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Qin F, Zheng H, Wu J, Liu Z, Zheng Y, Yang X, Chen J, Deng W, Luo Z, Tan J, Cai W, Jian B, Zeng Y, Qin X, Liao H. APOC1 expressed in macrophages promotes the pulmonary metastasis of colorectal cancer via CCL2/CCL5. Int Immunopharmacol 2025; 154:114611. [PMID: 40194454 DOI: 10.1016/j.intimp.2025.114611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 03/16/2025] [Accepted: 03/31/2025] [Indexed: 04/09/2025]
Abstract
Metastasis is the main cause of death in colorectal cancer (CRC), and the lungs are common sites of metastasis. However, there is little effective target to intervene colorectal cancer pulmonary metastasis (CCPM), especially on its unique immune microenvironment. In this study, sixteen genes were identified as core CCPM-related differentially expressed genes (DEGs) between CRC and CCPM. Three genes including Apolipoprotein C1 (APOC1) were associated with prognosis, stage and metastasis of CRC. In immunohistochemistry, APOC1 was mainly expressed in macrophages, and expressed more in CCPM than CRC. Patients with synchronous CCPM, higher stage, poorer OS and CCPM-free interval tended to have higher expression. In experiments in vitro, knockdown of APOC1 in macrophages reduced the migration, invasion, and epithelial-mesenchymal transition of CRC cells. Knockdown of APOC1 in macrophages significantly decreased secretion of chemokines like CCL2 and CCL5. The pro-metastatic effect of macrophages expressing APOC1 was partially blocked by the antibodies of CCL2 and CCL5. Activation of STAT3 was a key process in APOC1's regulation of CCL2 and CCL5. In experiments in vivo, knockdown of APOC1 in macrophages reduced pulmonary metastasis. To conclude, APOC1 is one of core CCPM-related DEGs and associated with the metastasis and survival of CRC. Macrophages expressing APOC1 promote the CCPM by APOC1-STAT3-CCL2/CCL5 axis. APOC1 and macrophages expressing APOC1 play vital roles and may be potential therapeutic targets in CCPM.
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Affiliation(s)
- Fei Qin
- Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Haosheng Zheng
- Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Jiayan Wu
- Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Zui Liu
- Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Yuzhen Zheng
- Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Xingping Yang
- Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Junguo Chen
- Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Weihao Deng
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Ziyin Luo
- Department of Otorhinolaryngology Head and Neck Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Jian Tan
- Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Weijie Cai
- Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Bozhu Jian
- Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Yushuai Zeng
- Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Xianyu Qin
- Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
| | - Hongying Liao
- Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
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Huang X, Pan Z, Shen L, Chen H, Chen C, Lv T, Mei Y. The mechanism of Weiqi decoction treating gastric cancer: a work based on network pharmacology and experimental verification. Hereditas 2025; 162:67. [PMID: 40259338 PMCID: PMC12012975 DOI: 10.1186/s41065-025-00434-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 04/08/2025] [Indexed: 04/23/2025] Open
Abstract
BACKGROUND Weiqi Decoction (WQD) is an empirical prescription traditionally used in China for the treatment of precancerous gastric cancer (GC) lesions. This study aimed to elucidate the potential pharmacological mechanisms of WQD in GC therapy. METHODS Active ingredients, corresponding targets, and GC-related genes were identified using public databases. A protein-protein interaction (PPI) network was constructed via the STRING database, and functional enrichment analyses were conducted using the DAVID platform. Gene expression and survival analyses were performed using the GEPIA database. Molecular docking was conducted with AutoDock Vina and visualized using PyMOL. The effects of WQD on GC cell viability, proliferation, migration, and invasion were evaluated through CCK-8, colony formation, and Transwell assays. RESULTS WQD contained 43 active ingredients targeting 751 potential genes, including 458 GC-related targets. Quercetin, luteolin, and kaempferol were identified as key active compounds. PPI network analysis revealed nine core targets, including TP53 and SRC, which may mediate the anti-GC effects of WQD. GO enrichment analysis indicated involvement in 726 biological processes, 91 cellular components, and 177 molecular functions, while KEGG pathway analysis suggested modulation of the AGE-RAGE, PI3K-Akt, and HIF-1 signaling pathways. GEPIA database analysis confirmed that EP300, HSP90AA1, HSP90AB1, SRC, and TP53 were highly expressed in GC. Molecular docking demonstrated strong binding affinities between the key active compounds and core targets. In vitro experiments further validated that WQD extract inhibited GC cell viability, proliferation, migration, and invasion. CONCLUSION WQD exhibits therapeutic potential against GC by regulating multiple targets and signaling pathways. These findings provide mechanistic insights into the pharmacological actions of WQD in GC treatment.
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Affiliation(s)
- Xu Huang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, P.R. China
| | - Zhihong Pan
- Department of Gastroenterology, The First College of Clinical Medical Science, China Three Gorges University, Jiefang Road No. 2, Xiling District, Yichang, Hubei, 443000, P.R. China
| | - Lei Shen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, P.R. China.
| | - Huan Chen
- Department of Gastroenterology, The First College of Clinical Medical Science, China Three Gorges University, Jiefang Road No. 2, Xiling District, Yichang, Hubei, 443000, P.R. China
| | - Chang Chen
- Department of Gastroenterology, The First College of Clinical Medical Science, China Three Gorges University, Jiefang Road No. 2, Xiling District, Yichang, Hubei, 443000, P.R. China
| | - Tingting Lv
- Department of Gastroenterology, The First College of Clinical Medical Science, China Three Gorges University, Jiefang Road No. 2, Xiling District, Yichang, Hubei, 443000, P.R. China
| | - Yuzhou Mei
- Department of Gastroenterology, The First College of Clinical Medical Science, China Three Gorges University, Jiefang Road No. 2, Xiling District, Yichang, Hubei, 443000, P.R. China
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Song H, Zhang M, Guo C, Guo X, Ma Y, Ma Y. Implication of protein post translational modifications in gastric cancer. Front Cell Dev Biol 2025; 13:1523958. [PMID: 39968176 PMCID: PMC11833226 DOI: 10.3389/fcell.2025.1523958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 01/10/2025] [Indexed: 02/20/2025] Open
Abstract
Gastric cancer (GC) is one of the most common and highly lethal malignant tumors worldwide, and its occurrence and development are regulated by multiple molecular mechanisms. Post-translational modifications (PTM) common forms include ubiquitylation, phosphorylation, acetylation and methylation. Emerging research has highlighted lactylation and glycosylation. The diverse realm of PTM and PTM crosstalk is linked to many critical signaling events involved in neoplastic transformation, carcinogenesis and metastasis. This review provides a comprehensive overview of the impact of PTM on the occurrence and progression of GC. Specifically, aberrant PTM have been shown to alter the proliferation, migration, and invasion capabilities of GC cells. Moreover, PTM are closely associated with resistance to chemotherapeutic agents in GC. Notably, this review also discusses the phenomenon of PTM crosstalk, highlighting the interactions among PTM and their roles in regulating signaling pathways and protein functions. Therefore, in-depth investigation into the mechanisms of PTM and the development of targeted therapeutic strategies hold promise for advancing early diagnosis, treatment, and prognostic evaluation of GC, offering novel insights and future research directions.
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Affiliation(s)
- Houji Song
- The First Clinical Medical College, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Mingze Zhang
- The First Clinical Medical College, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Chengwang Guo
- The First Clinical Medical College, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Xi Guo
- The First Clinical Medical College, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Yuqi Ma
- The First Clinical Medical College, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Yuntao Ma
- The First Clinical Medical College, Gansu University of Traditional Chinese Medicine, Lanzhou, China
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China
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Tang S, Xu J, Wan P, Jin S, Zhang Y, Xun L, Wang J, Luo M, Chen W, Zuo Z, Tang H, Qi J. Recent advances in the role of high-salt diet in anti- and pro-cancer progression. Front Immunol 2025; 16:1542157. [PMID: 39944693 PMCID: PMC11814453 DOI: 10.3389/fimmu.2025.1542157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 01/13/2025] [Indexed: 05/09/2025] Open
Abstract
Dietary behaviors significantly influence tumor progression, with increasing focus on high-salt diets (HSD) in recent years. Traditionally, HSD has been regarded as a major risk factor for multiple health issues, including hypertension, cardiovascular disease, kidney disease, cancer, and osteoporosis. However, recent studies have uncovered a novel aspect of HSD, suggesting that HSD may inhibit tumor growth in specific pathological conditions by modulating the activity of immune cells that infiltrate tumors and enhancing the effectiveness of PD-1 immunotherapy. This review focused on the duel molecular mechanisms of HSD in cancer development, which are based on the tumor microenvironment, the gut microbiota, and the involvement of sodium transporter channels. The objective of this review is to explore whether HSD could be a potential future oncological therapeutic strategy under specific situation.
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Affiliation(s)
- Shiwei Tang
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Juan Xu
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Ping Wan
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Affiliated by Kunming University of Science and Technology, Kunming, Yunnan, China
- Yunnan Province Clinical Research Center for Senile Diseases, First People’s Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Shumen Jin
- Yunnan Institute of Food and Drug Supervision and Control, Medical Products Administration of Yunnan Province, Kuming, Yunnan, China
| | - Ying Zhang
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Affiliated by Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Linting Xun
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Affiliated by Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Jinli Wang
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Affiliated by Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Mei Luo
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Affiliated by Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Wenjie Chen
- State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
- Guangdong-Hongkong-Macao Joint Laboratory of Respiratory Infectious Disease, Guangzhou Medical University, Guangzhou, China
| | - Zan Zuo
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Affiliated by Kunming University of Science and Technology, Kunming, Yunnan, China
- Yunnan Provincial Key Laboratory of Clinical Virology, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Hui Tang
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Affiliated by Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Jialong Qi
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Affiliated by Kunming University of Science and Technology, Kunming, Yunnan, China
- Yunnan Province Clinical Research Center for Senile Diseases, First People’s Hospital of Yunnan Province, Kunming, Yunnan, China
- Yunnan Provincial Key Laboratory of Clinical Virology, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, China
- Yunnan Provincial Key Laboratory of Birth Defects and Genetic Diseases, First People’s Hospital of Yunnan Province, Kunming, Yunnan, China
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Horta M, Soares P, Sarmento B, Leite Pereira C, Lima RT. Nanostructured lipid carriers for enhanced batimastat delivery across the blood-brain barrier: an in vitro study for glioblastoma treatment. Drug Deliv Transl Res 2025:10.1007/s13346-024-01775-8. [PMID: 39760929 DOI: 10.1007/s13346-024-01775-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2024] [Indexed: 01/07/2025]
Abstract
Glioblastoma presents a significant treatment challenge due to the blood-brain barrier (BBB) hindering drug delivery, and the overexpression of matrix metalloproteinases (MMPs), which promotes tumor invasiveness. This study introduces a novel nanostructured lipid carrier (NLC) system designed for the delivery of batimastat, an MMP inhibitor, across the BBB and into the glioblastoma microenvironment. The NLCs were functionalized with epidermal growth factor (EGF) and a transferrin receptor-targeting construct to enhance BBB penetration and entrapment within the tumor microenvironment. NLCs were prepared by ultrasonicator-assisted hot homogenization, followed by surface functionalization with EGF and the construct though carbodiimide chemistry. The construct was successfully conjugated with an efficiency of 81%. Two functionalized NLC formulations, fMbat and fNbat, differing in the surfactant amount, were characterized. fMbat had a size of 302 nm, a polydispersity index (PDI) of 0.298, a ζ-potential (ZP) of -27.1 mV and an 85% functionalization efficiency (%FE), whereas fNbat measured 285 nm, with a PDI of 0.249, a ZP of -28.6 mV and a %FE of 92%. Both formulations achieved a drug loading of 0.42 μg/mg. In vitro assays showed that fNbat was cytotoxic and failed to cross the BBB, while fMbat showed cytocompatibility at concentrations 10 times higher than the drug's IC50. Additionally, fMbat inhibited MMP-2 activity between 11 and 62% across different cell lines and achieved a three-fold increase in BBB penetration upon functionalization. Our results suggest that the fMbat formulation has potential for enhancing GB treatment by overcoming current drug delivery limitations and may be combined with other therapeutic strategies for improved outcomes.
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Affiliation(s)
- Miguel Horta
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
- IPATIMUP - Instituto de Patologia e Imunologia Molecular, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal
- FMUP - Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Paula Soares
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
- IPATIMUP - Instituto de Patologia e Imunologia Molecular, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal
- FMUP - Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Bruno Sarmento
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
- INEB - Instituto de Engenharia Biomédica, University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
- IUCS-CESPU - Instituto Universitário de Ciências da Saúde, Rua Central de Gandra 1317, 4585-116, Gandra, Portugal
| | - Catarina Leite Pereira
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal.
- INEB - Instituto de Engenharia Biomédica, University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal.
| | - Raquel T Lima
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
- IPATIMUP - Instituto de Patologia e Imunologia Molecular, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal
- FMUP - Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
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Li S, Hao L, Hu X. Biological Roles and Clinical Therapeutic Applications of Tumor-Associated Macrophages in Colorectal Liver Metastasis. J Inflamm Res 2024; 17:8429-8443. [PMID: 39529996 PMCID: PMC11552512 DOI: 10.2147/jir.s493656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
Colorectal cancer (CRC) commonly metastasizes to the liver, and this poses a significant clinical challenge. Tumor-associated macrophages (TAMs), key players within the TME, play a significant role in promoting CRC metastasis by secreting various chemokines, growth factors, and cytokines. This review not only aims to enhance our knowledge of TAMs' functions in CRC progression and metastasis but also examines innovative therapeutic strategies to address the clinical problem of colorectal liver metastasis (CLM). By targeting TAMs, we may be able to develop more effective treatments and offer hope to patients suffering from this devastating disease.
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Affiliation(s)
- Shenghao Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
| | - Liyuan Hao
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
| | - Xiaoyu Hu
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
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Zeng Q, Zeng S, Dai X, Ding Y, Huang C, Ruan R, Xiong J, Tang X, Deng J. MDM2 inhibitors in cancer immunotherapy: Current status and perspective. Genes Dis 2024; 11:101279. [PMID: 39263534 PMCID: PMC11388719 DOI: 10.1016/j.gendis.2024.101279] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 02/13/2024] [Accepted: 02/21/2024] [Indexed: 09/13/2024] Open
Abstract
Murine double minute 2 (MDM2) plays an essential role in the cell cycle, apoptosis, DNA repair, and oncogene activation through p53-dependent and p53-independent signaling pathways. Several preclinical studies have shown that MDM2 is involved in tumor immune evasion. Therefore, MDM2-based regulation of tumor cell-intrinsic immunoregulation and the immune microenvironment has attracted increasing research attention. In recent years, immune checkpoint inhibitors targeting PD-1/PD-L1 have been widely used in the clinic. However, the effectiveness of a single agent is only approximately 20%-40%, which may be related to primary and secondary drug resistance caused by the dysregulation of oncoproteins. Here, we reviewed the role of MDM2 in regulating the immune microenvironment, tumor immune evasion, and hyperprogression during immunotherapy. In addition, we summarized preclinical and clinical findings on the use of MDM2 inhibitors in combination with immunotherapy in tumors with MDM2 overexpression or amplification. The results reveal that the inhibition of MDM2 could be a promising strategy for enhancing immunotherapy.
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Affiliation(s)
- Qinru Zeng
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
| | - Shaocheng Zeng
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
| | - Xiaofeng Dai
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
| | - Yun Ding
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
| | - Chunye Huang
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
| | - Ruiwen Ruan
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
| | - Xiaomei Tang
- Department of Oncology, Jiangxi Chest Hospital, Nanchang, Jiangxi 330006, China
| | - Jun Deng
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
- Postdoctoral Innovation Practice Base, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
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8
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Zhang F, Guo J, Yu S, Zheng Y, Duan M, Zhao L, Wang Y, Yang Z, Jiang X. Cellular senescence and metabolic reprogramming: Unraveling the intricate crosstalk in the immunosuppressive tumor microenvironment. Cancer Commun (Lond) 2024; 44:929-966. [PMID: 38997794 PMCID: PMC11492308 DOI: 10.1002/cac2.12591] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 06/23/2024] [Accepted: 07/07/2024] [Indexed: 07/14/2024] Open
Abstract
The intrinsic oncogenic mechanisms and properties of the tumor microenvironment (TME) have been extensively investigated. Primary features of the TME include metabolic reprogramming, hypoxia, chronic inflammation, and tumor immunosuppression. Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME. Specifically, hypoxic adaptation, metabolic dysregulation, and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation, thereby promoting the progression of tumor events. This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME, with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells. The available findings suggest that components of the TME collectively contribute to the progression of tumor events. The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.
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Affiliation(s)
- Fusheng Zhang
- Department of General SurgeryThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
- Department of Hepatobiliary and Pancreatic SurgeryPeking University First HospitalBeijingP. R. China
| | - Junchen Guo
- Department of RadiologyThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Shengmiao Yu
- Outpatient DepartmentThe Fourth Affiliated HospitalChina Medical UniversityShenyangLiaoningP. R. China
| | - Youwei Zheng
- Department of General SurgeryThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Meiqi Duan
- Department of General SurgeryThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Liang Zhao
- Department of General SurgeryThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Yihan Wang
- Department of General SurgeryThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Zhi Yang
- Department of General SurgeryThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Xiaofeng Jiang
- Department of General SurgeryThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
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Gao Y, Wu R, Pei Z, Ke C, Zeng D, Li X, Zhang Y. Cell cycle associated protein 1 associates with immune infiltration and ferroptosis in gastrointestinal cancer. Heliyon 2024; 10:e28794. [PMID: 38586390 PMCID: PMC10998105 DOI: 10.1016/j.heliyon.2024.e28794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 03/23/2024] [Accepted: 03/25/2024] [Indexed: 04/09/2024] Open
Abstract
Background Cell Cycle-Associated Protein 1 (CAPRIN1) play an important role in cell proliferation, oxidative stress, and inflammatory response. Nonetheless, its role in tumor immunity and ferroptosis is largely unknown in gastrointestinal cancer patients. Methods Through comprehensive bioinformatics, we investigate CAPRIN1 expression patterns and its role in diagnosis, functional signaling pathways, tumor immune infiltration and ferroptosis of different gastrointestinal cancer subtypes. Besides, immunohistochemistry (IHC) and immune blot were used to validate our esophagus cancer clinical data. The ferroptotic features of CAPRIN1 in vitro were assessed through knockdown assays in esophagus cancer cells. Results CAPRIN1 expression was significantly upregulated, correlated with poor prognosis, and served as an independent risk factor for most gastrointestinal cancer. Moreover, CAPRIN1 overexpression positively correlated with gene markers of most infiltrating immune cells, and immune checkpoints. CAPRIN1 knockdown significantly decreased the protein level of major histocompatibility complex class I molecules. We also identified a link between CAPRIN1 and ferroptosis-related genes in gastrointestinal cancer. Knockdown of CAPRIN1 significantly increased the production of lipid reactive oxygen species and malondialdehyde. Inhibition of CAPRIN1 expression promoted ferroptotic cell death induced by RAS-selective lethal 3 and erastin in human esophagus cancer cells. Conclusion Collectively, our results demonstrate that CAPRIN1 is aberrantly expressed in gastrointestinal cancer, is associated with poor prognosis, and could potentially influence immune infiltration and ferroptosis.
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Affiliation(s)
- Yan Gao
- Department of Pharmacy, Taihe Hospital, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, P.R. China
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Ruimin Wu
- Department of Pharmacy, Taihe Hospital, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Zhijun Pei
- Department of Pharmacy, Taihe Hospital, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Changbin Ke
- Department of Pharmacy, Taihe Hospital, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Daobing Zeng
- Department of Pharmacy, Taihe Hospital, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xiaohui Li
- Department of Pharmacy, Taihe Hospital, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yanmin Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, P.R. China
- State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an Jiaotong University, Xi'an, 710061, China
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10
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Wang H, Yang J, Li X, Zhao H. Current state of immune checkpoints therapy for glioblastoma. Heliyon 2024; 10:e24729. [PMID: 38298707 PMCID: PMC10828821 DOI: 10.1016/j.heliyon.2024.e24729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 01/12/2024] [Accepted: 01/12/2024] [Indexed: 02/02/2024] Open
Abstract
Glioblastoma (GBM), one of the most aggressive forms of brain cancer, has limited treatment options. Recent years have witnessed the remarkable success of checkpoint inhibitor immunotherapy across various cancer types. Against this backdrop, several clinical trials investigating checkpoint inhibitors for GBM are underway in multiple countries. Furthermore, the integration of immunotherapy with traditional treatment approaches is now emerging as a highly promising strategy. This review summarizes the latest advancements in checkpoint inhibitor immunotherapy for GBM treatment. We provide a concise yet comprehensive overview of current GBM immunotherapy options. Additionally, this review underscores combination strategies and potential biomarkers for predicting response and resistance in GBM immunotherapies.
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Affiliation(s)
- He Wang
- Department of Neurosurgery, the Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, Shandong, 266005, China
| | - Jing Yang
- Department of Emergency Surgery, the Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, Shandong, 266005, China
| | - Xiangjun Li
- School of medicine, Department of Breast surgery, the Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong, 266000, China
| | - Hai Zhao
- Department of Neurosurgery, the Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, Shandong, 266005, China
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11
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Hou S, Zhao Y, Chen J, Lin Y, Qi X. Tumor-associated macrophages in colorectal cancer metastasis: molecular insights and translational perspectives. J Transl Med 2024; 22:62. [PMID: 38229160 PMCID: PMC10792812 DOI: 10.1186/s12967-024-04856-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 01/03/2024] [Indexed: 01/18/2024] Open
Abstract
Metastasis is the leading cause of high mortality in colorectal cancer (CRC), which is not only driven by changes occurring within the tumor cells, but is also influenced by the dynamic interaction between cancer cells and components in the tumor microenvironment (TME). Currently, the exploration of TME remodeling and its impact on CRC metastasis has attracted increasing attention owing to its potential to uncover novel therapeutic avenues. Noteworthy, emerging studies suggested that tumor-associated macrophages (TAMs) within the TME played important roles in CRC metastasis by secreting a variety of cytokines, chemokines, growth factors and proteases. Moreover, TAMs are often associated with poor prognosis and drug resistance, making them promising targets for CRC therapy. Given the prognostic and clinical value of TAMs, this review provides an updated overview on the origin, polarization and function of TAMs, and discusses the mechanisms by which TAMs promote the metastatic cascade of CRC. Potential TAM-targeting techniques for personalized theranostics of metastatic CRC are emphasized. Finally, future perspectives and challenges for translational applications of TAMs in CRC development and metastasis are proposed to help develop novel TAM-based strategies for CRC precision medicine and holistic healthcare.
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Affiliation(s)
- Siyu Hou
- School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou, 215011, China
| | - Yuanchun Zhao
- School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou, 215011, China
| | - Jiajia Chen
- School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou, 215011, China
| | - Yuxin Lin
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, China.
- Center for Systems Biology, Department of Bioinformatics, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, 215123, China.
| | - Xin Qi
- School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou, 215011, China.
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12
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Liu Z, Huang H, Yu Y, Li L, Shi X, Wang F. Exploring the mechanism of ellagic acid against gastric cancer based on bioinformatics analysis and network pharmacology. J Cell Mol Med 2023; 27:3878-3896. [PMID: 37794689 PMCID: PMC10718161 DOI: 10.1111/jcmm.17967] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 08/17/2023] [Accepted: 08/30/2023] [Indexed: 10/06/2023] Open
Abstract
Ellagic acid (EA) is a natural polyphenolic compound. Recent studies have shown that EA has potential anticancer properties against gastric cancer (GC). This study aims to reveal the potential targets and mechanisms of EA against GC. This study adopted methods of bioinformatics analysis and network pharmacology, including the weighted gene co-expression network analysis (WGCNA), construction of protein-protein interaction (PPI) network, receiver operating characteristic (ROC) and Kaplan-Meier (KM) survival curve analysis, Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, molecular docking and molecular dynamics simulations (MDS). A total of 540 EA targets were obtained. Through WGCNA, we obtained a total of 2914 GC clinical module genes, combined with the disease database for screening, a total of 606 GC-related targets and 79 intersection targets of EA and GC were obtained by constructing Venn diagram. PPI network was constructed to identify 14 core candidate targets; TP53, JUN, CASP3, HSP90AA1, VEGFA, HRAS, CDH1, MAPK3, CDKN1A, SRC, CYCS, BCL2L1 and CDK4 were identified as the key targets of EA regulation of GC by ROC and KM curve analysis. The enrichment analysis of GO and KEGG pathways of key targets was performed, and they were mainly enriched in p53 signalling pathway, PI3K-Akt signalling pathway. The results of molecular docking and MDS showed that EA could effectively bind to 13 key targets to form stable protein-ligand complexes. This study revealed the key targets and molecular mechanisms of EA against GC and provided a theoretical basis for further study of the pharmacological mechanism of EA against GC.
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Affiliation(s)
- Zhiyao Liu
- Department of Rehabilitation MedicineShandong University of Traditional Chinese MedicineJinanChina
| | - Hailiang Huang
- Department of Rehabilitation MedicineShandong University of Traditional Chinese MedicineJinanChina
| | - Ying Yu
- Innovative Institute of Chinese Medicine and PharmacyShandong University of Traditional Chinese MedicineJinanChina
| | - Lingling Li
- Department of Rehabilitation MedicineShandong University of Traditional Chinese MedicineJinanChina
| | - Xin Shi
- Department of Rehabilitation MedicineShandong University of Traditional Chinese MedicineJinanChina
| | - Fangqi Wang
- Department of Rehabilitation MedicineShandong University of Traditional Chinese MedicineJinanChina
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13
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Gong X, Liu Y, Liang K, Chen Z, Ding K, Qiu L, Wei J, Du H. Cucurbitacin I Reverses Tumor-Associated Macrophage Polarization to Affect Cancer Cell Metastasis. Int J Mol Sci 2023; 24:15920. [PMID: 37958903 PMCID: PMC10650020 DOI: 10.3390/ijms242115920] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/29/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
The tumor microenvironment plays a critical role in tumor progression and immune regulation. As one of the most important components of the tumor microenvironment, macrophages have become a new therapeutic target for inhibiting tumor progression. Despite the well-documented anticancer activity of cucurbitacin I, its effect on macrophages remains unclear. In this study, we established a coculture system of macrophages and cancer cells under hypoxic conditions to simulate the tumor-promoting environment mediated by M2-like macrophages. We determined whether cucurbitacin I modulates M2-like polarization in macrophages in vitro and conducted RNA sequencing to identify gene expression changes induced by cucurbitacin I in macrophages. The results indicated a remarkable inhibition of the M2-like polarization phenotype in macrophages following treatment with cucurbitacin I, which was accompanied by the significant downregulation of heme oxygenase-1. Moreover, we found that cucurbitacin I-treated macrophages reduced the migration of cancer cells by inhibiting the M2 polarization in vitro. These findings highlight the potential of cucurbitacin I as a therapeutic agent that targets M2-like macrophages to inhibit cancer cell metastasis. Our study provides novel insights into the intricate interplay among macrophage polarization, cucurbitacin I, and heme oxygenase-1, thereby opening new avenues for cancer treatment.
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Affiliation(s)
| | | | | | | | | | | | - Jinfen Wei
- School of Biology and Biological Engineering, South China University of Technology, University Town Campus, Guangzhou Higher Education Mega Centre, Panyu District, Guangzhou 510006, China; (X.G.); (Y.L.); (K.L.); (Z.C.); (K.D.); (L.Q.)
| | - Hongli Du
- School of Biology and Biological Engineering, South China University of Technology, University Town Campus, Guangzhou Higher Education Mega Centre, Panyu District, Guangzhou 510006, China; (X.G.); (Y.L.); (K.L.); (Z.C.); (K.D.); (L.Q.)
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14
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Silveira MJ, Martins C, Cruz T, Castro F, Amorim-Costa Â, Chester K, Oliveira MJ, Sarmento B. scFv biofunctionalized nanoparticles to effective and safe targeting of CEA-expressing colorectal cancer cells. J Nanobiotechnology 2023; 21:357. [PMID: 37784150 PMCID: PMC10544461 DOI: 10.1186/s12951-023-02126-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 09/21/2023] [Indexed: 10/04/2023] Open
Abstract
Colorectal cancer (CRC) is one of the deadliest cancers worldwide, with the 5 year survival rate in metastatic cases limited to 12%. The design of targeted and effective therapeutics remains a major unmet clinical need in CRC treatment. Carcinoembryonic antigen (CEA), a glycoprotein overexpressed in most colorectal tumors, may constitute a promising molecule for generating novel CEA-targeted therapeutic strategies for CRC treatment. Here, we developed a smart nanoplatform based on chemical conjugation of an anti-CEA single-chain variable fragment (scFv), MFE-23, with PLGA-PEG polymers to deliver the standard 5-Fluorouracil (5-FU) chemotherapy to CRC cells. We confirmed the specificity of the developed CEA-targeted NPs on the internalization by CEA-expressing CRC cells, with an enhance of threefold in the cell uptake. Additionally, CEA-targeted NPs loaded with 5-FU induced higher cytotoxicity in CEA-expressing cells, after 24 h and 48 h of treatment, reinforcing the specificity of the targeted NPs. Lastly, the safety of CEA-targeted NPs loaded with 5-FU was evaluated in donor-isolated macrophages, with no relevant impact on their metabolic activity nor polarization. Altogether, this proof of concept supports the CEA-mediated internalization of targeted NPs as a promising chemotherapeutic strategy for further investigation in different CEA-associated cancers and respective metastatic sites.Authors: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Author 1 Given name: [Maria José] Last name [Silveira]. Author 7 Given name: [Maria José] Last name [Oliveira]. Also, kindly confirm the details in the metadata are correctokAffiliations: Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary.ok.
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Affiliation(s)
- Maria José Silveira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal
| | - Cláudia Martins
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
| | - Tânia Cruz
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
| | - Flávia Castro
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
| | - Ângela Amorim-Costa
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
| | - Kerry Chester
- UCL - University College London Cancer Institute, London, UK
| | - Maria José Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal
- FMUP - Faculdade de Medicina, Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Bruno Sarmento
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal.
- IUCS-CESPU, Rua Central de Gandra 1317, 4585-116, Gandra, Portugal.
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15
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Pérez-Baena MJ, Cordero-Pérez FJ, Pérez-Losada J, Holgado-Madruga M. The Role of GAB1 in Cancer. Cancers (Basel) 2023; 15:4179. [PMID: 37627207 PMCID: PMC10453317 DOI: 10.3390/cancers15164179] [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: 07/17/2023] [Revised: 08/16/2023] [Accepted: 08/18/2023] [Indexed: 08/27/2023] Open
Abstract
GRB2-associated binder 1 (GAB1) is the inaugural member of the GAB/DOS family of pleckstrin homology (PH) domain-containing proteins. Upon receiving various stimuli, GAB1 transitions from the cytoplasm to the membrane where it is phosphorylated by a range of kinases. This event recruits SH2 domain-containing proteins like SHP2, PI3K's p85 subunit, CRK, and others, thereby activating distinct signaling pathways, including MAPK, PI3K/AKT, and JNK. GAB1-deficient embryos succumb in utero, presenting with developmental abnormalities in the heart, placenta, liver, skin, limb, and diaphragm myocytes. Oncogenic mutations have been identified in the context of cancer. GAB1 expression levels are disrupted in various tumors, and elevated levels in patients often portend a worse prognosis in multiple cancer types. This review focuses on GAB1's influence on cellular transformation particularly in proliferation, evasion of apoptosis, metastasis, and angiogenesis-each of these processes being a cancer hallmark. GAB1 also modulates the resistance/sensitivity to antitumor therapies, making it a promising target for future anticancer strategies.
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Affiliation(s)
- Manuel Jesús Pérez-Baena
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (M.J.P.-B.); (J.P.-L.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | | | - Jesús Pérez-Losada
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (M.J.P.-B.); (J.P.-L.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Marina Holgado-Madruga
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
- Departamento de Fisiología y Farmacología, Universidad de Salamanca, 37007 Salamanca, Spain
- Instituto de Neurociencias de Castilla y León (INCyL), 37007 Salamanca, Spain
- Virtual Institute for Good Health and Well Being (GLADE), European Campus of City Universities (EC2U), 86073 Poitiers, France
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16
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Shehadeh-Tout F, Milioli HH, Roslan S, Jansson PJ, Dharmasivam M, Graham D, Anderson R, Wijesinghe T, Azad MG, Richardson DR, Kovacevic Z. Innovative Thiosemicarbazones that Induce Multi-Modal Mechanisms to Down-Regulate Estrogen-, Progesterone-, Androgen- and Prolactin-Receptors in Breast Cancer. Pharmacol Res 2023:106806. [PMID: 37244387 DOI: 10.1016/j.phrs.2023.106806] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 05/29/2023]
Abstract
The estrogen receptor-α (ER-α) is a key driver of breast cancer (BC) and the ER-antagonist, tamoxifen, is a central pillar of BC treatment. However, cross-talk between ER-α, other hormone and growth factor receptors enables development of de novo resistance to tamoxifen. Herein, we mechanistically dissect the activity of a new class of anti-cancer agents that inhibit multiple growth factor receptors and down-stream signaling for the treatment of ER-positive BC. Using RNA sequencing and comprehensive protein expression analysis, we examined the activity of di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), on the expression and activation of hormone and growth factor receptors, co-factors, and key resistance pathways in ER-α-positive BC. DpC differentially regulated 106 estrogen-response genes, and this was linked to decreased mRNA levels of 4 central hormone receptors involved in BC pathogenesis, namely ER, progesterone receptor (PR), androgen receptor (AR), and prolactin receptor (PRL-R). Mechanistic investigation demonstrated that due to DpC and Dp44mT binding metal ions, these agents caused a pronounced decrease in ER-α, AR, PR, and PRL-R protein expression. DpC and Dp44mT also inhibited activation and down-stream signaling of the epidermal growth factor (EGF) family receptors, and expression of co-factors that promote ER-α transcriptional activity, including SRC3, NF-κB p65, and SP1. In vivo, DpC was highly tolerable and effectively inhibited ER-α-positive BC growth. Through bespoke, non-hormonal, multi-modal mechanisms, Dp44mT and DpC decrease the expression of PR, AR, PRL-R, and tyrosine kinases that act with ER-α to promote BC, constituting an innovative therapeutic approach.
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Affiliation(s)
- Faten Shehadeh-Tout
- School of Medical Sciences, University of Sydney, NSW 2006, Australia; Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, The Hashemite University, Zarqa 13133, Jordan
| | - Heloisa H Milioli
- Connie Johnson Breast Cancer Research Laboratory, Garvan Institute of Medical Research, NSW 2010 Australia
| | - Suraya Roslan
- Metastasis Research Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg Vic 3084, Australia
| | - Patric J Jansson
- Cancer Drug Resistance and Stem Cell Program, School of Medical Sciences, University of Sydney, NSW 2006, Australia
| | - Mahendiran Dharmasivam
- Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Dinny Graham
- Breast Cancer Group, The Westmead Institute for Medical Research and Westmead Clinical School, University of Sydney, NSW 2145 Australia
| | - Robin Anderson
- Metastasis Research Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg Vic 3084, Australia; School of Cancer Medicine, La Trobe University, Bundoora, 3086, Victoria, Australia
| | - Tharushi Wijesinghe
- Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Mahan Gholam Azad
- Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Des R Richardson
- Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
| | - Zaklina Kovacevic
- School of Medical Sciences, University of Sydney, NSW 2006, Australia; Department of Physiology, School of Biomedical Sciences, University of NSW, NSW 2052 Australia.
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17
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Wu Z, Fang ZX, Hou YY, Wu BX, Deng Y, Wu HT, Liu J. Exosomes in metastasis of colorectal cancers: Friends or foes? World J Gastrointest Oncol 2023; 15:731-756. [PMID: 37275444 PMCID: PMC10237026 DOI: 10.4251/wjgo.v15.i5.731] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/07/2023] [Accepted: 04/04/2023] [Indexed: 05/12/2023] Open
Abstract
Colorectal cancer (CRC), the third most common type of cancer worldwide, threaten human health and quality of life. With multidisciplinary, including surgery, chemotherapy and/or radiotherapy, patients with an early diagnosis of CRC can have a good prognosis. However, metastasis in CRC patients is the main risk factor causing cancer-related death. To elucidate the underlying molecular mechanisms of CRC metastasis is the difficult and research focus on the investigation of the CRC mechanism. On the other hand, the tumor microenvironment (TME) has been confirmed as having an essential role in the tumorigenesis and metastasis of malignancies, including CRCs. Among the different factors in the TME, exosomes as extracellular vesicles, function as bridges in the communication between cancer cells and different components of the TME to promote the progression and metastasis of CRC. MicroRNAs packaged in exosomes can be derived from different sources and transported into the TME to perform oncogenic or tumor-suppressor roles accordingly. This article focuses on CRC exosomes and illustrates their role in regulating the metastasis of CRC, especially through the packaging of miRNAs, to evoke exosomes as novel biomarkers for their impact on the metastasis of CRC progression.
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Affiliation(s)
- Zheng Wu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Ze-Xuan Fang
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yan-Yu Hou
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Bing-Xuan Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu Deng
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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18
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Huang K, Xu H, Han L, Xu R, Xu Z, Xie Y. Identification of therapeutic targets and prognostic biomarkers among frizzled family genes in glioma. Front Mol Biosci 2023; 9:1054614. [PMID: 36699699 PMCID: PMC9868451 DOI: 10.3389/fmolb.2022.1054614] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 12/28/2022] [Indexed: 01/11/2023] Open
Abstract
Background: The biological functions of the Frizzled gene family (FZDs), as the key node of wingless-type MMTV integration site family (Wnt) and mammalian target of rapamycin signaling pathways, have not been fully elucidated in glioma. This study aims to identify novel therapeutic targets and prognostic biomarkers for gliomas, which may help us understand the role of FZDs. Methods: RNA-sequence data were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) projects. Survival analyses, Cox regression analyses, nomograms, calibration curves, receiver operating characteristic (ROC) curves, gene function enrichment analyses, and immune cell infiltration analyses were conducted using R. Results: High expressions of FZDs were positively associated with the activation of mTOR signaling. FZD1/2/3/4/5/7/8 was significantly highly expressed in tumor tissues, and the high expression of FZD1/2/5/6/7/8 was significantly positively associated with poorer prognosis. FZD2 and FZD6 positively served as independent predictors of poor prognosis. Gene function analysis showed that FZDs were associated with mTOR signaling, immune response, cytokine-cytokine receptor interaction, extracellular matrix organization, apoptosis, and p53 signaling pathway. Conclusions: Our finding strongly indicated a crucial role of FZDs in glioma. FZD1/2/5/6/7/8 could be an unfavorable prognostic factor in glioma and FZD2 and FZD6 may be novel independent predictors of poor prognosis in glioma.
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Affiliation(s)
- Ke Huang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, China,School/Hospital of Stomatology, Lanzhou University, Lanzhou, China
| | - Huimei Xu
- Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Liang Han
- School/Hospital of Stomatology, Lanzhou University, Lanzhou, China
| | - Ruiming Xu
- The Second Hospital of Dalian Medical University, Dalian, China
| | - Zhaoqing Xu
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, China,*Correspondence: Zhaoqing Xu, ; Yi Xie,
| | - Yi Xie
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China,Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China,Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province, Lanzhou, China,*Correspondence: Zhaoqing Xu, ; Yi Xie,
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Hashemi M, Mirdamadi MSA, Talebi Y, Khaniabad N, Banaei G, Daneii P, Gholami S, Ghorbani A, Tavakolpournegari A, Farsani ZM, Zarrabi A, Nabavi N, Zandieh MA, Rashidi M, Taheriazam A, Entezari M, Khan H. Pre-clinical and clinical importance of miR-21 in human cancers: Tumorigenesis, therapy response, delivery approaches and targeting agents. Pharmacol Res 2023; 187:106568. [PMID: 36423787 DOI: 10.1016/j.phrs.2022.106568] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/18/2022] [Accepted: 11/19/2022] [Indexed: 11/23/2022]
Abstract
The field of non-coding RNA (ncRNA) has made significant progress in understanding the pathogenesis of diseases and has broadened our knowledge towards their targeting, especially in cancer therapy. ncRNAs are a large family of RNAs with microRNAs (miRNAs) being one kind of endogenous RNA which lack encoded proteins. By now, miRNAs have been well-coined in pathogenesis and development of cancer. The current review focuses on the role of miR-21 in cancers and its association with tumor progression. miR-21 has both oncogenic and onco-suppressor functions and most of the experiments are in agreement with the tumor-promoting function of this miRNA. miR-21 primarily decreases PTEN expression to induce PI3K/Akt signaling in cancer progression. Overexpression of miR-21 inhibits apoptosis and is vital for inducing pro-survival autophagy. miR-21 is vital for metabolic reprogramming and can induce glycolysis to enhance tumor progression. miR-21 stimulates EMT mechanisms and increases expression of MMP-2 and MMP-9 thereby elevating tumor metastasis. miR-21 is a target of anti-cancer agents such as curcumin and curcumol and its down-regulation impairs tumor progression. Upregulation of miR-21 results in cancer resistance to chemotherapy and radiotherapy. Increasing evidence has revealed the role of miR-21 as a biomarker as it is present in both the serum and exosomes making them beneficial biomarkers for non-invasive diagnosis of cancer.
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Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Motahare Sadat Ayat Mirdamadi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Biology, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Yasmin Talebi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Biology, Islamic Azad University Central Tehran Branch, Tehran, Iran
| | - Nasrin Khaniabad
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Gooya Banaei
- Group of Mutagenesis, Department of Genetics and Microbiology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193 Barcelona, Spain
| | - Pouria Daneii
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Sadaf Gholami
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Amin Ghorbani
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Alireza Tavakolpournegari
- Group of Mutagenesis, Department of Genetics and Microbiology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193 Barcelona, Spain
| | - Zoheir Mohammadian Farsani
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Industrial and Environmental Biotechnology, National Institute for Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkey
| | - Noushin Nabavi
- Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H3Z6, Canada
| | - Mohammad Arad Zandieh
- Department of Food Hygiene and Quality Control, Division of epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran.
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, 23200, Pakistan.
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20
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Chen QY, Gao B, Tong D, Huang C. Crosstalk between extracellular vesicles and tumor-associated macrophage in the tumor microenvironment. Cancer Lett 2023; 552:215979. [PMID: 36306939 DOI: 10.1016/j.canlet.2022.215979] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 10/18/2022] [Accepted: 10/19/2022] [Indexed: 11/11/2022]
Abstract
In concert with hijacking key genes to drive tumor progression, cancer cells also have the unique ability to dynamically interact with host microenvironment and discreetly manipulate the surrounding stroma, also known as the tumor microenvironment (TME), to provide optimal conditions for tumor cells to thrive and evade host immunity. Complex cellular crosstalk and molecular signaling between cancer cells, surrounding non-malignant cells, and non-cellular components are involved in this process. While intercellular communication traditionally centers around chemokines, cytokines, inflammatory mediators, and growth factors, emerging pathways involving extracellular vesicles (EVs) are gaining increasing attention. The immunosuppressive TME is created and maintained in part by the large abundance of tumor-associated macrophages (TMAs), which are associated with drug resistance, poor prognosis, and have emerged as potential targets for cancer immunotherapy. TMAs are highly dynamic, and can be polarized into either M1 or M2-like macrophages. EVs are efficient cell-cell communication molecules that have been catapulted to the center of TMA polarization. In this article, we provide detailed examination of the determinative role of EVs in sustaining the TME through mediating crosstalk between tumor cells and tumor-associated macrophages.
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Affiliation(s)
- Qiao Yi Chen
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China
| | - Beibei Gao
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China
| | - Dongdong Tong
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China.
| | - Chen Huang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Biomedical Experimental Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China; Environmenta and Genes Related to Diseases Key Laboratory of Education Ministry, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China.
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21
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Wu X, Lu W, Xu C, Jiang C, Zhuo Z, Wang R, Zhang D, Cui Y, Chang L, Zuo X, Wang Y, Mei H, Zhang W, Zhang M, Li C. Macrophages Phenotype Regulated by IL-6 Are Associated with the Prognosis of Platinum-Resistant Serous Ovarian Cancer: Integrated Analysis of Clinical Trial and Omics. J Immunol Res 2023; 2023:6455704. [PMID: 37124547 PMCID: PMC10132904 DOI: 10.1155/2023/6455704] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 12/06/2022] [Accepted: 03/22/2023] [Indexed: 05/02/2023] Open
Abstract
Background The treatment of platinum-resistant recurrent ovarian cancer (PROC) is a clinical challenge and a hot topic. Tumor microenvironment (TME) as a key factor promoting ovarian cancer progression. Macrophage is a component of TME, and it has been reported that macrophage phenotype is related to the development of PROC. However, the mechanism underlying macrophage polarization and whether macrophage phenotype can be used as a prognostic indicator of PROC remains unclear. Methods We used ESTIMATE to calculate the number of immune and stromal components in high-grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas database. The differential expression genes (DEGs) were analyzed via protein-protein interaction network, Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) analysis to reveal major pathways of DEGs. CD80 was selected for survival analysis. IL-6 was selected for gene set enrichment analysis (GSEA). A subsequent cohort study was performed to confirm the correlation of IL-6 expression with macrophage phenotype in peripheral blood and to explore the clinical utility of macrophage phenotype for the prognosis of PROC patients. Results A total of 993 intersecting genes were identified as candidates for further survival analysis. Further analysis revealed that CD80 expression was positively correlated with the survival of HGSOC patients. The results of GO and KEGG analysis suggested that macrophage polarization could be regulated via chemokine pathway and cytokine-cytokine receptor interaction. GSEA showed that the genes were mainly enriched in IL-6-STAT-3. Correlation analysis for the proportion of tumor infiltration macrophages revealed that M2 was correlated with IL-6. The results of a cohort study demonstrated that the regulation of macrophage phenotype by IL-6 is bidirectional. The high M1% was a protective factor for progression-free survival. Conclusion Thus, the macrophage phenotype is a prognostic indicator in PROC patients, possibly via a hyperactive IL-6-related pathway, providing an additional clue for the therapeutic intervention of PROC.
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Affiliation(s)
- Xiaoqing Wu
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Wenping Lu
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Chaojie Xu
- The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Cuihong Jiang
- Department of Oncology, Guang'anmen Hospital South Campus, China Academy of Chinese Medical Sciences, Beijing 102627, China
| | - Zhili Zhuo
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ruipeng Wang
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Dongni Zhang
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Yongjia Cui
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Lei Chang
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Xi Zuo
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ya'nan Wang
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Heting Mei
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Weixuan Zhang
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Mengfan Zhang
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Chen Li
- Department of Biology, Chemistry, and Pharmacy, Free University of Berlin, Berlin 14195, Germany
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22
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Chen M, Li C, Sun M, Li Y, Sun X. Recent developments in PD-1/PD-L1 blockade research for gastroesophageal malignancies. Front Immunol 2022; 13:1043517. [PMID: 36505480 PMCID: PMC9731511 DOI: 10.3389/fimmu.2022.1043517] [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: 09/13/2022] [Accepted: 11/03/2022] [Indexed: 11/25/2022] Open
Abstract
Gastroesophageal cancers (GECs) comprise malignancies in the stomach, esophagus, and gastroesophageal junction. Despite ongoing improvements in chemoradiotherapy, the clinical outcomes of GEC have not significantly improved over the years, and treatment remains challenging. Immune checkpoint inhibitors (ICIs) have been the subject of clinical trials worldwide for several years. Encouraging results have been reported in different countries, but further research is required to apply ICIs in the clinical care of patients with GEC. This review summarizes completed and ongoing clinical trials with programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway blockers in GEC and current biomarkers used for predicting PD-1/PD-L1 blockade efficacy. This review captures the main findings of PD-1/PD-L1 antibodies combined with chemotherapy as an effective first-line treatment and a monotherapy in second-line or more treatment and in maintenance therapy. This review aims to provide insight that will help guide future research and clinical trials, thereby improving the outcomes of patients with GEC.
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Affiliation(s)
- Meng Chen
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Chenyan Li
- Department of Endocrinology and Metabolism, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Mingjun Sun
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yiling Li
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xuren Sun
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China,*Correspondence: Xuren Sun,
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23
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Wang Y, Gao P, Hao Z, Chen L, Li X, Jiao Y, Liu J, Li J, Zhang Y, Peng X, Ning B, Zhan X. The effect of neoadjuvant chemotherapy on the tumor immune microenvironment in gastrointestinal tumors. Front Oncol 2022; 12:1054598. [PMID: 36439457 PMCID: PMC9682409 DOI: 10.3389/fonc.2022.1054598] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 10/21/2022] [Indexed: 04/27/2025] Open
Abstract
In recent years, numerous studies have demonstrated that the tumor immune microenvironment (TIME) is capable of regulating the growth of tumors, and tumor-infiltrating immune cells in the TIME can affect the prognosis and treatment responses of patients. Consequently, therapies targeting these immune cells have emerged as important antitumor treatments. As a crucial componet of the perioperative treatment of malignant tumors, neoadjuvant chemotherapy (NACT) can improve the surgical resection rate and prognosis of patients and is a suitable clinical model to evaluate the effect of chemotherapy on the TIME. To provide a rationale for developing valid combinational therapies, this review summarizes the impact of NACT on the TIME, the relationship between tumor-infiltrating immune cells and treatment responses of patients, and the prognostic value of these infiltrating immune cells.
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Affiliation(s)
- Yujie Wang
- Department of Oncology, Changhai Hospital, Naval Military Medical University, Shanghai, China
| | - Peng Gao
- Clinical Cancer Institute, Center for Translational Medicine, Naval Military Medical University, Shanghai, China
| | - Zhibin Hao
- Department of Oncology, Changhai Hospital, Naval Military Medical University, Shanghai, China
| | - Ling Chen
- Department of Oncology, Changhai Hospital, Naval Military Medical University, Shanghai, China
| | - Xiaoxiao Li
- Department of Oncology, Changhai Hospital, Naval Military Medical University, Shanghai, China
| | - Yuan Jiao
- Department of Oncology, Changhai Hospital, Naval Military Medical University, Shanghai, China
| | - Jingyu Liu
- Department of Oncology, Changhai Hospital, Naval Military Medical University, Shanghai, China
| | - Jie Li
- Department of Oncology, Changhai Hospital, Naval Military Medical University, Shanghai, China
| | - Yingyi Zhang
- Department of Oncology, Changhai Hospital, Naval Military Medical University, Shanghai, China
| | - Xiaobo Peng
- Department of Oncology, Changhai Hospital, Naval Military Medical University, Shanghai, China
| | - Beifang Ning
- Department of Gastroenterology, Changzheng Hospital, Naval Military Medical University, Shanghai, China
| | - Xianbao Zhan
- Department of Oncology, Changhai Hospital, Naval Military Medical University, Shanghai, China
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Sukri A, Hanafiah A, Kosai NR. The Roles of Immune Cells in Gastric Cancer: Anti-Cancer or Pro-Cancer? Cancers (Basel) 2022; 14:cancers14163922. [PMID: 36010915 PMCID: PMC9406374 DOI: 10.3390/cancers14163922] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/05/2022] [Accepted: 08/07/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Gastric cancer is still one of the leading causes of death caused by cancer in developing countries. The emerging role of immunotherapy in cancer treatment has led to more research to elucidate the roles of essential immune cells in gastric cancer prognosis. We reviewed the roles of immune cells including T cells, B cells, dendritic cells, macrophages and natural killer cells in gastric cancer. Although the studies conducted on the roles of immune cells in gastric cancer pathogenesis produced conflicting results, understanding the roles of immune cells in gastric cancer will help us to harness them for application in immunotherapy for better prognosis and management of gastric cancer patients. Abstract Despite the fact that the incidence of gastric cancer has declined over the last decade, it is still the world’s leading cause of cancer-related death. The diagnosis of early gastric cancer is difficult, as symptoms of this cancer only manifest at a late stage of cancer progression. Thus, the prognosis of gastric cancer is poor, and the current treatment for improving patients’ outcomes involves the application of surgery and chemotherapy. Immunotherapy is one of the most recent therapies for gastric cancer, whereby the immune system of the host is programmed to combat cancer cells, and the therapy differs based upon the patient’s immune system. However, an understanding of the role of immune cells, namely the cell-mediated immune response and the humoral immune response, is pertinent for applications of immunotherapy. The roles of immune cells in the prognosis of gastric cancer have yielded conflicting results. This review discusses the roles of immune cells in gastric cancer pathogenesis, specifically, T cells, B cells, macrophages, natural killer cells, and dendritic cells, as well as the evidence presented thus far. Understanding how cancer cells interact with immune cells is of paramount importance in designing treatment options for gastric cancer immunotherapy.
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Affiliation(s)
- Asif Sukri
- Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM), Bandar Puncak Alam, Shah Alam 43200, Malaysia
| | - Alfizah Hanafiah
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
- Correspondence:
| | - Nik Ritza Kosai
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
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25
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Almeida A, Castro F, Resende C, Lúcio M, Schwartz S, Sarmento B. Oral delivery of camptothecin-loaded multifunctional chitosan-based micelles is effective in reduce colorectal cancer. J Control Release 2022; 349:731-743. [PMID: 35905784 DOI: 10.1016/j.jconrel.2022.07.029] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 07/01/2022] [Accepted: 07/22/2022] [Indexed: 10/16/2022]
Abstract
Colorectal cancer (CRC) is a heterogeneous disease with high incidence and mortality worldwide. The efficacy of conventional CRC chemotherapy is hampered by poor drug solubility and bioavailability and suboptimal pharmacokinetic profiles. In this work, camptothecin (CPT), a potent anticancer drug, was loaded into an amphiphilic chitosan modified with PEG and oleic acid, to reduce CRC progression after oral administration. While CPT-loaded micelles presented anticancer activity against HCT116, Caco-2 and HT29 CRC cell lines in vitro, empty micelles demonstrated a safe profile when incubated with human blood cells and colorectal cancer cell lines. In a more complex 3D CRC multicellular spheroid model, CPT-loaded micelles also exhibited a significant effect on the spheroid's metabolic activity and size reduction. Remarkably, in vivo studies performed in a HCT116 xenograft model, showed a significant reduction on the tumor growth during and after treatment with CPT-loaded micelles. Moreover, in a more biological relevant in vivo model of chemically-induced CRC, orally administered CPT-loaded micelles demonstrated a significant reduction on tumor incidence and inflammation signs. The findings here reported indicate that CPT-loaded into chitosan-based micelles, by improving drug solubility, alongside its safety profile for normal tissues, may have a promising role CRC chemotherapy.
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Affiliation(s)
- Andreia Almeida
- INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Flávia Castro
- INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
| | - Carlos Resende
- INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
| | - Marlene Lúcio
- CF-UM-UP, Centro de Física das Universidades do Minho e Porto, Departamento de Física da Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal; CBMA, Centro de Biologia Molecular e Ambiental, Departamento de Biologia, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
| | - Simó Schwartz
- Banc de Sang i Teixits, Passeig del Taulat, 116, 08005 Barcelona, Spain
| | - Bruno Sarmento
- INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central da Gandra, 137, 4585-116 Gandra, Portugal.
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Loureiro JP, Cruz MS, Cardoso AP, Oliveira MJ, Macedo MF. Human iNKT Cells Modulate Macrophage Survival and Phenotype. Biomedicines 2022; 10:1723. [PMID: 35885028 PMCID: PMC9313099 DOI: 10.3390/biomedicines10071723] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 07/11/2022] [Accepted: 07/14/2022] [Indexed: 11/16/2022] Open
Abstract
CD1d-restricted invariant Natural Killer T (iNKT) cells are unconventional innate-like T cells whose functions highly depend on the interactions they establish with other immune cells. Although extensive studies have been reported on the communication between iNKT cells and macrophages in mice, less data is available regarding the relevance of this crosstalk in humans. Here, we dove into the human macrophage-iNKT cell axis by exploring how iNKT cells impact the survival and polarization of pro-inflammatory M1-like and anti-inflammatory M2-like monocyte-derived macrophages. By performing in vitro iNKT cell-macrophage co-cultures followed by flow cytometry analysis, we demonstrated that antigen-stimulated iNKT cells induce a generalized activated state on all macrophage subsets, leading to upregulation of CD40 and CD86 expression. CD40L blocking with a specific monoclonal antibody prior to co-cultures abrogated CD40 and CD86 upregulation, thus indicating that iNKT cells required CD40-CD40L co-stimulation to trigger macrophage activation. In addition, activated iNKT cells were cytotoxic towards macrophages in a CD1d-dependent manner, killing M1-like macrophages more efficiently than their naïve M0 or anti-inflammatory M2-like counterparts. Hence, this work highlighted the role of human iNKT cells as modulators of macrophage survival and phenotype, untangling key features of the human macrophage-iNKT cell axis and opening perspectives for future therapeutic modulation.
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Affiliation(s)
- J. Pedro Loureiro
- Cell Activation and Gene Expression Group, Institute for Molecular and Cell Biology (IBMC), Institute for Research and Innovation in Health (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (J.P.L.); (M.S.C.)
- Experimental Immunology Group, Department of Biomedicine (DBM), University Hospital Basel, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland
| | - Mariana S. Cruz
- Cell Activation and Gene Expression Group, Institute for Molecular and Cell Biology (IBMC), Institute for Research and Innovation in Health (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (J.P.L.); (M.S.C.)
- Department of Medical Sciences, University of Aveiro (UA), 3810-193 Aveiro, Portugal
| | - Ana P. Cardoso
- Tumour and Microenvironment Interactions Group, Institute of Biomedical Engineering (INEB), Institute for Research and Innovation in Health (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (A.P.C.); (M.J.O.)
| | - Maria J. Oliveira
- Tumour and Microenvironment Interactions Group, Institute of Biomedical Engineering (INEB), Institute for Research and Innovation in Health (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (A.P.C.); (M.J.O.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - M. Fátima Macedo
- Cell Activation and Gene Expression Group, Institute for Molecular and Cell Biology (IBMC), Institute for Research and Innovation in Health (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (J.P.L.); (M.S.C.)
- Department of Medical Sciences, University of Aveiro (UA), 3810-193 Aveiro, Portugal
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27
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Song S, Zhou J, Li Y, Liu J, Li J, Shu P. Network pharmacology and experimental verification based research into the effect and mechanism of Aucklandiae Radix-Amomi Fructus against gastric cancer. Sci Rep 2022; 12:9401. [PMID: 35672352 PMCID: PMC9174187 DOI: 10.1038/s41598-022-13223-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 05/23/2022] [Indexed: 12/19/2022] Open
Abstract
To investigate the mechanism of the Aucklandiae Radix–Amomi Fructus (AR–AF) herb pair in treating gastric cancer (GC) by using network pharmacology and experimental verification. Using the traditional Chinese medicine system pharmacology database and analysis platform (TCMSP), the major active components and their corresponding targets were estimated and screened out. Using Cytoscape 3.7.2 software, a visual network was established using the active components of AR–AF and the targets of GC. Based on STRING online database, the protein interaction network of vital targets was built and analyzed. With the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server, the gene ontology (GO) biological processes and the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways of the target enrichment were performed. AutoDock Vina was used to perform molecular docking and calculate the binding affinity. The mRNA and protein expression levels of the hub targets were analyzed by the Oncomine, GEPIA, HPA databases and TIMER online tool, and the predicted targets were verified by qRT–PCR in vitro. Eremanthin, cynaropicrin, and aceteugenol were identified as vital active compounds, and AKT1, MAPK3, IL6, MAPK1, as well as EGFR were considered as the major targets. These targets exerted therapeutic effects on GC by regulating the cAMP signaling pathway, and PI3K-Akt signaling pathway. Molecular docking revealed that these active compounds and targets showed good binding interactions. The validation in different databases showed that most of the results were consistent with this paper. The experimental results confirmed that eremanthin could inhibit the proliferation of AGS by reducing the mRNA expression of hub targets. As predicted by network pharmacology and validated by the experimental results, AR–AF exerts antitumor effects through multiple components, targets, and pathways, thereby providing novel ideas and clues for the development of preparations and the treatment of GC.
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Affiliation(s)
- Siyuan Song
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China.,Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China.,Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Jiayu Zhou
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China.,Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China.,Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Ye Li
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China.,Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China.,Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Jiatong Liu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China.,Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Jingzhan Li
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China.,Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China.,Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Peng Shu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China. .,Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China. .,Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, Jiangsu, China.
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Liang S, Fang K, Li S, Liu D, Yi Q. Immune Microenvironment Terms Signature Robustly Predicts the Prognosis and Immunotherapy Response in Bladder Cancer Based on Large Population Cohorts. Front Genet 2022; 13:872441. [PMID: 35615381 PMCID: PMC9126043 DOI: 10.3389/fgene.2022.872441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 03/28/2022] [Indexed: 11/18/2022] Open
Abstract
Immune microenvironment is implicated in cancer progression. However, the role of immune microenvironment in bladder cancer has not been fully explored. Open-accessed datasets GSE120736, GSE128959, GSE13507, GSE31684, GSE32548, GSE48075, GSE83586, and The Cancer Genome Atlas (TCGA) database were enrolled in our study. Single-sample gene set enrichment analysis (ssGSEA) was used to quantify 53 immune terms in combined BLCA cohorts. The top 10 important immune terms were identified through random forest algorithm for model establishment. Our model showed satisfactory efficacy in prognosis prediction. Furthermore, we explored clinical and genomic feature differences between high- and low-risk groups. The results indicated that the patients in the high-risk group might be associated with worse clinical features. Gene set enrichment analysis showed that epithelial–mesenchymal translational, mTORC1 signaling, mitotic spindle, glycolysis, E2F target, and G2M checkpoint pathways were aberrantly activated in high-risk patients, partially explaining its worse prognosis. Patients in the low-risk group showed better immunotherapy response according to TIDE and TCIA analysis, indicating that our model could effectively predict the immunotherapy response rate. KCNH4, UGT1A1, TPO, SHANK1, PITX3, MYH1, MYH13, KRT3, DEC1, and OBP2A genes were identified as feature genes in the high- and low-risk patients. CMAP analysis was performed to identify potential compounds targeting the riskscore.
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Affiliation(s)
- Shengjie Liang
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Kai Fang
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Simin Li
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Dong Liu
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Qingtong Yi
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
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Alzawi A, Iftikhar A, Shalgm B, Jones S, Ellis I, Islam M. Receptor, Signal, Nucleus, Action: Signals That Pass through Akt on the Road to Head and Neck Cancer Cell Migration. Cancers (Basel) 2022; 14:2606. [PMID: 35681586 PMCID: PMC9179418 DOI: 10.3390/cancers14112606] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/20/2022] [Accepted: 05/23/2022] [Indexed: 02/06/2023] Open
Abstract
This review aims to provide evidence for the role of the tumour microenvironment in cancer progression, including invasion and metastasis. The tumour microenvironment is complex and consists of tumour cells and stromal-derived cells, in addition to a modified extracellular matrix. The cellular components synthesise growth factors such as EGF, TGFα and β, VEGF, and NGF, which have been shown to initiate paracrine signalling in head and neck cancer cells by binding to cell surface receptors. One example is the phosphorylation, and hence activation, of the signalling protein Akt, which can ultimately induce oral cancer cell migration in vitro. Blocking of Akt activation by an inhibitor, MK2206, leads to a significant decrease, in vitro, of cancer-derived cell migration, visualised in both wound healing and scatter assays. Signalling pathways have therefore been popular targets for the design of chemotherapeutic agents, but drug resistance has been observed and is related to direct tumour-tumour cell communication, the tumour-extracellular matrix interface, and tumour-stromal cell interactions. Translation of this knowledge to patient care is reliant upon a comprehensive understanding of the complex relationships present in the tumour microenvironment and could ultimately lead to the design of efficacious treatment regimens such as targeted therapy or novel therapeutic combinations.
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Affiliation(s)
| | | | | | | | | | - Mohammad Islam
- Unit of Cell & Molecular Biology, School of Dentistry, University of Dundee, Dundee DD1 4HN, UK; (A.A.); (A.I.); (B.S.); (S.J.); (I.E.)
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30
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Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets. J Hematol Oncol 2022; 15:61. [PMID: 35585567 PMCID: PMC9118588 DOI: 10.1186/s13045-022-01282-8] [Citation(s) in RCA: 270] [Impact Index Per Article: 90.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 05/03/2022] [Indexed: 02/08/2023] Open
Abstract
Immunotherapies like the adoptive transfer of gene-engineered T cells and immune checkpoint inhibitors are novel therapeutic modalities for advanced cancers. However, some patients are refractory or resistant to these therapies, and the mechanisms underlying tumor immune resistance have not been fully elucidated. Immunosuppressive cells such as myeloid-derived suppressive cells, tumor-associated macrophages, tumor-associated neutrophils, regulatory T cells (Tregs), and tumor-associated dendritic cells are critical factors correlated with immune resistance. In addition, cytokines and factors secreted by tumor cells or these immunosuppressive cells also mediate the tumor progression and immune escape of cancers. Thus, targeting these immunosuppressive cells and the related signals is the promising therapy to improve the efficacy of immunotherapies and reverse the immune resistance. However, even with certain success in preclinical studies or in some specific types of cancer, large perspectives are unknown for these immunosuppressive cells, and the related therapies have undesirable outcomes for clinical patients. In this review, we comprehensively summarized the phenotype, function, and potential therapeutic targets of these immunosuppressive cells in the tumor microenvironment.
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Jiang Y, Zeng Z, Xiong S, Jiang M, Huang G, Zhang C, Xi X. New Prognostic Gene Signature and Immune Escape Mechanisms of Bladder Cancer. Front Cell Dev Biol 2022; 10:775417. [PMID: 35646934 PMCID: PMC9133907 DOI: 10.3389/fcell.2022.775417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 04/14/2022] [Indexed: 11/13/2022] Open
Abstract
Background: The immune microenvironment profoundly affects tumor prognosis and therapy. The present study aimed to reveal potential immune escape mechanisms and construct a novel prognostic signature via systematic bioinformatic analysis of the bladder cancer (BLCA) immune microenvironment. Patients and Methods: The transcriptomic data and clinicopathological information for patients with BLCA were obtained from The Cancer Genome Atlas (TCGA). Consensus clustering analysis based on the CIBERSORT and ESTIMATE algorithms was performed with patients with BLCA, which divided them into two clusters. Subsequently, the differentially expressed genes (DEGs) in the two were subjected to univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses to identify prognostic genes, which were used to construct a prognostic model. The predictive performance of the model was verified by receiver operating characteristic (ROC) and Kaplan–Meier (K-M) analyses. In addition, we analyzed the differentially altered immune cells, mutation burden, neoantigen load, and subclonal genome fraction between the two clusters to reveal the immune escape mechanism. Results: Based on the ESTIMATE and clustering analyses, patients with BLCA were classified into two heterogeneous clusters: ImmuneScoreH and ImmuneScoreL. Univariate Cox and LASSO regression analyses identified CD96 (HR = 0.83) and IBSP (HR = 1.09), which were used to construct a prognostic gene signature with significant predictive accuracy. Regarding potential immune escape mechanisms, ImmuneScoreH and ImmuneScoreL were characterized by inactivation of innate immune cell chemotaxis. In ImmuneScoreL, a low tumor antigen load might contribute to immune escape. ImmuneScoreH featured high expression of immune checkpoint molecules. Conclusion: CD96 and IBSP were considered prognostic factors for BLCA. Innate immune inactivation and a low tumor antigen load may be associated with immune escape mechanisms in both clusters. Our research complements the exploration of the immune microenvironment in BLCA.
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Affiliation(s)
- Yi Jiang
- Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhenhao Zeng
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Situ Xiong
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ming Jiang
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Gaomin Huang
- Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chiyu Zhang
- Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiaoqing Xi
- Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Xiaoqing Xi,
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Wei W, Ying X, Chen L, Sun Q, Lu X, Xia Y, Xu R, Zhu Z, Zhang D, Tang Q, Li L, Xie J, Yu H. RecQ mediated genome instability 2 ( RMI2): a potential prognostic and immunological biomarker for pan-cancers. Aging (Albany NY) 2022; 14:4107-4136. [PMID: 35552266 PMCID: PMC9134953 DOI: 10.18632/aging.204076] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/02/2022] [Indexed: 11/25/2022]
Abstract
Background: RecQ mediated genome instability 2 (RMI2) is an essential component of the BLM-TopoIIIa-RMI1-RMI2 (BTR) complex. However, the mysterious veil of the potential immunological relationship of RMI2 in tumorigenesis and development has not been revealed. Methods: We conducted the differential expression (DE) analysis of the RMI2 in pan-cancer using data onto Oncomine, TIMER, and GEPIA databases. Afterward, survival analysis and clinical-stage correlation analysis were performed via the TCGA database. Subsequently, we used R software to further explore the relationship between the expression level of RMI2 and tumor mutation burden (TMB), microsatellite instability (MSI), tumor microenvironment (TME), tumor immune-infiltrated cells (TILs), immune checkpoints (ICP), mismatch repairs (MMRs) -related genes, m6A-related genes, DNA methylation-related genes. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional networks were also performed for annotation via gene set enrichment analysis (GSEA). Results: The RMI2 expressed remarkably high in most cancer types compared to cancer adjacent normal tissues (P < 0.05). High expression of RMI2 was linked to unfavorable prognosis and advanced stage of disease, especially in LIHC and PAAD. RMI2 expression was related to TMB in 16 cancer types and MSI in 8 cancer types. Furthermore, it is significant positive correlations between RMI2 and stromal and immune cells, ICP-related genes, MMRs-related genes, m6A-related genes, and DNA methylation-related genes. Finally, GSEA analysis revealed that RMI2 was engaged in a variety of signaling pathways in pan-cancers. Conclusions: RMI2 may serve as a potential biological target and probably assume a crucial part in tumorigenesis and progression.
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Affiliation(s)
- Wei Wei
- Department of General Surgery, Fuyang Hospital of Anhui Medical University, Fuyang 236000, Anhui, China
| | - Xiaomei Ying
- Department of General Surgery, Suzhou Hospital of Anhui Medical University, Suzhou 234000, China
| | - Liang Chen
- Department of General Surgery, Fuyang Hospital of Anhui Medical University, Fuyang 236000, Anhui, China
| | - Qingmei Sun
- Pancreas Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Xiaohuan Lu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Yang Xia
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China
| | - Rubin Xu
- Department of General Surgery, Fuyang Hospital of Anhui Medical University, Fuyang 236000, Anhui, China
| | - Zhechen Zhu
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Dong Zhang
- The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Qikai Tang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Li Li
- Department of General Surgery, Fuyang Hospital of Anhui Medical University, Fuyang 236000, Anhui, China
| | - Jiaheng Xie
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Hongzhu Yu
- Department of General Surgery, Fuyang Hospital of Anhui Medical University, Fuyang 236000, Anhui, China
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Wu WR, Shi XD, Zhang FP, Zhu K, Zhang R, Yu XH, Qin YF, He SP, Fu HW, Zhang L, Zeng H, Zhu MS, Xu LB, Wong PP, Liu C. Activation of the Notch1-c-myc-VCAM1 signalling axis initiates liver progenitor cell-driven hepatocarcinogenesis and pulmonary metastasis. Oncogene 2022; 41:2340-2356. [DOI: 10.1038/s41388-022-02246-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 02/02/2022] [Accepted: 02/11/2022] [Indexed: 12/14/2022]
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Liu T, Shen J, He Q, Xu S. Identification of a Novel Immune-Related lncRNA CTD-2288O8.1 Regulating Cisplatin Resistance in Ovarian Cancer Based on Integrated Analysis. Front Genet 2022; 13:814291. [PMID: 35237300 PMCID: PMC8884246 DOI: 10.3389/fgene.2022.814291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 01/17/2022] [Indexed: 11/13/2022] Open
Abstract
Ovarian cancer (OC) is the most lethal gynecological malignancy, in which chemoresistance is a crucial factor leading to the poor prognosis. Recently, immunotherapy has brought new light for the treatment of solid tumors. Hence, as a kind of immunologically active cancer, it is reasonably necessary to explore the potential mechanism between immune characteristics and cisplatin resistance in OC. Our study focused on the important role of cisplatin resistance-related lncRNAs on mediating the OC tumor immune microenvironment (TIME) using an integrative analysis based on the Cancer Genome Atlas (TCGA) database. First, the cisplatin resistance-related differentially expressed lncRNAs (DELs) and mRNAs (DEMs) were preliminarily screened to construct a DEL–DEM co-expression network. Next, the protein–protein interaction (PPI) network and pivot analysis were performed to reveal the relevance of these lncRNAs with tumor immune response. Second, the novel lncRNA CTD-2288O8.1 was identified as a key gene for the OC cisplatin resistance formation by qRT-PCR and survival analysis. Gain- and loss-of-function assays (Cell Counting Kit-8 (CCK-8) assay, wound-healing scratch assay, transwell assay, and colony formation assay) further verified the activity of CTD-2288O8.1 in OC progression as well. Third, gene set enrichment analysis (GSEA) was applied along with the correlation analyses of CTD-2288O8.1 with ImmuneScore, tumor-infiltrating immune cells (TICs), and immune inhibitory checkpoint molecules, illustrating that CTD-2288O8.1 was strongly associated with the TIME and has the potential to predict the effect of OC immunotherapy. In addition, basic experiments demonstrated that the expression of CTD-2288O8.1 impacted the EGFR/AKT signal pathway activity of OC tumor cells. Of greater significance, it promoted the M2 polarization of macrophage, which is a type of the most important components of the TIME in solid tumor. Taking together, our study revealed cisplatin resistance-related lncRNAs closely linked with tumor immunity in OC, underscoring the potential mechanism of the TIME in conferring cisplatin resistance, which provided the research basis for further clinical treatment. CTD-2288O8.1 was identified to mediate cisplatin resistance and affect the response of immunotherapy, which could serve as a promising biomarker for guiding clinical treatment and improving prognosis in OC.
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Affiliation(s)
- Tingwei Liu
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jiacheng Shen
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qizhi He
- Department of Pathology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Qizhi He, ; Shaohua Xu,
| | - Shaohua Xu
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Qizhi He, ; Shaohua Xu,
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Gonçalves RM, Saggese T, Yong Z, Ferreira JR, Ignatius A, Wilke HJ, Neidlinger-Wilke C, Teixeira GQ. Interleukin-1β More Than Mechanical Loading Induces a Degenerative Phenotype in Human Annulus Fibrosus Cells, Partially Impaired by Anti-Proteolytic Activity of Mesenchymal Stem Cell Secretome. Front Bioeng Biotechnol 2022; 9:802789. [PMID: 35155408 PMCID: PMC8831733 DOI: 10.3389/fbioe.2021.802789] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/27/2021] [Indexed: 12/04/2022] Open
Abstract
Mesenchymal stem/stromal cell (MSC)–based therapies for low back pain and intervertebral disc (IVD) degeneration have been emerging, despite the poor knowledge of their full mechanism of action. As failure of the annulus fibrosus (AF) is often associated with IVD herniation and inflammation, the objective of the present study was to investigate the impact of the MSC secretome on human AF cells exposed to mechanical loading and a pro-inflammatory environment. Human AF cells isolated from IVD biopsies from patients with adolescent idiopathic scoliosis (AIS) or disc degeneration (DD) were exposed to physiological cyclic tensile strain (CTS) for 72 h in a custom-made device, with or without interleukin (IL)-1β medium supplementation. AF cells stimulated with CTS + IL-1β were then treated with secretome from IL-1β–preconditioned MSCs for 48 h. AF cell metabolic activity, gene expression, protein secretion, matrix metalloproteinase (MMP) activity, and tissue inhibitor of MMPs (TIMP) concentration were evaluated. Expanded AF cells from AIS and DD patients revealed similar metabolic activity and gene expression profiles. CTS stimulation upregulated collagen type I (COL1A1) expression, while IL-1β significantly stimulated IL-6, IL-8, MMP-1, and MMP-3 gene expression and prostaglandin E2 production by AF cells but downregulated COL1A1. The combination of CTS + IL-1β had a similar outcome as IL-1β alone, accompanied by a significant upregulation of elastin. The MSC secretome did not show any immunomodulatory effect on CTS + IL-1β–stimulated AF cells but significantly decreased MMP-1, MMP-2, MMP-3, and MMP-9, while increasing the production of TIMP-1. The obtained results demonstrate a stronger impact of the inflammatory milieu on human AF cells than upper physiologic mechanical stress. In addition, a new MSC mechanism of action in degenerated IVD consisting of the modulation of AF MMP activity was also evidenced, contributing to the advancement of knowledge in AF tissue metabolism.
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Affiliation(s)
- Raquel M. Gonçalves
- Institute of Orthopaedic Research and Biomechanics, Trauma Research Centre, Ulm University, Ulm, Germany
- Instituto de Investigação e Inovação Em Saúde (i3S), Universidade Do Porto, Porto, Portugal
- Instituto de Engenharia Biomédica (INEB), Universidade Do Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
| | - Taryn Saggese
- Institute of Orthopaedic Research and Biomechanics, Trauma Research Centre, Ulm University, Ulm, Germany
| | - Zhiyao Yong
- Institute of Orthopaedic Research and Biomechanics, Trauma Research Centre, Ulm University, Ulm, Germany
| | - Joana R. Ferreira
- Instituto de Investigação e Inovação Em Saúde (i3S), Universidade Do Porto, Porto, Portugal
- Instituto de Engenharia Biomédica (INEB), Universidade Do Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
| | - Anita Ignatius
- Institute of Orthopaedic Research and Biomechanics, Trauma Research Centre, Ulm University, Ulm, Germany
| | - Hans-Joachim Wilke
- Institute of Orthopaedic Research and Biomechanics, Trauma Research Centre, Ulm University, Ulm, Germany
| | - Cornelia Neidlinger-Wilke
- Institute of Orthopaedic Research and Biomechanics, Trauma Research Centre, Ulm University, Ulm, Germany
| | - Graciosa Q. Teixeira
- Institute of Orthopaedic Research and Biomechanics, Trauma Research Centre, Ulm University, Ulm, Germany
- *Correspondence: Graciosa Q. Teixeira,
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Ma ES, Wang ZX, Zhu MQ, Zhao J. Immune evasion mechanisms and therapeutic strategies in gastric cancer. World J Gastrointest Oncol 2022; 14:216-229. [PMID: 35116112 PMCID: PMC8790417 DOI: 10.4251/wjgo.v14.i1.216] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/22/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a malignancy with a high incidence and mortality. The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression. Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion. In this review, we systematically summarize the intricate crosstalk between GC cells and immune cells, including tumor-associated macrophages, neutrophils, myeloid-derived suppressor cells, natural killer cells, effector T cells, regulatory T cells, and B cells. We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack. We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies, both alone and in combination with conventional therapies. Anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment. However, the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients. This review provides a comprehensive understanding of the immune evasion mechanisms of GC, and highlights promising immunotherapeutic strategies.
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Affiliation(s)
- En-Si Ma
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Organ Transplantation, Fudan University, Shanghai 200040, China
| | - Zheng-Xin Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Organ Transplantation, Fudan University, Shanghai 200040, China
| | - Meng-Qi Zhu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Jing Zhao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
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All layers matter: Innovative three-dimensional epithelium-stroma-endothelium intestinal model for reliable permeability outcomes. J Control Release 2021; 341:414-430. [PMID: 34871636 DOI: 10.1016/j.jconrel.2021.11.048] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/19/2021] [Accepted: 11/30/2021] [Indexed: 12/15/2022]
Abstract
Drug development is an ever-growing field, increasingly requesting reliable in vitro tools to speed up early screening phases, reducing the need for animal experiments. In oral delivery, understanding the absorption pattern of a new drug in the small intestine is paramount. Classical two-dimensional (2D) in vitro models are generally too simplistic and do not accurately represent native tissues. The main goal of this work was to develop an advanced three-dimensional (3D) in vitro intestinal model to test absorption in a more reliable manner, by better mimicking the native environment. The 3D model is composed of a collagen-based stromal layer with embedded fibroblasts mimicking the intestinal lamina propria and providing support for the epithelium, composed of enterocytes and mucus-secreting cells. An endothelial layer, surrogating the absorptive capillary network, is also present. The cellular crosstalk between the different cells present in the model is unveiled, disclosing key players, namely those involved in the contraction of collagen by fibroblasts. The developed 3D model presents lower levels of P-glycoprotein (P-gp) and Multidrug Resistance Protein 2 (MRP2) efflux transporters, which are normally overexpressed in traditional Caco-2 models, and are paramount in the absorption of many compounds. This, allied with transepithelial electrical resistance (TEER) values closer to physiological ranges, leads to improved and more reliable permeability outcomes, which are observed when comparing our results with in vivo data.
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Ding Z, Li R, Han J, Sun D, Shen L, Wu G. Identification of an Immune-Related LncRNA Signature in Gastric Cancer to Predict Survival and Response to Immune Checkpoint Inhibitors. Front Cell Dev Biol 2021; 9:739583. [PMID: 34722522 PMCID: PMC8548421 DOI: 10.3389/fcell.2021.739583] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 09/10/2021] [Indexed: 12/18/2022] Open
Abstract
Immune microenvironment in gastric cancer is closely associated with patient’s prognosis. Long non-coding RNAs (lncRNAs) are emerging as key regulators of immune responses. In this study, we aimed to construct a prognostic model based on immune-related lncRNAs (IRLs) to predict the overall survival and response to immune checkpoint inhibitors (ICIs) of gastric cancer (GC) patients. The IRL signature was constructed through a bioinformatics method, and its predictive capability was validated. A stratification analysis indicates that the IRL signature can distinguish different risk patients. A nomogram based on the IRL and other clinical variables efficiently predicted the overall survival of GC patients. The landscape of tumor microenvironment and mutation status partially explain this signature’s predictive capability. We found the level of cancer-associated fibroblasts, endothelial cells, M2 macrophages, and stroma cells was high in the high-risk group, while the number of CD8+ T cells and T follicular helper cells was high in the low-risk group. Immunophenoscore (IPS) is validated for ICI response, and the IRL signature low-risk group received higher IPS, representing a more immunogenic phenotype that was more inclined to respond to ICIs. In addition, we found RNF144A-AS1 was highly expressed in GC patients and promoted the proliferation, migration, and invasive capacity of GC cells. We concluded that the IRL signature represents a novel useful model for evaluating GC survival outcomes and could be implemented to optimize the selection of patients to receive ICI treatment.
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Affiliation(s)
- Zuoyou Ding
- Department of General Surgery, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Ran Li
- State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Han
- Department of General Surgery, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Diya Sun
- Department of General Surgery, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Lei Shen
- Department of General Surgery, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Guohao Wu
- Department of General Surgery, Zhongshan Hospital of Fudan University, Shanghai, China
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Reed T, Schorey J, D'Souza-Schorey C. Tumor-Derived Extracellular Vesicles: A Means of Co-opting Macrophage Polarization in the Tumor Microenvironment. Front Cell Dev Biol 2021; 9:746432. [PMID: 34692700 PMCID: PMC8531490 DOI: 10.3389/fcell.2021.746432] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/20/2021] [Indexed: 12/26/2022] Open
Abstract
Extracellular vesicles (EVs) are a heterogeneous population of membrane-bound parcels of bioactive proteins, nucleic acids, and lipids released from almost all cell types. The diversity of cargo packaged into EVs proffer the induction of an array of effects on recipient cells. EVs released from tumor cells have emerged as a vital means of communication and immune modulation within the tumor microenvironment (TME). Macrophages are an important contributor to the TME with seemingly paradoxical roles promoting either pro- or anti-tumoral immune function depending on their activated phenotypes. Here, we discuss the influence of tumor-derived extracellular vesicles on the functional plasticity of macrophages in tumor progression.
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Affiliation(s)
- Theodore Reed
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, United States
| | - Jeffrey Schorey
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, United States
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Bayat Z, Farhadi Z, Taherkhani A. Identification of potential biomarkers associated with poor prognosis in oral squamous cell carcinoma through integrated bioinformatics analysis: A pilot study. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101243] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Wang G, Zhang M, Cheng M, Wang X, Li K, Chen J, Chen Z, Chen S, Chen J, Xiong G, Xu X, Wang C, Chen D. Tumor microenvironment in head and neck squamous cell carcinoma: Functions and regulatory mechanisms. Cancer Lett 2021; 507:55-69. [PMID: 33741424 DOI: 10.1016/j.canlet.2021.03.009] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 02/07/2023]
Abstract
The tumor microenvironment has been recently reported to play a pivotal role in sustaining tumor cells survival and protecting them from immunotherapy and chemotherapy-induced death. It remains largely unknown how the specific signaling pathway exerts the tumor microenvironment in head and neck squamous cell carcinoma though previous studies have elucidated the regulatory mechanisms involve in tumor immune microenvironment, stromal cells, tumor angiogenesis and cancer stem cell. These components are responsible for tumor progression as well as anti-cancer therapy resistance, leading to rapid tumor growth and treatment failure. In this review, we focus on discussing the interaction between tumor cells and the surrounding components for better understanding of anti-cancer treatment ineffectiveness and its underlying molecular mechanisms.
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Affiliation(s)
- Ganping Wang
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Ming Zhang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 510030, China
| | - Maosheng Cheng
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Xiaochen Wang
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Kang Li
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Jianwen Chen
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Zhi Chen
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Shuang Chen
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Jie Chen
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Gan Xiong
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 510030, China
| | - Xiuyun Xu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 510030, China
| | - Cheng Wang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 510030, China
| | - Demeng Chen
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
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Sacco A, Battaglia AM, Botta C, Aversa I, Mancuso S, Costanzo F, Biamonte F. Iron Metabolism in the Tumor Microenvironment-Implications for Anti-Cancer Immune Response. Cells 2021; 10:303. [PMID: 33540645 PMCID: PMC7913036 DOI: 10.3390/cells10020303] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 01/26/2021] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
New insights into the field of iron metabolism within the tumor microenvironment have been uncovered in recent years. Iron promotes the production of reactive oxygen species, which may either trigger ferroptosis cell death or contribute to malignant transformation. Once transformed, cancer cells divert tumor-infiltrating immune cells to satisfy their iron demand, thus affecting the tumor immunosurveillance. In this review, we highlight how the bioavailability of this metal shapes complex metabolic pathways within the tumor microenvironment and how this affects both tumor-associated macrophages and tumor-infiltrating lymphocytes functions. Furthermore, we discuss the potentials as well as the current clinical controversies surrounding the use of iron metabolism as a target for new anticancer treatments in two opposed conditions: i) the "hot" tumors, which are usually enriched in immune cells infiltration and are extremely rich in iron availability within the microenvironment, and ii) the "cold" tumors, which are often very poor in immune cells, mainly due to immune exclusion.
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Affiliation(s)
- Alessandro Sacco
- Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (A.S.); (A.M.B.); (I.A.); (F.C.)
| | - Anna Martina Battaglia
- Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (A.S.); (A.M.B.); (I.A.); (F.C.)
| | | | - Ilenia Aversa
- Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (A.S.); (A.M.B.); (I.A.); (F.C.)
| | - Serafina Mancuso
- U.O. Biochimica Clinica, Azienda Ospedaliero Universitaria Mater Domini, 88100 Catanzaro, Italy;
| | - Francesco Costanzo
- Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (A.S.); (A.M.B.); (I.A.); (F.C.)
- Center of Interdepartmental Services (CIS), “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy
| | - Flavia Biamonte
- Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (A.S.); (A.M.B.); (I.A.); (F.C.)
- Center of Interdepartmental Services (CIS), “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy
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Study of the active ingredients and mechanism of Sparganii rhizoma in gastric cancer based on HPLC-Q-TOF-MS/MS and network pharmacology. Sci Rep 2021; 11:1905. [PMID: 33479376 PMCID: PMC7820434 DOI: 10.1038/s41598-021-81485-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 01/05/2021] [Indexed: 12/21/2022] Open
Abstract
Sparganii rhizoma (SL) has potential therapeutic effects on gastric cancer (GC), but its main active ingredients and possible anticancer mechanism are still unclear. In this study, we used HPLC-Q-TOF–MS/MS to comprehensively analyse the chemical components of the aqueous extract of SL. On this basis, a network pharmacology method incorporating target prediction, gene function annotation, and molecular docking was performed to analyse the identified compounds, thereby determining the main active ingredients and hub genes of SL in the treatment of GC. Finally, the mRNA and protein expression levels of the hub genes of GC patients were further analysed by the Oncomine, GEPIA, and HPA databases. A total of 41 compounds were identified from the aqueous extract of SL. Through network
analysis, we identified seven main active ingredients and ten hub genes: acacetin, sanleng acid, ferulic acid, methyl 3,6-dihydroxy-2-[(2-hydroxyphenyl) ethynyl]benzoate, caffeic acid, adenine nucleoside, azelaic acid and PIK3R1, PIK3CA, SRC, MAPK1, AKT1, HSP90AA1, HRAS, STAT3, FYN, and RHOA. The results indicated that SL might play a role in GC treatment by controlling the PI3K-Akt and other signalling pathways to regulate biological processes such as proliferation, apoptosis, migration, and angiogenesis in tumour cells. In conclusion, this study used HPLC-Q-TOF–MS/MS combined with a network pharmacology approach to provide an essential reference for identifying the chemical components of SL and its mechanism of action in the treatment of GC.
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Gao H, Ma J, Cheng Y, Zheng P. Exosomal Transfer of Macrophage-Derived miR-223 Confers Doxorubicin Resistance in Gastric Cancer. Onco Targets Ther 2020; 13:12169-12179. [PMID: 33268995 PMCID: PMC7701146 DOI: 10.2147/ott.s283542] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 11/05/2020] [Indexed: 12/26/2022] Open
Abstract
Purpose Macrophages are a major component of the tumour microenvironment and play an important role in chemoresistance of cancer. However, how exosomal microRNAs (miRNAs) derived from macrophages contribute to the development of doxorubicin resistance in gastric cancer (GC) are not clearly defined. The aim of this study was to investigate whether macrophage-derived exosomes mediate doxorubicin resistance in GC. Methods Exosomes isolated from macrophage culture medium were characterized and co-cultured with GC cells and the miR-223 level was detected using real-time quantitative PCR (RT-qPCR). The internalization of exosomes and transfer of miR-223 were observed via immunofluorescence. Macrophages were transfected with an miR-223 inhibitor or negative control. Cell Counting Kit-8 and flow cytometry were employed to explore the effect of macrophage-derived exosomes on the doxorubicin resistance of GC cells. Western blot and RT-qPCR assay were also performed to explore the regulation of GC chemotherapy resistance by exosomal miR-223. Results Here, the macrophages and macrophage-derived exosomes promoted doxorubicin resistance in GC cells. MiR-223 was enriched in macrophage-derived exosomes and they could be transferred to co-cultivated GC cells. The miR-223 knockdown in macrophages could reduce the effects of exosomes on GC cells. Functional studies revealed that exosomal miR-223 derived from macrophages promoted doxorubicin resistance in GC cells by inhibiting F-box and WD repeat domain-containing 7 (FBXW7). Clinically, the expression of miR-223 significantly increased in GC tissues and high expression of plasma exosomal miR-223 was highly linked with doxorubicin resistance in GC patients. Conclusion The exosomal transfer of macrophage-derived miR-223 conferred doxorubicin resistance in GC and targeting exosome communication may be a promising new therapeutic strategy for GC patients.
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Affiliation(s)
- Huijie Gao
- Department of Oncology, The First Affiliated Hospital of Henan University, Kaifeng, Henan 475000, People's Republic of China
| | - Jincheng Ma
- Department of Oncology, The First Affiliated Hospital of Henan University, Kaifeng, Henan 475000, People's Republic of China
| | - Yanhui Cheng
- Department of Oncology, The First Affiliated Hospital of Henan University, Kaifeng, Henan 475000, People's Republic of China
| | - Peiming Zheng
- Department of Clinical Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, Henan 450003, People's Republic of China
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Abstract
The activation of the cGAS-STING pathway has tremendous potential to improve anti-tumor immunity by generating type I interferons. In recent decades, we have witnessed that producing dsDNA upon various stimuli is an initiative factor, triggering the cGAS-SING pathway for a defensive host. The understanding of both intracellular cascade reaction and the changes of molecular components gains insight into type I IFNs and adaptive immunity. Based on the immunological study, the STING-cGAS pathway is coupled to cancer biotherapy. The most challenging problem is the limited therapeutic effect. Therefore, people view 5, 6-dimethylxanthenone-4-acetic acid, cyclic dinucleotides and various derivative as cGAS-STING pathway agonists. Even so, these agonists have flaws in decreasing biotherapeutic efficacy. Subsequently, we exploited agonist delivery systems (nanocarriers, microparticles and hydrogels). The article will discuss the activation of the cGAS-STING pathway and underlying mechanisms, with an introduction of cGAS-STING agonists, related clinical trials and agonist delivery systems.
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46
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Gerada C, Ryan KM. Autophagy, the innate immune response and cancer. Mol Oncol 2020; 14:1913-1929. [PMID: 32745353 PMCID: PMC7463325 DOI: 10.1002/1878-0261.12774] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/22/2020] [Accepted: 06/24/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a cellular degradation and recycling system, which can interact with components of innate immune signalling pathways to enhance pathogen clearance, in both immune and nonimmune cells. Whilst this interaction is often beneficial for pathogen clearance, it can have varying outcomes in regard to tumorigenesis. Autophagy and the innate immune response can have both pro- and antitumorigenic effects at different stages of tumorigenesis due to the plastic nature of the tumour microenvironment (TME). Although both of these components have been studied in isolation as potential therapeutic targets, there has been less research concerning the interaction between autophagy and the innate immune response within the TME. As the innate immune response is critical for the formation of an effective antitumour adaptive immune response, targeting autophagy pathways in both tumour cells and innate immune cells could enhance tumour clearance. Within tumour cells, autophagy pathways are intertwined with pattern recognition receptor (PRR), inflammatory and cell death pathways, and therefore can alter the immunogenicity of the TME and development of the antitumour immune response. In innate immune cells, autophagy components can have autophagy-independent roles in functional pathways, and therefore could be valuable targets for enhancing immune cell function in the TME and immunotherapy. This review highlights the individual importance of autophagy and the innate immune response to tumorigenesis, and also explains the complex interactions between these pathways in the TME.
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Affiliation(s)
- Chelsea Gerada
- Cancer Research UK Beatson InstituteGarscube EstateGlasgowUK
| | - Kevin M. Ryan
- Cancer Research UK Beatson InstituteGarscube EstateGlasgowUK
- Institute of Cancer SciencesUniversity of GlasgowGarscube EstateGlasgowUK
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47
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Zhang X, Bandyopadhyay S, Araujo LP, Tong K, Flores J, Laubitz D, Zhao Y, Yap G, Wang J, Zou Q, Ferraris R, Zhang L, Hu W, Bonder EM, Kiela PR, Coffey R, Verzi MP, Ivanov II, Gao N. Elevating EGFR-MAPK program by a nonconventional Cdc42 enhances intestinal epithelial survival and regeneration. JCI Insight 2020; 5:135923. [PMID: 32686657 PMCID: PMC7455142 DOI: 10.1172/jci.insight.135923] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 07/09/2020] [Indexed: 01/05/2023] Open
Abstract
The regulatory mechanisms enabling the intestinal epithelium to maintain a high degree of regenerative capacity during mucosal injury remain unclear. Ex vivo survival and clonogenicity of intestinal stem cells (ISCs) strictly required growth response mediated by cell division control 42 (Cdc42) and Cdc42-deficient enteroids to undergo rapid apoptosis. Mechanistically, Cdc42 engaging with EGFR was required for EGF-stimulated, receptor-mediated endocytosis and sufficient to promote MAPK signaling. Proteomics and kinase analysis revealed that a physiologically, but nonconventionally, spliced Cdc42 variant 2 (V2) exhibited stronger MAPK-activating capability. Human CDC42-V2 is transcriptionally elevated in some colon tumor tissues. Accordingly, mice engineered to overexpress Cdc42-V2 in intestinal epithelium showed elevated MAPK signaling, enhanced regeneration, and reduced mucosal damage in response to irradiation. Overproducing Cdc42-V2 specifically in mouse ISCs enhanced intestinal regeneration following injury. Thus, the intrinsic Cdc42-MAPK program is required for intestinal epithelial regeneration, and elevating this signaling cascade is capable of initiating protection from genotoxic injury.
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Affiliation(s)
- Xiao Zhang
- Department of Biological Sciences, Division of Life Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey, USA
| | - Sheila Bandyopadhyay
- Department of Biological Sciences, Division of Life Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey, USA
| | - Leandro Pires Araujo
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
| | - Kevin Tong
- Department of Genetics, Division of Life Sciences, School of Arts and Sciences, Rutgers University, New Brunswick, New Jersey, USA
| | - Juan Flores
- Department of Biological Sciences, Division of Life Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey, USA
| | - Daniel Laubitz
- Department of Pediatrics, University of Arizona, Tucson, Arizona, USA
| | - Yanlin Zhao
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey, USA
| | - George Yap
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey, USA
| | - Jingren Wang
- Department of Mechanical and Aerospace Engineering, School of Engineering, Rutgers University, Piscataway, New Jersey, USA
| | - Qingze Zou
- Department of Mechanical and Aerospace Engineering, School of Engineering, Rutgers University, Piscataway, New Jersey, USA
| | - Ronaldo Ferraris
- Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, New Jersey, USA
| | - Lanjing Zhang
- Department of Biological Sciences, Division of Life Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey, USA
- Department of Pathology, University Medical Center of Princeton, Plainsboro, New Jersey, USA
| | - Wenwei Hu
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
| | - Edward M. Bonder
- Department of Biological Sciences, Division of Life Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey, USA
| | - Pawel R. Kiela
- Department of Pediatrics, University of Arizona, Tucson, Arizona, USA
| | - Robert Coffey
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Michael P. Verzi
- Department of Genetics, Division of Life Sciences, School of Arts and Sciences, Rutgers University, New Brunswick, New Jersey, USA
| | - Ivaylo I. Ivanov
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
| | - Nan Gao
- Department of Biological Sciences, Division of Life Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey, USA
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
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Najdaghi S, Razi S, Rezaei N. An overview of the role of interleukin-8 in colorectal cancer. Cytokine 2020; 135:155205. [PMID: 32721849 DOI: 10.1016/j.cyto.2020.155205] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 02/07/2023]
Abstract
Colorectal Cancer (CRC), a common malignancy, is developing globally among people. Mutagenic insults activate peripheral nucleated cells to secrete chemokines in order to cause an inflammatory state. Despite the presence of multi-retrieving factors, elevated production of minor cytokines may speed-up the sever stages of the baseline inflammation targeting normal compensatory mechanism. IL-8 is a pro-inflammatory cytokine that is believed to be up-regulated in CRC to proceed primary condition into tumor behavior via induction of proliferation, angiogenesis and metastasis. Here, we assess the role of IL-8 in every step of CRC from signaling pathway and formation to invasion and discuss around new perspective therapy that targets IL-8 to manage CRC worldwide incidence and survival rate, more precisely.
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Affiliation(s)
- Soroush Najdaghi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Isfahan Neurosciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Sheffield, UK.
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Kwon Y, Kim M, Kim Y, Jung HS, Jeoung D. Exosomal MicroRNAs as Mediators of Cellular Interactions Between Cancer Cells and Macrophages. Front Immunol 2020; 11:1167. [PMID: 32595638 PMCID: PMC7300210 DOI: 10.3389/fimmu.2020.01167] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023] Open
Abstract
Tumor microenvironment consists of cancer cells and various stromal cells such as endothelial cells, cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), neutrophils, macrophages, and other innate and adaptive immune cells. Of these innate immune cells, macrophages are an extremely heterogeneous population, and display both pro-inflammatory and anti-inflammatory functions. While M1 macrophages (classically activated macrophages) display anti-tumoral and pro-inflammatory functions, M2 macrophages display pro-tumoral and anti-inflammatory functions. Cellular interactions and molecular factors in the tumor microenvironment affect the polarization of macrophages. We review molecules and immune cells that influence the polarization status of macrophages. Tumor-associated macrophages (TAMs) generally express M2 phenotype, and mediate many processes that include tumor initiation, angiogenesis, and metastasis. A high number of TAMs has been associated with the poor prognosis of cancers. MicroRNAs (miRNAs) have been known to regulate cellular interactions that involve cancer cells and macrophages. Tumor-derived exosomes play critical roles in inducing the M1 or M2-like polarization of macrophages. The roles of exosomal miRNAs from tumor cells in the polarization of macrophages are also discussed and the targets of these miRNAs are presented. We review the effects of exosomal miRNAs from TAMs on cancer cell invasion, growth, and anti-cancer drug resistance. The relevance of exosomal microRNAs (miRNAs) as targets for the development of anti-cancer drugs is discussed. We review recent progress in the development of miRNA therapeutics aimed at elevating or decreasing levels of miRNAs.
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Affiliation(s)
- Yoojung Kwon
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, South Korea
| | - Misun Kim
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, South Korea
| | - Youngmi Kim
- Institute of New Frontier Research, College of Medicine, Hallym University, Chuncheon, South Korea
| | - Hyun Suk Jung
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, South Korea
| | - Dooil Jeoung
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, South Korea
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50
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Jiang X, Cao G, Gao G, Wang W, Zhao J, Gao C. Triptolide decreases tumor-associated macrophages infiltration and M2 polarization to remodel colon cancer immune microenvironment via inhibiting tumor-derived CXCL12. J Cell Physiol 2020; 236:193-204. [PMID: 32495392 DOI: 10.1002/jcp.29833] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 05/05/2020] [Accepted: 05/20/2020] [Indexed: 12/13/2022]
Abstract
Colon cancer is a common and deadly human digestive tract malignant tumor with poor prognosis. Immunotherapy has elicited tremendous success as a treatment modality for multiple solid tumors. Triptolide is extracted from the traditional Chinese medicine Tripterygium wilfordii Hook. F which shows various pharmacological actions including antitumor, anti-inflammatory, antimicrobial, antifibrosis, and antirheumatic. However, the influence of triptolide treatment on remodeling tumor immune microenvironment is still unknown in colon cancer. This study was aimed to investigate the therapeutic effect of triptolide treatment on colon cancer and the impact on tumor immune microenvironment and its underlying mechanism. We used CT26 subcutaneous tumors to conduct in vivo experiments and HT29, CT16, and Raw264.7 cells to perform in vitro assays. Triptolide had a therapeutic effect against colon cancer in vivo. Triptolide treatment distinctly inhibited the proliferation of colon cancer cells and induced apoptosis in vitro. In colon cancer immune microenvironment, triptolide treatment decreased the infiltration of tumor-associated macrophages through downregulating tumor-derived CXCL12 expression via nuclear factor kappa B and extracellular signal-regulated protein kinases 1 and 2 axis to remodel the immune microenvironment. Triptolide-educated colon cancers retarded the macrophages polarize to anti-inflammatory M2 status by decreasing the expression of Arg-1, CD206, and interleukin-10. Moreover, triptolide inhibited the migration of colon cancer cells via decreasing vascular endothelial growth factor expression. Our results identified the role of triptolide treatment in remodeling colon cancer immune microenvironment along with the distinct cytotoxicity function against colon cancer cells, which may provide the evidence for triptolide treatment in clinical.
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Affiliation(s)
- Xuan Jiang
- Department of Oncology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, Jiangsu, China
| | - Gang Cao
- Department of Respiratory Medicine, Hongze District People's Hospital, Hongze, Jiangsu, China
| | - Guangyi Gao
- Department of Oncology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, Jiangsu, China
| | - Wei Wang
- Department of Oncology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, Jiangsu, China
| | - Jiasheng Zhao
- Department of Oncology, Huaiyin Hospital of Huai'an City, Huai'an, China
| | - Chao Gao
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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