
| | - Gui-Qing Li
- Department of Immunology, Third Military Medical University, Chongqing 400038, PR China
| | - Li Zhang
- Department of Pediatrics, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China
| | - Ming Tang
- Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China
| | - Xu Cao
- Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China
| | - Gui-Lian Xu
- Department of Immunology, Third Military Medical University, Chongqing 400038, PR China.
| | - Yu-Zhang Wu
- Department of Immunology, Third Military Medical University, Chongqing 400038, PR China.
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41
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Foersch S. [Cellular senescence and colorectal cancer]. DER PATHOLOGE 2017; 38:205-210. [PMID: 28939937 DOI: 10.1007/s00292-017-0357-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Apart from proliferation and cell death, cellular senescence is an important response to numerous stress-associated stimuli. Originally described as an in vitro phenomenon, it is involved in various physiological and pathophysiological processes. For example, during the development of solid and generalized tumors, senescence induction poses an important barrier against disease progression. This could be demonstrated for malignant lymphomas, melanomas and various carcinomas using sophisticated animal models. However, senescent cells remain highly secretorically active and have a profound effect on neighboring cells as well as the entire tissue network. This article tries to provide insight into the current literature and discusses clinical implications and future applications.
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Affiliation(s)
- S Foersch
- Institut für Pathologie, Universitätsmedizin Mainz, Langenbeckstr. 1, Gebäude 706, 55131, Mainz, Deutschland.
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42
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Mlecnik B, Van den Eynde M, Bindea G, Church SE, Vasaturo A, Fredriksen T, Lafontaine L, Haicheur N, Marliot F, Debetancourt D, Pairet G, Jouret-Mourin A, Gigot JF, Hubert C, Danse E, Dragean C, Carrasco J, Humblet Y, Valge-Archer V, Berger A, Pagès F, Machiels JP, Galon J. Comprehensive Intrametastatic Immune Quantification and Major Impact of Immunoscore on Survival. J Natl Cancer Inst 2017; 110:4093937. [DOI: 10.1093/jnci/djx123] [Citation(s) in RCA: 170] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 05/24/2017] [Indexed: 12/31/2022] Open
Affiliation(s)
- Bernhard Mlecnik
- Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, Paris, France
- Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, Paris, France
- Inovarion, Paris, France
| | - Marc Van den Eynde
- Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, Paris, France
- Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, Paris, France
- Department of Medical Oncology, Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Institut Roi Albert II, Université Catholique de Louvain, Brussels, Belgium
| | - Gabriela Bindea
- Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, Paris, France
- Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, Paris, France
| | - Sarah E Church
- Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, Paris, France
- Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, Paris, France
| | - Angela Vasaturo
- Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, Paris, France
- Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, Paris, France
| | - Tessa Fredriksen
- Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, Paris, France
- Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, Paris, France
| | - Lucie Lafontaine
- Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, Paris, France
- Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, Paris, France
| | - Nacilla Haicheur
- Department of Immunology, HEGP, Assistance Publique-Hopitaux de Paris, Paris, France
| | - Florence Marliot
- Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, Paris, France
- Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, Paris, France
- Department of Immunology, HEGP, Assistance Publique-Hopitaux de Paris, Paris, France
| | - Daphné Debetancourt
- Department of Medical Oncology, Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Institut Roi Albert II, Université Catholique de Louvain, Brussels, Belgium
| | - Géraldine Pairet
- Department of Medical Oncology, Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Institut Roi Albert II, Université Catholique de Louvain, Brussels, Belgium
| | - Anne Jouret-Mourin
- Department of Medical Oncology, Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Institut Roi Albert II, Université Catholique de Louvain, Brussels, Belgium
| | - Jean-Francois Gigot
- Department of Medical Oncology, Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Institut Roi Albert II, Université Catholique de Louvain, Brussels, Belgium
| | - Catherine Hubert
- Department of Medical Oncology, Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Institut Roi Albert II, Université Catholique de Louvain, Brussels, Belgium
| | - Etienne Danse
- Department of Medical Oncology, Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Institut Roi Albert II, Université Catholique de Louvain, Brussels, Belgium
| | - Cristina Dragean
- Department of Medical Oncology, Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Institut Roi Albert II, Université Catholique de Louvain, Brussels, Belgium
| | | | - Yves Humblet
- Department of Medical Oncology, Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Institut Roi Albert II, Université Catholique de Louvain, Brussels, Belgium
| | | | - Anne Berger
- Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, Paris, France
- Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, Paris, France
- Departments of General and Digestive Surgery, HEGP, AP-HP, Assistance Publique-Hopitaux de Paris, Paris, France
| | - Franck Pagès
- Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, Paris, France
- Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, Paris, France
- Department of Immunology, HEGP, Assistance Publique-Hopitaux de Paris, Paris, France
| | - Jean-Pascal Machiels
- Department of Medical Oncology, Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Institut Roi Albert II, Université Catholique de Louvain, Brussels, Belgium
| | - Jérôme Galon
- Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, Paris, France
- Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, Paris, France
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Xing W, Xiao Y, Lu X, Zhu H, He X, Huang W, Lopez ES, Wong J, Ju H, Tian L, Zhang F, Xu H, Wang SD, Li X, Karin M, Ren H. GFI1 downregulation promotes inflammation-linked metastasis of colorectal cancer. Cell Death Differ 2017; 24:929-943. [PMID: 28387757 PMCID: PMC5423119 DOI: 10.1038/cdd.2017.50] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 02/27/2017] [Accepted: 03/06/2017] [Indexed: 12/21/2022] Open
Abstract
Inflammation is frequently associated with initiation, progression, and metastasis of colorectal cancer (CRC). Here, we unveil a CRC-specific metastatic programme that is triggered via the transcriptional repressor, GFI1. Using data from a large cohort of clinical samples including inflammatory bowel disease and CRC, and a cellular model of CRC progression mediated by cross-talk between the cancer cell and the inflammatory microenvironment, we identified GFI1 as a gating regulator responsible for a constitutively activated signalling circuit that renders CRC cells competent for metastatic spread. Further analysis of mouse models with metastatic CRC and human clinical specimens reinforced the influence of GFI1 downregulation in promoting CRC metastatic spread. The novel role of GFI1 is uncovered for the first time in a human solid tumour such as CRC. Our results imply that GFI1 is a potential therapeutic target for interfering with inflammation-induced CRC progression and spread.
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Affiliation(s)
- Wenjing Xing
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Yun Xiao
- Department of Bioinformatics, College of Bioinformatics, Harbin Medical University, Harbin 150081, China
| | - Xinliang Lu
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China.,Center of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Hongyan Zhu
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Xiangchuan He
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Wei Huang
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Elsa S Lopez
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Jerry Wong
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Huanyu Ju
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Linlu Tian
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Fengmin Zhang
- Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Hongwei Xu
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Sheng Dian Wang
- Center of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Xia Li
- Department of Bioinformatics, College of Bioinformatics, Harbin Medical University, Harbin 150081, China
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Huan Ren
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China.,College of basic medicine, Shanghai University Of Medicine & Health Sciences, Shanghai 201318, China
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Liu J, An H, Yuan W, Feng Q, Chen L, Ma J. Prognostic Relevance and Function of MSX2 in Colorectal Cancer. J Diabetes Res 2017; 2017:3827037. [PMID: 28286778 PMCID: PMC5327771 DOI: 10.1155/2017/3827037] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 12/01/2016] [Indexed: 12/20/2022] Open
Abstract
Colorectal cancer patients with diabetes had the high risks of total mortality. High expression of MSX2 is related to development of diabetes. There are few reports about the clinical implications and function of MSX2 in colorectal cancer (CRC). The purpose of this study is to investigate the relationship between the expression of MSX2 and clinical relevance and discover the possible mechanism of MSX2 in the development of CRC. Compared with adjacent tissues, the expression of MSX2 was higher in tumor tissues in both mRNA and protein levels (P < 0.01). Kaplan-Meier survival analysis showed that high mRNA expression of MSX2 was associated with short survival time (P = 0.013). Chi-squared test analysis indicated that MSX2 expression was related to tumor size (P = 0.04), tumor locus (P = 0.025), clinical stage (P < 0.001), tumor invasion (P = 0.003), lymphatic metastasis (P = 0.01), and distant metastasis (P = 0.033). In vitro experiments demonstrated that knockdown of MSX2 expression attenuated cell proliferation and invasion, promoted cell cycle arrest and apoptosis, and inactivated Akt phosphorylation. In conclusion, MSX2 played a crucial role in the progression of CRC and may be a potential novel prognostic factor and therapeutic target for CRC therapy. Our work may provide certain enlightenment for investigating the mechanism of MSX2 in the process of diabetes.
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Affiliation(s)
- Jiancheng Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Huaying An
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wei Yuan
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Clinical Immunology Center, Chinese Academy of Medical Science, Beijing 100730, China
| | - Qiang Feng
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lianzhen Chen
- Department of Pharmacy, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- *Lianzhen Chen: and
| | - Jie Ma
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Clinical Immunology Center, Chinese Academy of Medical Science, Beijing 100730, China
- Beijing Hospital, National Center of Gerontology, Beijing 100730, China
- *Jie Ma:
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45
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Seebauer CT, Brunner S, Glockzin G, Piso P, Ruemmele P, Schlitt HJ, Geissler EK, Fichtner-Feigl S, Kesselring R. Peritoneal carcinomatosis of colorectal cancer is characterized by structural and functional reorganization of the tumor microenvironment inducing senescence and proliferation arrest in cancer cells. Oncoimmunology 2016; 5:e1242543. [PMID: 28439450 DOI: 10.1080/2162402x.2016.1242543] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 09/21/2016] [Accepted: 09/23/2016] [Indexed: 12/19/2022] Open
Abstract
Background : Peritoneal carcinomatosis (PC) is a terminal evolution from primary colorectal cancer (pCRC) associated with poor patient survival. Impact of the immune cell infiltrate on PC pathogenesis is unknown. Therefore, we characterized the immunological tumor microenvironment regarding proliferation, senescence and neovascularization. Methods : Formalin-fixed and paraffin-embedded (FFPE) tissue of PC and pCRC was examined by immunohistochemistry. Cells infiltrating resected tissue were isolated and analyzed by flow cytometry. PCR arrays detected the expression of genes relevant for helper T (TH) cell responses, like TH1, TH2 and TH17 response. Results : PC tumor cells demonstrate significantly lower proliferation rates than pCRC, but show significantly more senescence. PC is surrounded by significantly increased numbers of cytotoxic active Natural Killer (NK) cells, follicular helper T cells (TFH) and B cells, whereas pCRC shows more CD4+ TH cells, CD8+ cytotoxic T (TC) cells, eosinophilic granulocytes, TH17 and regulatory T (Treg) cells. PC is characterized by significantly increased interferon-γ (IFNγ), an upregulation of tumor necrosis factor (TNF) and the NK cell-regulating cytokine interleukin-15 (IL-15). An upregulation of angiogenesis-related genes, like vascular endothelial growth factor-A (VEGF-A), leads to severe neovascularization in PC. Correlations of PC results reveal that elevated numbers of interleukin-17 (IL-17) positive cells are associated with high cancer cell proliferation, whereas high numbers of IFNγ positive cells correlate with more tumor cells in senescence. Conclusion : The cellular immune reaction is modified during metastasis, inducing senescence in PC tumor cells. Immune surveillance in PC is facilitated by NK cells and high levels of IFNγ and TNF. Counteracting this effect, TFH and B cells combined with VEGF-A enhancement promote neovascularization in PC (Illustration 1). During metastasis from primary CRC to PC the immune cell infiltrate changes, accompanied by the induction of senescence in PC cancer cells (marked red): In pCRC, the antitumor immune response is facilitated by CD4+TH cells, CD8+TC cells and PRG2+ eosinophilic granulocytes. The premetastatic niche development is promoted by Treg cells and TH17 cells producing systemic factors like VEGF-A, TGF-β and TNF. Along with TFH and B cells, as with a pro-tumor immune response, they support metastatic formation and lead to severe neovascularization in PC. This is counterbalanced by the IL-15-induced activation and proliferation of NK cells. The secreted cytokines IFNγ and TNF mediate immunosurveillance.
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Affiliation(s)
| | - Stefan Brunner
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Gabriel Glockzin
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Pompiliu Piso
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Petra Ruemmele
- Department of Pathology, University Medical Center Regensburg, Regensburg, Germany
| | - Hans-Juergen Schlitt
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | | | - Stefan Fichtner-Feigl
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany.,Regensburg Center of Interventional Immunology, Regensburg, Germany
| | - Rebecca Kesselring
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany.,Regensburg Center of Interventional Immunology, Regensburg, Germany
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Francica P, Aebersold DM, Medová M. Senescence as biologic endpoint following pharmacological targeting of receptor tyrosine kinases in cancer. Biochem Pharmacol 2016; 126:1-12. [PMID: 27574725 DOI: 10.1016/j.bcp.2016.08.022] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 08/25/2016] [Indexed: 12/11/2022]
Abstract
Cellular senescence was first described in 1961 in a seminal study by Hayflick and Moorhead as a limit to the replicative lifespan of somatic cells after serial cultivation. Since then, major advances in our understanding of senescence have been achieved suggesting that this mechanism is activated also by oncogenic stimuli, oxidative stress and DNA damage, giving rise to the concept of premature senescence. Regardless of the initial trigger, numerous experimental observations have been provided to support the notion that both replicative and premature senescence play pivotal roles in early stages of tumorigenesis and in response of tumor cells to anticancer treatments. Moreover, various studies have suggested that the induction of senescence by both chemo- and radiotherapy in a variety of cancer types correlates with treatment outcome. As it is widely accepted that cellular senescence may function as a fundamental barrier of tumor progression, the significance of senescence for clinical interventions that make use of novel molecular targeting-based modalities needs to be well defined. Interestingly, despite numerous studies evaluating efficacies of receptor tyrosine kinases (RTKs) targeting strategies in both preclinical and clinical settings, the relevance of RTKs inhibition-associated senescence in tumors remains less characterized. Here we review the available literature that describes premature senescence as a major mechanism following targeting of RTKs in preclinical as well as in clinical settings. Additionally, we discuss the possible role of diverse RTKs in regulating the induction of senescence following cellular stress and possible implications of this crosstalk in identification of biomarkers of inhibitor-mediated chemo- and radiosensitization approaches.
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Affiliation(s)
- Paola Francica
- Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3008 Bern, Switzerland
| | - Daniel M Aebersold
- Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3008 Bern, Switzerland
| | - Michaela Medová
- Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
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Knieling F, Waldner MJ. Light and sound - emerging imaging techniques for inflammatory bowel disease. World J Gastroenterol 2016; 22:5642-5654. [PMID: 27433080 PMCID: PMC4932202 DOI: 10.3748/wjg.v22.i25.5642] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/02/2016] [Accepted: 05/23/2016] [Indexed: 02/06/2023] Open
Abstract
Patients with inflammatory bowel disease are known to have a high demand of recurrent evaluation for therapy and disease activity. Further, the risk of developing cancer during the disease progression is increasing from year to year. New, mostly non-radiant, quick to perform and quantitative methods are challenging, conventional endoscopy with biopsy as gold standard. Especially, new physical imaging approaches utilizing light and sound waves have facilitated the development of advanced functional and molecular modalities. Besides these advantages they hold the promise to predict personalized therapeutic responses and to spare frequent invasive procedures. Within this article we highlight their potential for initial diagnosis, assessment of disease activity and surveillance of cancer development in established techniques and recent advances such as wide-view full-spectrum endoscopy, chromoendoscopy, autofluorescence endoscopy, endocytoscopy, confocal laser endoscopy, multiphoton endoscopy, molecular imaging endoscopy, B-mode and Doppler ultrasound, contrast-enhanced ultrasound, ultrasound molecular imaging, and elastography.
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48
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From mice to men: Murine models of colorectal cancer for use in translational research. Crit Rev Oncol Hematol 2015; 98:94-105. [PMID: 26558688 DOI: 10.1016/j.critrevonc.2015.10.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 08/28/2015] [Accepted: 10/27/2015] [Indexed: 12/18/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common carcinoma worldwide and despite advances in treatment, survival for patients with metastatic disease remains poor. With nearly 50% of patients developing metastases, in vivo investigation is essential to improve outcomes for these patients and numerous murine models of CRC have been developed to allow the study of chemoprevention and chemotherapy, in addition to improving our understanding of the pathogenesis of CRC. Selecting the most appropriate murine model for a specific application will maximize the conversion of potential therapies from the laboratory to clinical practice and requires an understanding of the various models available. This review will provide an overview of the murine models currently used in CRC research, discussing the limitations and merits of each and their most relevant application. It is aimed at the developing researcher, acting as a guide to prompt further reading in planning a specific study.
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