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1
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Yang SF, Chen XC, Pan YJ. Microbiota-derived metabolites in tumorigenesis: mechanistic insights and therapeutic implications. Front Pharmacol 2025; 16:1598009. [PMID: 40444051 PMCID: PMC12119621 DOI: 10.3389/fphar.2025.1598009] [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: 03/22/2025] [Accepted: 05/06/2025] [Indexed: 06/02/2025] Open
Abstract
Intestinal microbiota is a complex ecosystem of microorganisms that perform diverse metabolic activities to maintain gastrointestinal homeostasis. These microorganisms provide energy and nutrients for growth and reproduction while producing numerous metabolites including lipopolysaccharides (LPS), Bacteroides fragilis toxin (BFT), bile acids (BAs), polyamines (PAs), and short-chain fatty acids (SCFAs). These metabolites are linked to inflammation and various metabolic diseases, such as obesity, type-2 diabetes, non-alcoholic fatty liver disease, cardiometabolic disease, and malnutrition. In addition, they may contribute to tumorigenesis. Evidence suggests that these microbes can increase the susceptibility to certain cancers and affect treatment responses. In this review, we discuss the current knowledge on how the gut microbiome and its metabolites influence tumorigenesis, highlighting the potential molecular mechanisms and prospects for basic and translational research in this emerging field.
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Affiliation(s)
| | | | - Yao-Jie Pan
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
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2
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Luo Y, Zhang G, Hu C, Huang L, Wang D, Chen Z, Wang Y. The Role of Natural Products from Herbal Medicine in TLR4 Signaling for Colorectal Cancer Treatment. Molecules 2024; 29:2727. [PMID: 38930793 PMCID: PMC11206024 DOI: 10.3390/molecules29122727] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 05/24/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
The toll-like receptor 4 (TLR4) signaling pathway constitutes an intricate network of protein interactions primarily involved in inflammation and cancer. This pathway triggers intracellular signaling cascades, modulating transcription factors that regulate gene expression related to immunity and malignancy. Previous studies showed that colon cancer patients with low TLR4 expression exhibit extended survival times and the TLR4 signaling pathway holds a significant role in CRC pathogenesis. In recent years, traditional Chinese medicines (TCMs) have garnered substantial attention as an alternative therapeutic modality for CRC, primarily due to their multifaceted composition and ability to target multiple pathways. Emerging evidence indicates that specific TCM products, such as andrographolide, rosmarinic acid, baicalin, etc., have the potential to impede CRC development through the TLR4 signaling pathway. Here, we review the role and biochemical processes of the TLR4 signaling pathway in CRC, and natural products from TCMs affecting the TLR4 pathway. This review sheds light on potential treatment strategies utilizing natural TLR4 inhibitors for CRC, which contributes to the advancement of research and accelerates their clinical integration into CRC treatment.
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Affiliation(s)
- Yan Luo
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.L.); (G.Z.); (L.H.); (D.W.)
| | - Guochen Zhang
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.L.); (G.Z.); (L.H.); (D.W.)
| | - Chao Hu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China;
| | - Lijun Huang
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.L.); (G.Z.); (L.H.); (D.W.)
| | - Dong Wang
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.L.); (G.Z.); (L.H.); (D.W.)
| | - Zhejie Chen
- Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yumei Wang
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.L.); (G.Z.); (L.H.); (D.W.)
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3
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Goïta AA, Guenot D. Colorectal Cancer: The Contribution of CXCL12 and Its Receptors CXCR4 and CXCR7. Cancers (Basel) 2022; 14:1810. [PMID: 35406582 PMCID: PMC8997717 DOI: 10.3390/cancers14071810] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/22/2022] [Accepted: 03/29/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is one of the most common cancers, and diagnosis at late metastatic stages is the main cause of death related to this cancer. This progression to metastasis is complex and involves different molecules such as the chemokine CXCL12 and its two receptors CXCR4 and CXCR7. The high expression of receptors in CRC is often associated with a poor prognosis and aggressiveness of the tumor. The interaction of CXCL12 and its receptors activates signaling pathways that induce chemotaxis, proliferation, migration, and cell invasion. To this end, receptor inhibitors were developed, and their use in preclinical and clinical studies is ongoing. This review provides an overview of studies involving CXCR4 and CXCR7 in CRC with an update on their targeting in anti-cancer therapies.
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Affiliation(s)
| | - Dominique Guenot
- INSERM U1113/Unistra, IRFAC—Interface de Recherche Fondamentale et Appliquée en Cancérologie, 67200 Strasbourg, France;
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4
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Shi A, Wang T, Jia M, Dong L, Shi H. Effects of SDF-1/CXCR7 on the Migration, Invasion and Epithelial-Mesenchymal Transition of Gastric Cancer Cells. Front Genet 2021; 12:760048. [PMID: 34858476 PMCID: PMC8630678 DOI: 10.3389/fgene.2021.760048] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/27/2021] [Indexed: 12/24/2022] Open
Abstract
We found that SDF-1/CXCR7 axis played an important role in the growth and proliferation of gastric cancer in the previous studies. The objectives of this study were to explore the effects of SDF-1/CXCR7 on the metastatic ability of gastric cancer cells and the possible mechanisms. CXCR7 expression in SGC-7901 gastric cancer cells was stably knocked down via lentiviral vectors. The cell migration and invasion abilities were detected by transwell migration and invasion assays. The expressions of matrix metalloproteinase 2 (MMP-2), MMP-9, vascular endothelial growth factor (VEGF), epithelial-mesenchymal transition (EMT) markers and Akt phosphorylation were detected with real-time PCR and/or western blot. We found that SDF-1 markedly enhanced the migration and invasion abilities of SGC-7901 gastric cancer cells; CXCR7 knockdown inhibited these effects. SDF-1/CXCR7 increased the expressions of MMP-2, MMP-9 and VEGF. SDF-1/CXCR7 also downregulated E-cadherin expression but upregulated N-cadherin, vimentin and Snail expressions, suggesting that SDF-1/CXCR7 could promote the development of EMT in gastric cancer cells. Furthermore, SDF-1/CXCR7 could promote Akt phosphorylation. Our results indicated that SDF-1/CXCR7 enhanced the migration, invasion and EMT of gastric cancer cells and thus CXCR7 supression may be a strategy for inhibiting gastric cancer metastasis.
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Affiliation(s)
- Ameng Shi
- Department of Ultrasound, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ting Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Miao Jia
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lei Dong
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Haitao Shi
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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5
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Qin J, Li H, Yu W, Wei L, Wen B. Effect of cold exposure and capsaicin on the expression of histone acetylation and Toll-like receptors in 1,2-dimethylhydrazine-induced colon carcinogenesis. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:60981-60992. [PMID: 34165751 DOI: 10.1007/s11356-021-14849-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 06/08/2021] [Indexed: 06/13/2023]
Abstract
Previous studies have indicated that capsaicin-rich diet and cold weather have shown strong association with tumor incidence. Thus, we investigated the effects of capsaicin and cold exposure in 1,2-dimethylhydrazine (DMH)-induced colorectal cancer as well as the mechanisms underlying capsaicin and cold-induced CRC. Rats were randomly divided into four groups and received cold still water and capsaicin via intragastric gavage until the end of the experiment. The rat's body weight, thymus weight, and food intakes were assessed. Global levels of histone H3K9, H3K18, H3K27, and H4K16 acetylation and histone deacetylase (HDACs) in colon mucosa were assessed by western blot. Expression levels of Toll-like receptors 2 (TLR2) and Toll-like receptors 4 (TLR4) were measured by western blot and reverse-transcriptase quantitative polymerase chain reaction (qPCR). We found that cold and low-dose capsaicin increased tumor numbers and multiplicity, although there were no differences in tumor incidence. Additionally, rat exposure to cold water and capsaicin display further higher levels of histone H3 lysine 9 (H3K9AC), histone H3 lysine 18 (H3K18AC), histone H3 lysine 27 (H3K27AC), and HDACs compared with the DMH and normal rats. In contrast, a considerable decrease of histone H4 lysine 16 (H4K16AC) was detected in the colon mucosa. Cold and low-dose capsaicin exposure groups were also increased TLR2 and TLR4 protein levels and mRNA levels. These results suggest that chronic cold exposure and capsaicin at a low-dose intervention exacerbate ectopic expression of global histone acetylation and TLR level, which are crucial mechanisms responsible for the progression of colorectal cancer in rats.
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Affiliation(s)
- Jingchun Qin
- Institute of Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Huixuan Li
- National Center for Respiratory Medicine, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Weitao Yu
- The Second People's Hospital Lianyungang, Lianyungang, China
| | - Li Wei
- Liuzhou Municipal Liutie Central Hospital, Liuzhou, China
| | - Bin Wen
- Institute of Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China.
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6
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Toll-Like Receptors (TLRs): Structure, Functions, Signaling, and Role of Their Polymorphisms in Colorectal Cancer Susceptibility. BIOMED RESEARCH INTERNATIONAL 2021; 2021:1157023. [PMID: 34552981 PMCID: PMC8452412 DOI: 10.1155/2021/1157023] [Citation(s) in RCA: 174] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/04/2021] [Accepted: 08/19/2021] [Indexed: 12/14/2022]
Abstract
Toll-like receptors (TLRs) are the important mediators of inflammatory pathways in the gut which play a major role in mediating the immune responses towards a wide variety of pathogen-derived ligands and link adaptive immunity with the innate immunity. Numerous studies in different populations across the continents have reported on the significant roles of TLR gene polymorphisms in modulating the risk of colorectal cancer (CRC). CRC is one of the major malignancies affecting the worldwide population and is currently ranking the third most common cancer in the world. In this review, we have attempted to discuss the structure, functions, and signaling of TLRs in comprehensive detail together with the role played by various TLR gene SNPs in CRC susceptibility.
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7
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Wang G, Li HN, Cui XQ, Xu T, Dong ML, Li SY, Li XR. S100A1 is a Potential Biomarker for Papillary Thyroid Carcinoma Diagnosis and Prognosis. J Cancer 2021; 12:5760-5771. [PMID: 34475990 PMCID: PMC8408122 DOI: 10.7150/jca.51855] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 07/20/2021] [Indexed: 12/18/2022] Open
Abstract
S100 calcium binding protein A1 (S100A1) is an important member of the S100 family and known to express in a variety of cancers. However, the biological functions of S100A1 in thyroid carcinoma have not been thoroughly studied. In this report, bioinformatics analyses and immunohistochemistry assays were applied to assess the expression profile of S100A1 as well as its relationship with the pathological features and prognosis of papillary thyroid carcinoma (PTC). Meanwhile, functions of S100A1 in PTC cells were analyzed with either in vitro or in vivo experiments. S100A1 was significantly up-regulated in PTC tissues compared with adjacent non-cancerous tissues. S100A1 protein expression was significantly associated with tumor size (p=0.0032) or lymph node metastasis (p=0.0331). More importantly, an elevated S100A1 expression was significantly correlated with a worse recurrence-free survival (RFS) (HR=2.26, p=0.042). Further, knockdown of S100A1 dramatically inhibited cell proliferation and migration as well as increased apoptosis of PTC cells. S100A1 knockdown inhibited tumor progression as seen in in vivo experiments. In terms of mechanism, down-regulation of S100A1 induced yes associated protein (YAP) phosphorylation in the cytoplasm and diminished Hippo/YAP pathway activation. Therefore, S100A1 may serve as a novel oncogene and a promising biomarker for PTC diagnosis and prognosis.
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Affiliation(s)
- Ge Wang
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China
| | - Han-Ning Li
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China
| | - Xiao-Qing Cui
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China
| | - Tao Xu
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China.,Department of Obstetrics and Gynecology, Cancer Biology Research Center, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China
| | - Meng-Lu Dong
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China
| | - Shu-Yu Li
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China
| | - Xing-Rui Li
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China
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8
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Khare T, Bissonnette M, Khare S. CXCL12-CXCR4/CXCR7 Axis in Colorectal Cancer: Therapeutic Target in Preclinical and Clinical Studies. Int J Mol Sci 2021; 22:7371. [PMID: 34298991 PMCID: PMC8305488 DOI: 10.3390/ijms22147371] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/05/2021] [Accepted: 07/07/2021] [Indexed: 12/24/2022] Open
Abstract
Chemokines are chemotactic cytokines that promote cancer growth, metastasis, and regulate resistance to chemotherapy. Stromal cell-derived factor 1 (SDF1) also known as C-X-C motif chemokine 12 (CXCL12), a prognostic factor, is an extracellular homeostatic chemokine that is the natural ligand for chemokine receptors C-X-C chemokine receptor type 4 (CXCR4), also known as fusin or cluster of differentiation 184 (CD184) and chemokine receptor type 7 (CXCR7). CXCR4 is the most widely expressed rhodopsin-like G protein coupled chemokine receptor (GPCR). The CXCL12-CXCR4 axis is involved in tumor growth, invasion, angiogenesis, and metastasis in colorectal cancer (CRC). CXCR7, recently termed as atypical chemokine receptor 3 (ACKR3), is amongst the G protein coupled cell surface receptor family that is also commonly expressed in a large variety of cancer cells. CXCR7, like CXCR4, regulates immunity, angiogenesis, stem cell trafficking, cell growth and organ-specific metastases. CXCR4 and CXCR7 are expressed individually or together, depending on the tumor type. When expressed together, CXCR4 and CXCR7 can form homo- or hetero-dimers. Homo- and hetero-dimerization of CXCL12 and its receptors CXCR4 and CXCR7 alter their signaling activity. Only few drugs have been approved for clinical use targeting CXCL12-CXCR4/CXCR7 axis. Several CXCR4 inhibitors are in clinical trials for solid tumor treatment with limited success whereas CXCR7-specific inhibitors are still in preclinical studies for CRC. This review focuses on current knowledge of chemokine CXCL12 and its receptors CXCR4 and CXCR7, with emphasis on targeting the CXCL12-CXCR4/CXCR7 axis as a treatment strategy for CRC.
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Affiliation(s)
- Tripti Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA;
| | - Marc Bissonnette
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, IL 60637, USA;
| | - Sharad Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA;
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
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9
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Kashani B, Zandi Z, Pourbagheri-Sigaroodi A, Bashash D, Ghaffari SH. The role of toll-like receptor 4 (TLR4) in cancer progression: A possible therapeutic target? J Cell Physiol 2020; 236:4121-4137. [PMID: 33230811 DOI: 10.1002/jcp.30166] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 10/13/2020] [Accepted: 11/05/2020] [Indexed: 12/13/2022]
Abstract
The toll-like receptor (TLR) family consists of vital receptors responsible for pattern recognition in innate immunity, making them the core proteins involved in pathogen detection and eliciting immune responses. The most studied member of this family, TLR4, has been the center of attention regarding its contributory role in many inflammatory diseases including sepsis shock and asthma. Notably, mounting pieces of evidence have proved that this receptor is aberrantly expressed on the tumor cells and the tumor microenvironment in a wide range of cancer types and it is highly associated with the initiation of tumorigenesis as well as tumor progression and drug resistance. Cancer therapy using TLR4 inhibitors has recently drawn scientists' attention, and the promising results of such studies may pave the way for more investigation in the foreseeable future. This review will introduce the key proteins of the TLR4 pathway and how they interact with major growth factors in the tumor microenvironment. Moreover, we will discuss the many aspects of tumor progression affected by the activation of this receptor and provide an overview of the recent therapeutic approaches using various TLR4 antagonists.
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Affiliation(s)
- Bahareh Kashani
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Zandi
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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10
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Hossam N, Matboli M, Shehata HH, Aboelhussein MM, Hassan MK, Eissa S. Toll-like receptor immune modulatory role in personalized management of colorectal cancer, review of literature. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2020. [DOI: 10.1080/23808993.2020.1816136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Nourhan Hossam
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Marwa Matboli
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Hanan H. Shehata
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Marwa M. Aboelhussein
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohamed Kamel Hassan
- Zewail city for science and Technology, Helmy Institute for medical science, Center for Genomics, Giza, Egypt
- Department of Biology/Zoology, Biotechnology Program, Port Said University, Port Said, Egypt
| | - Sanaa Eissa
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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11
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Xin Q, Sun Q, Zhang CS, Zhang Q, Li CJ. Functions and mechanisms of chemokine receptor 7 in tumors of the digestive system. World J Clin Cases 2020; 8:2448-2463. [PMID: 32607322 PMCID: PMC7322425 DOI: 10.12998/wjcc.v8.i12.2448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 05/12/2020] [Accepted: 06/02/2020] [Indexed: 02/05/2023] Open
Abstract
Chemokine (C-X-C motif) receptor 7 (CXCR7), recently termed ACKR3, belongs to the G protein-coupled cell surface receptor family, binds to stromal cell-derived factor-1 [SDF-1, or chemokine (C-X-C motif) ligand 12] or chemokine (C-X-C motif) ligand 11, and is the most common chemokine receptor expressed in a variety of cancer cells. SDF-1 binds to its receptor chemokine (C-X-C motif) receptor 4 (CXCR4) and regulates cell proliferation, survival, angiogenesis and migration. In recent years, another new receptor for SDF-1, CXCR7, has been discovered, and CXCR7 has also been found to be expressed in a variety of tumor cells and tumor-related vascular endothelial cells. Many studies have shown that CXCR7 can promote the growth and metastasis of a variety of malignant tumor cells. Unlike CXCR4, CXCR7 exhibits a slight modification in the DRYLAIV motif and does not induce intracellular Ca2+ release following ligand binding, which is essential for recruiting and activating G proteins. CXCR7 is generally thought to work in three ways: (1) Recruiting β-arrestin 2; (2) Heterodimerizing with CXCR4; and (3) Acting as a “scavenger” of SDF-1, thus lowering the level of SDF-1 to weaken the activity of CXCR4. In the present review, the expression and role of CXCR7, as well as its prognosis in cancers of the digestive system, were investigated.
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Affiliation(s)
- Qi Xin
- Department of Pathology, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin 300170, China
- Tianjin Key Laboratory of Brain Science and Neural Engineering, Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China
| | - Quan Sun
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin 300170, China
| | - Chuan-Shan Zhang
- Department of Pathology, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin 300170, China
| | - Qin Zhang
- Department of Pathology, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin 300170, China
| | - Chun-Jun Li
- Department of Endocrinology, Health Management Center, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin 300121, China
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12
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Daniel SK, Seo YD, Pillarisetty VG. The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies. Semin Cancer Biol 2019; 65:176-188. [PMID: 31874281 DOI: 10.1016/j.semcancer.2019.12.007] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 12/03/2019] [Accepted: 12/11/2019] [Indexed: 02/07/2023]
Abstract
Single agent checkpoint inhibitor therapy has not been effective for most gastrointestinal solid tumors, but combination therapy with drugs targeting additional immunosuppressive pathways is being attempted. One such pathway, the CXCL12-CXCR4/CXCR7 chemokine axis, has attracted attention due to its effects on tumor cell survival and metastasis as well as immune cell migration. CXCL12 is a small protein that functions in normal hematopoietic stem cell homing in addition to repair of damaged tissue. Binding of CXCL12 to CXCR4 leads to activation of G protein signaling kinases such as P13K/mTOR and MEK/ERK while binding to CXCR7 leads to β-arrestin mediated signaling. While some gastric and colorectal carcinoma cells have been shown to make CXCL12, the primary source in pancreatic cancer and peritoneal metastases is cancer-associated fibroblasts. Binding of CXCL12 to CXCR4 and CXCR7 on tumor cells leads to anti-apoptotic signaling through Bcl-2 and survivin upregulation, as well as promotion of the epithelial-to-mesechymal transition through the Rho-ROCK pathway and alterations in cell adhesion molecules. High levels of CXCL12 seen in the bone marrow, liver, and spleen could partially explain why these are popular sites of metastases for many tumors. CXCL12 is a chemoattractant for lymphocytes at lower levels, but becomes chemorepellant at higher levels; it is unclear exactly what gradient exists in the tumor microenvironment and how this influences tumor-infiltrating lymphocytes. AMD3100 (Plerixafor or Mozobil) is a small molecule CXCR4 antagonist and is the most frequently used drug targeting the CXCL12-CXCR4/CXCR7 axis in clinical trials for gastrointestinal solid tumors currently. Other small molecules and monoclonal antibodies against CXCR4 are being trialed. Further understanding of the CXCL12- CXCR4/CXCR7 chemokine axis in the tumor microenvironment will allow more effective targeting of this pathway in combination immunotherapy.
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Affiliation(s)
- Sara K Daniel
- University of Washington, Dept. of Surgery, Seattle, WA, USA
| | - Y David Seo
- University of Washington, Dept. of Surgery, Seattle, WA, USA
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13
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Xue L, Yan H, Chen Y, Zhang Q, Xie X, Ding X, Wang X, Qian Z, Xiao F, Song Z, Wu Y, Peng Y, Xu H. EZH2 upregulation by ERα induces proliferation and migration of papillary thyroid carcinoma. BMC Cancer 2019; 19:1094. [PMID: 31718595 PMCID: PMC6852908 DOI: 10.1186/s12885-019-6306-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 10/29/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The incidence of papillary thyroid carcinoma (PTC) has been increasing worldwide in recent years. Therefore, novel potential therapeutic targets for PTC are urgently needed. Enhancer of zeste homolog 2 (EZH2), a methyltransferase belonging to PRC2, plays important roles in epigenetic silencing and cell cycle regulation. EZH2 overexpression has been found in several malignant tumor tissues, while its expression and function in PTC are largely unknown. METHODS Sixty-five cases of PTC tissue confirmed by pathology and 30 cases of normal thyroid tissue adjacent to PTC tissue were collected from patients undergoing surgical treatment, between February 2003 and February 2006. We investigated the clinic pathologic significance of EZH2 expression using Realtime-PCR and IHC in 65 human PTC tissues and 30 normal thyroid tissue samples. The EZH2 expression in human PTC cell lines (K1 and W3) and the normal thyroid follicular epithelial cell line Nthy-ori 3-1 was analyzed by Western blotting and Realtime PCR. The expressions of ERα and ERβ in cell lines were analyzed by Realtime PCR.The tumor cell biological behavior was evaluated by CCK8 assay, colony formation assay, transwell migration assay and xenograft tumors model. RESULTS Higher rate of EZH2 expression was found in PTC tissues than in normal thyroid tissues, EZH2 expression is associated with lymph node metastasis and recurrent. Inhibition of EZH2 in PTC cell lines downregulates cellular proliferation and migration. PTC is a disease with high incidence of female and E2-ERα upregulates EZH2 expression. CONCLUSIONS These results suggest a potential role of EZH2 for the PTC growth and metastasis. As a novel therapy, a pharmacological therapy targeting EZH2 has full potential in treatment of PTC.
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Affiliation(s)
- Liqiong Xue
- Department of Endocrinology and Metabolism, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hongzhu Yan
- Department of Pathology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Chen
- Department of Endocrinology and Metabolism, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qifa Zhang
- Department of Urology, Department of Endocrinology and Metabolism, Shanghai Traditional Chinese Medicine-Integrated hospital, Shanghai university of Traditional Chinese Medicine, Shanghai, China
| | - Xin Xie
- Department of Urology, Department of Endocrinology and Metabolism, Shanghai Traditional Chinese Medicine-Integrated hospital, Shanghai university of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoying Ding
- Department of Endocrinology and Metabolism, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaojing Wang
- Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, Bengbu Medical College, Bengbu, China
| | - Zhongqing Qian
- Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, Bengbu Medical College, Bengbu, China
| | - Feng Xiao
- Department of Pathology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhiyi Song
- Department of Endocrinology and Metabolism, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yijie Wu
- Department of Endocrinology and Metabolism, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yongde Peng
- Department of Endocrinology and Metabolism, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Huanbai Xu
- Department of Endocrinology and Metabolism, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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14
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Chu X, Zhou Q, Xu Y, Jiang J, Li Q, Zhou Q, Wu Q, Jin M, Wang H, Gu Y, Wang X, Wang B, He S, He X, Wu C, Zhang F, Zhang Y. Aberrant fatty acid profile and FFAR4 signaling confer endocrine resistance in breast cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:100. [PMID: 30795784 PMCID: PMC6387561 DOI: 10.1186/s13046-019-1040-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 01/15/2019] [Indexed: 12/30/2022]
Abstract
BACKGROUND Evidence suggests that fatty acid receptor FFAR4 plays a tumor-promoting role in adipose tissue-adjacent malignancies, but its clinical relevance remains unexplored. Here, we investigated the clinical significance and underlying mechanisms of FFAR4 in hormone receptor-positive breast cancer (HRPBC). METHODS FFAR4 expression was assessed by immunohistochemistry in an exploration cohort of 307 breast cancer cases collected from two independent institutes. Two public breast cancer microarray datasets served as validation cohorts. Gas chromatography-mass spectrometry was employed to identify FFAR4 ligands in normal and cancerous breast tissues. Survival analyses were performed in all cohorts and designated molecular subgroups. Mechanistic studies were performed in vitro in hormone receptor-positive breast cancer cell lines MCF-7 and T-47D. RESULTS Aberrant FFAR4 expression and endogenous FFAR4 ligands were identified in breast cancer tissues, five FFAR4 ligands showed significantly elevated proportions in cancerous versus normal tissues. In the exploration cohort, FFAR4 was demonstrated as an independent prognostic factor for recurrences (HR: 2.183, 95% CI: 1.360-3.504, P = 0.001) and breast cancer-specific deaths (HR: 2.102, 95% CI: 1.173-3.766, P = 0.013) in HRPBC cases. In contrast, FFAR4 expression was not associated with prognosis in hormone receptor-negative cases. In the validation cohorts, FFAR4 mRNA levels were also observed to be associated with disease recurrence in estrogen receptor-positive cases, but not so in estrogen receptor-negative cases. FFAR4 activation by endogenous ligands and a synthetic ligand TUG891 significantly dampened tamoxifen's efficacy on HRPBC cells, whereas FFAR4 knockdown or antagonist AH7614 abrogated this effect. Furthermore, FFAR4-induced tamoxifen resistance was dependent on ERK and AKT pathways in HRPBC. CONCLUSIONS Our results establish a novel role of FFAR4 and its ligands in the complicated interactions between tissue lipid profile and cancer biology. FFAR4 signaling confers tamoxifen resistance in HRPBC cell line and FFAR4 expression can serve as a prognostic biomarker for tamoxifen-treated HRPBC patients. FFAR4 may serve as a potential target for anti-breast cancer therapies, especially in endocrine resistant cases.
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Affiliation(s)
- Xiao Chu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Changzhou, Jiangsu, China.,Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Qi Zhou
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Changzhou, Jiangsu, China
| | - Yingchun Xu
- Department of Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China
| | - Jingting Jiang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Changzhou, Jiangsu, China
| | - Qing Li
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Changzhou, Jiangsu, China
| | - Qianjun Zhou
- Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qiong Wu
- Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Min Jin
- Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Hui Wang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Changzhou, Jiangsu, China
| | - Yuting Gu
- Department of Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China
| | - Xue Wang
- Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Bei Wang
- Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Songbing He
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Changzhou, Jiangsu, China
| | - Xiaozhou He
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Changzhou, Jiangsu, China
| | - Changping Wu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Changzhou, Jiangsu, China.
| | - Fengchun Zhang
- Department of Oncology, Suzhou Kowloon Hospital and Shanghai Ruijin Hospital, SJTUSM, Suzhou, Jiangsu, China.
| | - Yanyun Zhang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Changzhou, Jiangsu, China. .,Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
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15
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Abstract
Toll-like receptors (TLRs) are a type of pattern-recognition receptor (PRR) that are part of the innate immune system known to recognize pathogen-associated molecular patterns and thereby play a crucial role in host immune response. Among the various known TLRs, TLR4 is one of the most extensively studied PRRs expressed by immune, certain nonimmune, and tumor cells. When TLR4 binds with the bacterial lipopolysaccharide, it induces production of proinflammatory cytokines, chemokines, and effector molecules as part of the immune response. Continuous exposure to pathogens and TLR4 signaling results in chronic inflammation that may further lead to malignant transformation. TLR4 is a highly polymorphic gene, and genetic variations are known to influence host immune response, leading to dysregulation of signaling pathway, which may affect an individual's susceptibility to various diseases, including cancer. Furthermore, TLR4 expression in different tumor types may also serve as a marker for tumor proliferation, differentiation, metastasis, prognosis, and patient survival. This review aims to summarize various reports related to TLR4 polymorphisms and expression patterns and their influences on different cancer types with a special focus on solid tumors.
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Affiliation(s)
- Nilesh Pandey
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology (CHARUSAT), Changa, Anand, 388421, India
| | - Alex Chauhan
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology (CHARUSAT), Changa, Anand, 388421, India
| | - Neeraj Jain
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology (CHARUSAT), Changa, Anand, 388421, India.
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Otoukesh B, Boddouhi B, Moghtadaei M, Kaghazian P, Kaghazian M. Novel molecular insights and new therapeutic strategies in osteosarcoma. Cancer Cell Int 2018; 18:158. [PMID: 30349420 PMCID: PMC6192346 DOI: 10.1186/s12935-018-0654-4] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 10/01/2018] [Indexed: 12/18/2022] Open
Abstract
Osteosarcoma (OS) is one of the most prevalent malignant cancers with lower survival and poor overall prognosis mainly in children and adolescents. Identifying the molecular mechanisms and OS stem cells (OSCs) as new concepts involved in disease pathogenesis and progression may potentially lead to new therapeutic targets. Therefore, therapeutic targeting of OSCs can be one of the most important and effective strategies for the treatment of OS. This review describes the new molecular targets of OS as well as novel therapeutic approaches in the design of future investigations and treatment.
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Affiliation(s)
- Babak Otoukesh
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, 1445613131 Iran
| | - Bahram Boddouhi
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, 1445613131 Iran
| | - Mehdi Moghtadaei
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, 1445613131 Iran
| | - Peyman Kaghazian
- Department of Orthopedic and Traumatology, Universitätsklinikum Bonn, Bonn, Germany
| | - Maria Kaghazian
- Department of Biology, Jundishapur University of Medical Sciences, Ahvaz, Iran
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17
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Zhao Q, Zhang P, Qin G, Ren F, Zheng Y, Qiao Y, Sun T, Zhang Y. Role of CXCR7 as a Common Predictor for Prognosis in Solid Tumors: a Meta-Analysis. J Cancer 2018; 9:3138-3148. [PMID: 30210637 PMCID: PMC6134830 DOI: 10.7150/jca.25377] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 07/07/2018] [Indexed: 01/20/2023] Open
Abstract
Background: Accumulating evidence indicated that the CXC chemokine receptor (CXCR) 7 (CXCR7) was overexpressed in a variety of tumors. However, the value of the CXCR7 expression in predicting prognosis in solid tumors remains controversial. Therefore, we performed this meta-analysis to evaluate the correlation between CXCR7 expression and lymph node metastasis (LNM), tumor pathological grade and survival, including overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS). Methods: Eligible studies were searched in PubMed, Web of Science, and PMC up to April 2018. A total of 27 studies were included in this meta-analysis. Odds ratio (OR), hazard ratio (HR) and 95 % confidence intervals (CI) were used as effect measures. Results: The meta-analysis showed that high expression of CXCR7 predicted a high risk of LNM (pooled OR = 2.22, 95%CI: 1.41-3.50), high tumor grade (pooled OR = 1.94, 95%CI: 1.20-3.13), poor OS (pooled HR = 1.66, 95%CI: 1.30-2.03), and poor DFS/RFS (pooled HR = 1.82, 95%CI: 1.21-2.43). Subgroup analysis showed that CXCR7 expression had a positive correlation with LNM in pan-adenocarcinoma subgroup (pooled OR = 3.73, 95%CI: 2.21-6.30), while no correlation was found in pan-squamous cancer subgroup (pooled OR = 1.29, 95%CI: 0.56-2.96). Subgroup analysis of tumor grade revealed that high expression of CXCR7 predicted high tumor grade both in pan-squamous cancer and pan-adenocarcinoma (pooled OR = 3.58, 95%CI: 1.39-9.22, pooled OR = 2.25, 95%CI: 1.20-4.20). As in OS group, we divided the data based on analysis method and it turned out that overexpressed CXCR7 predicted worse OS both in multivariate analysis (pooled HR =1.57, 95%CI: 1.12-2.01) and univariate analysis subgroup (pooled HR =1.86, 95%CI: 1.23-2.49). Conclusions: Our meta-analysis revealed that high expression of CXCR7 predicted unfavorable prognosis and may serve as potential targets of cancer therapy.
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Affiliation(s)
- Qitai Zhao
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
- Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Penghua Zhang
- Imaging Department, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Guohui Qin
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
- Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Feifei Ren
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
- Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
- School of Life Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Yujia Zheng
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
- Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Yamin Qiao
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
- Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Ting Sun
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
- Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Yi Zhang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
- Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
- School of Life Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China
- Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan 450052, P.R. China
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18
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Silwedel C, Speer CP, Haarmann A, Fehrholz M, Claus H, Buttmann M, Glaser K. Novel insights into neuroinflammation: bacterial lipopolysaccharide, tumor necrosis factor α, and Ureaplasma species differentially modulate atypical chemokine receptor 3 responses in human brain microvascular endothelial cells. J Neuroinflammation 2018; 15:156. [PMID: 29792190 PMCID: PMC5966865 DOI: 10.1186/s12974-018-1170-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 04/19/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Atypical chemokine receptor 3 (ACKR3, synonym CXCR7) is increasingly considered relevant in neuroinflammatory conditions, in which its upregulation contributes to compromised endothelial barrier function and may ultimately allow inflammatory brain injury. While an impact of ACKR3 has been recognized in several neurological autoimmune diseases, neuroinflammation may also result from infectious agents, including Ureaplasma species (spp.). Although commonly regarded as commensals of the adult urogenital tract, Ureaplasma spp. may cause invasive infections in immunocompromised adults as well as in neonates and appear to be relevant pathogens in neonatal meningitis. Nonetheless, clinical and in vitro data on Ureaplasma-induced inflammation are scarce. METHODS We established a cell culture model of Ureaplasma meningitis, aiming to analyze ACKR3 variances as a possible pathomechanism in Ureaplasma-associated neuroinflammation. Non-immortalized human brain microvascular endothelial cells (HBMEC) were exposed to bacterial lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α), and native as well as LPS-primed HBMEC were cultured with Ureaplasma urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). ACKR3 responses were assessed via qRT-PCR, RNA sequencing, flow cytometry, and immunocytochemistry. RESULTS LPS, TNF-α, and Ureaplasma spp. influenced ACKR3 expression in HBMEC. LPS and TNF-α significantly induced ACKR3 mRNA expression (p < 0.001, vs. control), whereas Ureaplasma spp. enhanced ACKR3 protein expression in HBMEC (p < 0.01, vs. broth control). Co-stimulation with LPS and either Ureaplasma isolate intensified ACKR3 responses (p < 0.05, vs. LPS). Furthermore, stimulation wielded a differential influence on the receptor's ligands. CONCLUSIONS We introduce an in vitro model of Ureaplasma meningitis. We are able to demonstrate a pro-inflammatory capacity of Ureaplasma spp. in native and, even more so, in LPS-primed HBMEC, underlining their clinical relevance particularly in a setting of co-infection. Furthermore, our data may indicate a novel role for ACKR3, with an impact not limited to auto-inflammatory diseases, but extending to infection-related neuroinflammation as well. AKCR3-induced blood-brain barrier breakdown might constitute a potential common pathomechanism.
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Affiliation(s)
- Christine Silwedel
- University Children's Hospital, University of Wuerzburg, Josef-Schneider-Str. 2, 97080, Wuerzburg, Germany.
| | - Christian P Speer
- University Children's Hospital, University of Wuerzburg, Josef-Schneider-Str. 2, 97080, Wuerzburg, Germany
| | - Axel Haarmann
- Department of Neurology, University of Wuerzburg, Josef-Schneider-Str. 11, 97080, Wuerzburg, Germany
| | - Markus Fehrholz
- University Children's Hospital, University of Wuerzburg, Josef-Schneider-Str. 2, 97080, Wuerzburg, Germany
| | - Heike Claus
- Institute for Hygiene and Microbiology, University of Wuerzburg, Josef-Schneider-Str. 2, 97080, Wuerzburg, Germany
| | - Mathias Buttmann
- Department of Neurology, University of Wuerzburg, Josef-Schneider-Str. 11, 97080, Wuerzburg, Germany.,Department of Neurology, Caritas Hospital, Uhlandstr. 7, 97980, Bad Mergentheim, Germany
| | - Kirsten Glaser
- University Children's Hospital, University of Wuerzburg, Josef-Schneider-Str. 2, 97080, Wuerzburg, Germany
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19
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Wu ZF, Wang Y, Yang P, Hou JZ, Zhang JY, Hu Y, Zeng ZC. Toll-like receptor 4 and its associated proteins as prognostic factors for HCC treated by post-radiotherapy surgery. Oncol Lett 2018; 15:9599-9608. [PMID: 29928336 PMCID: PMC6004720 DOI: 10.3892/ol.2018.8583] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2015] [Accepted: 10/18/2017] [Indexed: 01/08/2023] Open
Abstract
Locally advanced hepatocellular carcinoma (HCC) treated by radiotherapy (RT) may be suited for further treatment with surgery. As a critical mediator of the post-RT immune response, Toll-like receptor 4 (TLR4) and its associated proteins may serve as prognostic factors for patients with HCC treated by post-RT surgery. In the present study, a total of 20 patients with HCC treated by post-RT surgery were enrolled. Resected tumor and peritumoral liver tissues were used to construct tissue microarrays that were assessed with immunohistochemical staining for the expression levels of TLR4, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and vascular endothelial growth factor receptor 2 (VEGFR2). The overall (OS) and disease-free (DFS) survival outcomes for each patient were assessed, and the severity of radiation-induced liver diseases (RILDs) was detected. The patients with low TLR4 or TRAIL expression exhibited significantly better OS times than those with high TLR4 (P=0.003) or TRAIL (P=0.007) expression, whereas the median DFS times for patients with low VEGFR2 or TRAIL were significantly longer than those with high VEGFR2 (P=0.003) or TRAIL (P=0.008) expression. No significant differences in OS or DFS times were identified according to the expression of TLR4, VEGFR2 or TRAIL in peritumoral liver tissue, although more severe RILDs were identified in patients with the high expression of these factors in the peritumoral liver tissue post-RT (P<0.05). Therefore, the expression levels of TLR4 and its associated proteins in HCC tumors may be suitable as prognostic factors for patients with HCC treated by post-RT surgery. The inhibition of TLR4, VEGFR2 and TRAIL expression in HCC and non-tumor liver tissue may lessen the severity of RILDs and improve survival outcomes in the future.
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Affiliation(s)
- Zhi-Feng Wu
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Ying Wang
- Department of Ultrasonography, Huashan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Ping Yang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Jia-Zhou Hou
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Jian-Ying Zhang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Yong Hu
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Zhao-Chong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
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20
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Flentie K, Gonzalez C, Kocher B, Wang Y, Zhu H, Marasa J, Piwnica-Worms D. Nucleoside Diphosphate Kinase-3 ( NME3) Enhances TLR5-Induced NF κB Activation. Mol Cancer Res 2018. [PMID: 29523766 DOI: 10.1158/1541-7786.mcr-17-0603] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Bacterial flagellin is a potent activator of NFκB signaling, inflammation, and host innate immunity, and recent data indicate that flagellin represents a novel antitumor ligand acting through toll-like receptor 5 (TLR5) and the NFκB pathway to induce host immunity and aid in the clearance of tumor xenografts. To identify innate signaling components of TLR5 responsible for these antitumor effects, a loss-of-function high-throughput screen was employed utilizing carcinoma cells expressing a dynamic NFκB bioluminescent reporter stimulated by Salmonella typhimurium expressing flagellin. A live cell screen of a siRNA library targeting 691 known and predicted human kinases to identify novel tumor cell modulators of TLR5-induced NFκB activation uncovered several interesting positive and negative candidate regulators not previously recognized, including nucleoside diphosphate kinase 3 (NME3), characterized as an enhancer of signaling responses to flagellin. Targeted knockdown and overexpression assays confirmed the regulatory contribution of NME3 to TLR5-mediated NFκB signaling, mechanistically downstream of MyD88. Furthermore, Kaplan-Meier survival analysis showed that NME3 expression correlated highly with TLR5 expression in breast, lung, ovarian, and gastric cancers, and furthermore, high-level expression of NME3 increased overall survival for patients with breast, lung, and ovarian cancer, but the opposite in gastric cancer. Together, these data identify a previously unrecognized proinflammatory role for NME3 in signaling downstream of TLR5 that may potentiate cancer immunotherapies.Implications: Proinflammatory signaling mediated by innate immunity engagement of flagellin-activated TLR5 in tumor cells results in antitumor effects through NME3 kinase, a positive downstream regulator of flagellin-mediated NFκB signaling, enhancing survival for several human cancers. Mol Cancer Res; 16(6); 986-99. ©2018 AACR.
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Affiliation(s)
- Kelly Flentie
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
| | - Caleb Gonzalez
- Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Brandon Kocher
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
| | - Yue Wang
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hongtu Zhu
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jayne Marasa
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
| | - David Piwnica-Worms
- Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas.
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21
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Wang W, Zhao E, Yu Y, Geng B, Zhang W, Li X. MiR-216a exerts tumor-suppressing functions in renal cell carcinoma by targeting TLR4. Am J Cancer Res 2018; 8:476-488. [PMID: 29637002 PMCID: PMC5883097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Accepted: 01/26/2018] [Indexed: 06/08/2023] Open
Abstract
MiR-216a, a tumor-related microRNA (miRNA), has been reported to be implicated in the tumorigenesis and progression of diverse types of human malignancies; however, its role in renal cell carcinoma (RCC) remains unclear. This study aimed to explore the biological role of miR-216a in RCC and clarify the potential mechanisms involved. In the present study, miR-216a was found to be significantly down-regulated in both RCC tissues and cell lines. Functional studies demonstrated that enhanced expression of miR-216a suppressed RCC cell proliferation, migration and invasion in vitro, inhibited tumor growth in vivo, and induced RCC cell cycle arrest and apoptosis. Moreover, the tumor-suppressing effects of miR-216a in RCC were abrogated by the miR-216a inhibitor treatment. Notably, toll-like receptor 4 (TLR4) was downregulated by miR-216a via direct binding to its 3' untranslated region in RCC cells. Furthermore, TLR4 expression was discovered to be markedly up-regulated and inversely correlated with miR-216a expression in RCC tissues. Mechanistic studies revealed that restoring the expression of TLR-4 alleviated miR-216a-induced inhibitory effects on proliferation, migration and invasion of RCC cells. Taken together, these findings suggest that miR-216a functions as a tumor suppressor in RCC by directly targeting TLR4 and that miR-216a might be a novel therapeutic target for RCC.
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Affiliation(s)
- Wanhui Wang
- Department of Urology, The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150086, China
| | - Enyang Zhao
- Department of Urology, The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150086, China
| | - Yang Yu
- Department of Urology, The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150086, China
| | - Bo Geng
- Department of Urology, The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150086, China
| | - Wenfu Zhang
- Department of Urology, The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150086, China
| | - Xuedong Li
- Department of Urology, The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150086, China
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Zou Y, Qin F, Chen J, Meng J, Wei L, Wu C, Zhang Q, Wei D, Chen X, Wu H, Chen X, Dai S. sTLR4/MD-2 complex inhibits colorectal cancer in vitro and in vivo by targeting LPS. Oncotarget 2018; 7:52032-52044. [PMID: 27409669 PMCID: PMC5239533 DOI: 10.18632/oncotarget.10496] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 06/30/2016] [Indexed: 12/18/2022] Open
Abstract
Colorectal cancer (CRC) is aggressive and associated with TLR4-MD-2 signaling. Toll-like receptor 4 (TLR4) and myeloid differentiation protein 2 (MD-2) were highly expressed in human CRC. The soluble form of extracellular TLR4 domain (sTLR4) and MD-2 may have important roles in binding lipopolysaccharide (LPS). In this study, sTLR4 and MD-2 protein and prepared sTLR4/MD-2 complex were synthesized successfully to restrain LPS-TLR4/MD-2 activation by competing with cellular membrane TLR4 for binding LPS. The sTLR4/MD-2 complex can significantly attenuate LPS induced pro-inflammatory and migration cytokine production in vitro and in vivo, and inhibit the effect of LPS on the cell cycle, migration and invasion of human CRC cells in vitro. Administration of sTLR4/MD-2 complex protected mice from tumor both in xenograft and implantation metastasis model. The sTLR4/MD-2 complex treated mice had smaller tumor, less body weight loss and lower expression of inflammatory cytokines. Here, the azoxymethane/dextran sulfate sodium salt (AOM/DSS) murine model was used as an experimental platform to simulate the physiological and pathological processes of cancers associated with chronic intestinal inflammation. AOM/DSS-induced tumors were inhibited in mice treated by sTLR4/MD-2 complex. It is demonstrated in our study that sTLR4/MD-2 complex could inhibit CRC by competing with binding LPS, raising the complex's possibility of a new prevention agent against CRC.
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Affiliation(s)
- Yan Zou
- Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 545005, P.R. China
| | - Fengxian Qin
- Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 545005, P.R. China
| | - Jifei Chen
- Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 545005, P.R. China
| | - Jie Meng
- Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 545005, P.R. China
| | - Liuhua Wei
- Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 545005, P.R. China
| | - Chunlin Wu
- Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 545005, P.R. China
| | - Qiaoyun Zhang
- Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 545005, P.R. China
| | - Dong Wei
- Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 545005, P.R. China
| | - Xiang Chen
- Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 545005, P.R. China
| | - Hao Wu
- Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 545005, P.R. China
| | - Xiaoli Chen
- Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 545005, P.R. China
| | - Shengming Dai
- Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 545005, P.R. China
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Shi Q, Xiong B, Zhong J, Wang H, Ma D, Miao C. MFHAS1 suppresses TLR4 signaling pathway via induction of PP2A C subunit cytoplasm translocation and inhibition of c-Jun dephosphorylation at Thr239. Mol Immunol 2017; 88:79-88. [PMID: 28609714 DOI: 10.1016/j.molimm.2017.06.017] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 05/30/2017] [Accepted: 06/02/2017] [Indexed: 11/20/2022]
Abstract
TLR4, an important Toll-like receptor in innate immunity, can be activated by LPS and induce proinflammatory cytokines to resist invasion of pathogenic microorganism, but excessive inflammation can trigger tissue injury. Many genes negatively regulate TLR4 signaling pathway. Recent studies found that malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) suppressed the expression of cytokine IL6 in Raw264.7 cells stimulated by LPS, but the mechanisms remained unclear. This study investigated the role of MFHAS1 in TLR4 signaling pathway and the possible mechanisms implicated. The results indicated that the expression of MFHAS1 was significantly increased in cells stimulated with LPS. Up-regulation of MFHAS1 effectively suppressed inflammatory cytokine expression in cells exposed to LPS, whereas down-regulation of MFHAS1 markedly increased inflammatory cytokines expression. Co-immunoprecipitation, pull-down and immunofluorescence tests demonstrated that MFHAS1 combined with the B and C subunits of PP2A and induced cytoplasm translocation of the C subunit, leading to decrease dephosphorylation of c-Jun at Thr239 and increase degradation of c-Jun. Reduction of c-Jun protein results in decreased AP-1 activity, which is independent of inhibition of JNK or p38MAPK phosphorylation. Taken together, these results indicate that MFHAS1 suppresses TLR4 signaling pathway through induction of PP2A C subunit cytoplasm translocation and subsequent c-Jun degradation, leading finally to decrease AP-1 activity and cytokines expression.
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Affiliation(s)
- Qiqing Shi
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Anesthesiology, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Bo Xiong
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Jing Zhong
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Huihui Wang
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Duan Ma
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Collaborative Innovation Center of Genetics and Development, Department of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China; Children's Hospital of Fudan University, Shanghai, 201102, China.
| | - Changhong Miao
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
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24
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D'Alterio C, Nasti G, Polimeno M, Ottaiano A, Conson M, Circelli L, Botti G, Scognamiglio G, Santagata S, De Divitiis C, Nappi A, Napolitano M, Tatangelo F, Pacelli R, Izzo F, Vuttariello E, Botti G, Scala S. CXCR4-CXCL12-CXCR7, TLR2-TLR4, and PD-1/PD-L1 in colorectal cancer liver metastases from neoadjuvant-treated patients. Oncoimmunology 2016; 5:e1254313. [PMID: 28123896 DOI: 10.1080/2162402x.2016.1254313] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Revised: 10/20/2016] [Accepted: 10/21/2016] [Indexed: 12/20/2022] Open
Abstract
A neoadjuvant clinical trial was previously conducted in patients with resectable colorectal cancer liver metastases (CRLM). At a median follow up of 28 months, 20/33 patients were dead of disease, 8 were alive with disease and 5 were alive with no evidence of disease. To shed further insight into biological features accounting for different outcomes, the expression of CXCR4-CXCL12-CXCR7, TLR2-TLR4, and the programmed death receptor-1 (PD-1)/programmed death-1 ligand (PD-L1) was evaluated in excised liver metastases. Expression profiles were assessed through qPCR in metastatic and unaffected liver tissue of 33 CRLM neoadjuvant-treated patients. CXCR4 and CXCR7, TLR2/TLR4, and PD-1/PD-L1 mRNA were significantly overexpressed in metastatic compared to unaffected liver tissues. CXCR4 protein was negative/low in 10/31, and high in 21/31, CXCR7 was negative/low in 16/31 and high in 15/31, CXCL12 was negative/low in 14/31 and high in 17/31 CRLM. PD-1 was negative in 19/30 and positive in 11/30, PD-L1 was negative/low in 24/30 and high in 6/30 CRLM. Stromal PD-L1 expression, affected the progression-free survival (PFS) in the CRLM population. Patients overexpressing CXCR4 experienced a worse PFS and cancer specific survival (CSS) (p = 0.001 and p = 0.0008); in these patients, KRAS mutation identified a subgroup with a significantly worse CSS (p < 0.01). Thus, CXCR4 and PD-L1 expression discriminate patients with the worse PFS within the CRLM evaluated patients. Within the CXCR4 high expressing patients carrying Mut-KRAS in CRLM identifies the worst prognostic group. Thus, CXCR4 targeting plus anti-PD-1 therapy should be explored to improve the prognosis of Mut-KRAS-high CXCR4-CRLMs.
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Affiliation(s)
- Crescenzo D'Alterio
- Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy
| | - Guglielmo Nasti
- Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy
| | - Marianeve Polimeno
- Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy
| | - Alessandro Ottaiano
- Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy
| | - Manuel Conson
- Department of Advanced Biomedical Sciences, Federico II University School of Medicine , Naples, Italy
| | - Luisa Circelli
- Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy
| | - Giovanni Botti
- Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy
| | - Giosuè Scognamiglio
- Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy
| | - Sara Santagata
- Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy
| | - Chiara De Divitiis
- Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy
| | - Anna Nappi
- Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy
| | - Maria Napolitano
- Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy
| | - Fabiana Tatangelo
- Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy
| | - Roberto Pacelli
- Department of Advanced Biomedical Sciences, Federico II University School of Medicine , Naples, Italy
| | - Francesco Izzo
- Hepatobiliary Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy
| | - Emilia Vuttariello
- Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy
| | - Gerardo Botti
- Department of Advanced Biomedical Sciences, Federico II University School of Medicine , Naples, Italy
| | - Stefania Scala
- Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy
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25
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McConnell AT, Ellis R, Pathy B, Plummer R, Lovat PE, O'Boyle G. The prognostic significance and impact of the CXCR4-CXCR7-CXCL12 axis in primary cutaneous melanoma. Br J Dermatol 2016; 175:1210-1220. [PMID: 27167239 DOI: 10.1111/bjd.14720] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/27/2016] [Indexed: 01/10/2023]
Abstract
BACKGROUND Expression of the chemokine receptor CXCR4 is known to regulate melanoma metastasis to distant sites with high expression of the CXCL12 ligand. However, the prognostic impact of CXCR4 expression and potential for autocrine-mediated activation of prosurvival mitogen-activated protein kinase signalling remains enigmatic. Furthermore, expression of the decoy receptor CXCR7 within the local cutaneous melanoma microenvironment remains undefined. OBJECTIVES To define the contribution and prognostic impact of CXCR4-CXCR7-CXCL12 signalling in primary cutaneous melanomas and the immediate tumour microenvironment. METHODS Immunohistochemical/immunofluorescent expression of CXCR4, CXCR7 or CXC12 was analysed in human metastatic melanoma cell lines, primary cutaneous cell types and a retrospective cohort of primary melanomas/benign naevi. CXCL12 secretion by melanoma/cutaneous cells was evaluated by enzyme-linked immunosorbent assay, and autocrine CXCR4-CXCL12 signalling was investigated by addition of a CXCL12-neutralizing antibody. RESULTS CXCR4 expression was significantly higher in primary melanomas that subsequently metastasized after 7 years (P = 0·037). Stratification for American Joint Committee on Cancer (AJCC) stage II disease revealed significantly decreased disease-free survival in patients with > 50% CXCR4 expression (P = 0·036), while comparative analysis of CXCL12 expression in the adjacent epidermis of all AJCC stage melanomas revealed increased CXCL12 correlated with prolonged time to metastasis (P = 0·014). CXCR7 was expressed within the primary melanoma microenvironment but was absent on primary tumours. Addition of anti-CXCL12 to BRAF-mutant melanoma cells resulted in downregulation of phospho-CXCR4 and phospho-extracellular signal-related kinase, indicating autocrine CXCR4-CXCL12 signalling. CONCLUSIONS CXCR4 expression defines a potential prognostic biomarker for AJCC stage II melanoma. Moreover, targeting the CXCR4-CXCR7-CXCL12 axis may represent a novel therapeutic strategy to prevent early melanoma progression.
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Affiliation(s)
- A T McConnell
- Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K
| | - R Ellis
- Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K.,James Cook University Hospital, Middlesbrough, U.K
| | - B Pathy
- Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K
| | - R Plummer
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, U.K
| | - P E Lovat
- Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K
| | - G O'Boyle
- Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K.,Faculty of Applied Sciences, University of Sunderland, Sunderland, U.K
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26
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YUN HWANJUNG, RYU HYEWON, CHOI YOONSEOK, SONG IKCHAN, JO DEOGYEON, KIM SAMYONG, LEE HYOJIN. C-X-C motif receptor 7 in gastrointestinal cancer. Oncol Lett 2015; 10:1227-1232. [PMID: 26622655 PMCID: PMC4533134 DOI: 10.3892/ol.2015.3407] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 05/22/2015] [Indexed: 02/06/2023] Open
Abstract
Chemokine receptors are key mediators of normal physiology and numerous pathological conditions, including inflammation and cancer. This receptor family is an emerging target for anticancer drug development. C-X-C motif receptor 7 (CXCR7) is an atypical chemokine receptor that was first cloned from a canine cDNA library as an orphan receptor and was initially named receptor dog cDNA 1 (RDC1). Shortly after demonstrating that RDC1 binds with its ligand, stromal cell-derived factor-1α and interferon-inducible T-cell α chemoattractant, RDC1 was officially deorphanized and renamed CXCR7, as the seventh receptor in the CXC class of the chemokine receptor family. Recent accumulating evidence has demonstrated that CXCR7 expression is augmented in the majority of tumor cells compared with their normal counterparts and is involved in cell proliferation, survival, migration, invasion and angiogenesis during the initiation and progression of breast, lung and prostate cancer. In the present review, the expression and role of CXCR7, as well as its clinical relevance in cancer of the gastrointestinal system, were investigated. In addition, the potential of this chemokine receptor as a therapeutic target in the treatment of gastrointestinal cancer was discussed.
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Affiliation(s)
- HWAN-JUNG YUN
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea
- Cancer Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, Republic of Korea
| | - HYEWON RYU
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea
| | - YOON SEOK CHOI
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea
| | - IK-CHAN SONG
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea
| | - DEOG-YEON JO
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea
- Cancer Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, Republic of Korea
| | - SAMYONG KIM
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea
- Cancer Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, Republic of Korea
| | - HYO JIN LEE
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea
- Cancer Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, Republic of Korea
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27
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Feng YF, Guo H, Yuan F, Shen MQ. Lipopolysaccharide Promotes Choroidal Neovascularization by Up-Regulation of CXCR4 and CXCR7 Expression in Choroid Endothelial Cell. PLoS One 2015; 10:e0136175. [PMID: 26288180 PMCID: PMC4545586 DOI: 10.1371/journal.pone.0136175] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2015] [Accepted: 07/31/2015] [Indexed: 01/01/2023] Open
Abstract
Stromal cell-derived factor-1 (SDF-1) has been confirmed to participate in the formation of choroidal neovascularization (CNV) via its two receptors: CXC chemokine receptors 4 (CXCR4) and CXCR7. Previous studies have indicated that the activation of Toll-like receptors (TLRs) by lipopolysaccharide (LPS) might elevate CXCR4 and/or CXCR7 expression in tumor cells, enhancing the response to SDF-1 to promote invasion and cell dissemination. However, the impact of LPS on the CXCR4 and CXCR7 expression in endothelial cells and subsequent pathological angiogenesis formation remains to be elucidated. The present study shows that LPS enhanced the CXCR4 and CXCR7 expression via activation of the TLR4 pathway in choroid-retinal endothelial (RF/6A) cells. In addition, the transcriptional regulation of CXCR4 and CXCR7 by LPS was found to be mediated by phosphorylation of the extracellular signal-related kinase (ERK) 1/2 and activation of nuclear factor kappa B (NF-κB) signaling pathways, which were blocked by ERK- or NF-κB-specific inhibitors. Furthermore, the increased CXCR4 and CXCR7 expression resulted in increased SDF-1-induced RF/6A cells proliferation, migration and tube formation. In vivo, LPS-treated rat had significantly higher mRNA levels of CXCR4 and CXCR7 expression and lager laser-induced CNV area than vehicle-treated rat. SDF-1 blockade with a neutralizing antibody attenuated the progression of CNV in LPS-treated rat after a single intravitreal injection. Altogether, these results demonstrated that LPS might influence CNV formation by enhancing CXCR7 and CXCR7 expression in endothelial cells, possibly providing a new perspective for the treatment of CNV-associated diseases.
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Affiliation(s)
- Yi-fan Feng
- Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Hua Guo
- Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Fei Yuan
- Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- * E-mail:
| | - Min-qian Shen
- Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
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Li TT, Ogino S, Qian ZR. Toll-like receptor signaling in colorectal cancer: Carcinogenesis to cancer therapy. World J Gastroenterol 2014; 20:17699-17708. [PMID: 25548469 PMCID: PMC4273121 DOI: 10.3748/wjg.v20.i47.17699] [Citation(s) in RCA: 112] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 08/27/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins, and signal expression of major histocompatibility complex proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These protein receptors are characterized by their ability to respond to invading pathogens promptly by recognizing particular TLR ligands, including flagellin and lipopolysaccharide of bacteria, nucleic acids derived from viruses, and zymosan of fungi. There are 2 major TLR pathways; one is mediated by myeloid differentiation factor 88 (MYD88) adaptor proteins, and the other is independent of MYD88. The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1) and all the TLRs, except TLR3, have been shown to activate this pathway. TLR3 and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling. TLRs play a vital role in activating immune responses. TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis, and are highly likely to be involved in the activation of a number of pathways following cancer therapy. Colorectal cancer (CRC) is one of the most common cancers, and accounts for almost half a million deaths annually worldwide. Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum. The key molecules involved in inflammation-driven carcinogenesis include TLRs. As sensors of cell death and tissue remodeling, TLRs may have a universal role in cancer; stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years. TLRs 3/4/7/8/9 are all validated targets for cancer therapy, and a number of companies are developing agonists and vaccine adjuvants. On the other hand, antagonists may favor inhibition of signaling responsible for autoimmune responses. In this paper, we review TLR signaling in CRC from carcinogenesis to cancer therapy.
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Hu SCS, Yu HS, Yen FL, Chen GS, Lan CCE. CXCR7 expression correlates with tumor depth in cutaneous squamous cell carcinoma skin lesions and promotes tumor cell survival through ERK activation. Exp Dermatol 2014; 23:902-8. [DOI: 10.1111/exd.12557] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/22/2014] [Indexed: 12/21/2022]
Affiliation(s)
- Stephen Chu-Sung Hu
- Department of Dermatology; Kaohsiung Medical University Hospital; Kaohsiung Taiwan
- Department of Dermatology; College of Medicine; Kaohsiung Medical University; Kaohsiung Taiwan
| | - Hsin-Su Yu
- Department of Dermatology; Kaohsiung Medical University Hospital; Kaohsiung Taiwan
- Department of Dermatology; College of Medicine; Kaohsiung Medical University; Kaohsiung Taiwan
| | - Feng-Lin Yen
- Department of Fragrance and Cosmetic Science; College of Pharmacy; Kaohsiung Medical University; Kaohsiung Taiwan
| | - Gwo-Shing Chen
- Department of Dermatology; Kaohsiung Medical University Hospital; Kaohsiung Taiwan
- Department of Dermatology; College of Medicine; Kaohsiung Medical University; Kaohsiung Taiwan
| | - Cheng-Che E. Lan
- Department of Dermatology; Kaohsiung Medical University Hospital; Kaohsiung Taiwan
- Department of Dermatology; College of Medicine; Kaohsiung Medical University; Kaohsiung Taiwan
- Department of Dermatology; Kaohsiung Municipal Ta-Tung Hospital; Kaohsiung Medical University; Kaohsiung Taiwan
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30
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He Z, Deng R, Huang X, Ni Y, Yang X, Wang Z, Hu Q. Lipopolysaccharide enhances OSCC migration by promoting epithelial-mesenchymal transition. J Oral Pathol Med 2014; 44:685-92. [PMID: 25367215 DOI: 10.1111/jop.12285] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/06/2014] [Indexed: 01/19/2023]
Abstract
BACKGROUND This study was performed to examine whether lipopolysaccharide can influence cell migration and epithelial-mesenchymal transition of oral squamous cell carcinoma. METHODS Three oral squamous cell carcinoma cell lines (HSC3, CAL27, and SCC4) were obtained for the study. TLR4 expression in three cell lines was analyzed by Q-PCR and Western blot. After cells treated with LPS, cell migration was analyzed by wound-healing and chemotaxis cell migration assay. Changes of E-cadherin and vimentin expression were tested by Western blot and immunofluorescence staining. To examine NF-κB activation, NF-κB nuclear translocation was investigated. RESULTS TLR4 was expressed in all three cell lines and was highest in HSC3 while lowest in SCC4. TLR4 ligand lipopolysaccharide accelerated wound healing and enhanced cell migration. Also, it stimulated epithelial-mesenchymal transition demonstrated by decreased E-cadherin and increased vimentin expression. Lipopolysaccharide also provoked NF-κB nuclear translocation. Either TLR4 or NF-κB blocking reverted these effects. CONCLUSIONS Lipopolysaccharide can induce TLR4-mediated epithelial-mesenchymal transition and cell migration in oral squamous cell carcinoma. These responses could further affect tumor progressing by inducing tumor cell metastasis.
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Affiliation(s)
- Zhifeng He
- Central Laboratory of Stomatology, Institute and Hospital of Stomatology, Nanjing University Medical School, Nanjing University, Nanjing, China
| | - Runzhi Deng
- Department of Oral and Maxillofacial Surgery, Institute and Hospital of Stomatology, Nanjing University Medical School, Nanjing University, Nanjing, China
| | - Xiaofeng Huang
- Central Laboratory of Stomatology, Institute and Hospital of Stomatology, Nanjing University Medical School, Nanjing University, Nanjing, China
| | - Yanhong Ni
- Central Laboratory of Stomatology, Institute and Hospital of Stomatology, Nanjing University Medical School, Nanjing University, Nanjing, China
| | - Xudong Yang
- Department of Oral and Maxillofacial Surgery, Institute and Hospital of Stomatology, Nanjing University Medical School, Nanjing University, Nanjing, China
| | - Zhiyong Wang
- Department of Oral and Maxillofacial Surgery, Institute and Hospital of Stomatology, Nanjing University Medical School, Nanjing University, Nanjing, China
| | - Qingang Hu
- Department of Oral and Maxillofacial Surgery, Institute and Hospital of Stomatology, Nanjing University Medical School, Nanjing University, Nanjing, China
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Roccaro AM, Sacco A, Purschke WG, Moschetta M, Buchner K, Maasch C, Zboralski D, Zöllner S, Vonhoff S, Mishima Y, Maiso P, Reagan MR, Lonardi S, Ungari M, Facchetti F, Eulberg D, Kruschinski A, Vater A, Rossi G, Klussmann S, Ghobrial IM. SDF-1 inhibition targets the bone marrow niche for cancer therapy. Cell Rep 2014; 9:118-128. [PMID: 25263552 PMCID: PMC4194173 DOI: 10.1016/j.celrep.2014.08.042] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Revised: 07/23/2014] [Accepted: 08/19/2014] [Indexed: 11/30/2022] Open
Abstract
Bone marrow (BM) metastasis remains one of the main causes of death associated with solid tumors as well as multiple myeloma (MM). Targeting the BM niche to prevent or modulate metastasis has not been successful to date. Here, we show that stromal cell-derived factor-1 (SDF-1/CXCL12) is highly expressed in active MM, as well as in BM sites of tumor metastasis and report on the discovery of the high-affinity anti-SDF-1 PEGylated mirror-image l-oligonucleotide (olaptesed-pegol). In vivo confocal imaging showed that SDF-1 levels are increased within MM cell-colonized BM areas. Using in vivo murine and xenograft mouse models, we document that in vivo SDF-1 neutralization within BM niches leads to a microenvironment that is less receptive for MM cells and reduces MM cell homing and growth, thereby inhibiting MM disease progression. Targeting of SDF-1 represents a valid strategy for preventing or disrupting colonization of the BM by MM cells.
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Affiliation(s)
- Aldo M Roccaro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Antonio Sacco
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | | | - Michele Moschetta
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | | | | | | | | | | | - Yuji Mishima
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Patricia Maiso
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Michaela R Reagan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Silvia Lonardi
- Department of Pathology, University of Brescia Medical School, Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Marco Ungari
- Department of Pathology, University of Brescia Medical School, Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Fabio Facchetti
- Department of Pathology, University of Brescia Medical School, Spedali Civili di Brescia, 25123 Brescia, Italy
| | | | | | | | - Giuseppe Rossi
- Spedali Civili di Brescia, Department of Hematology, Centro per la Ricerca Onco-ematologica AIL, (CREA), 25123 Brescia, Italy
| | | | - Irene M Ghobrial
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
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Wu ZF, Zhou XH, Hu YW, Zhou LY, Gao YB, Peng XH, Yang XH, Zhang JY, Hu Y, Zeng ZC. TLR4-dependant immune response, but not hepatitis B virus reactivation, is important in radiation-induced liver disease of liver cancer radiotherapy. Cancer Immunol Immunother 2014; 63:235-45. [PMID: 24337704 PMCID: PMC11029679 DOI: 10.1007/s00262-013-1504-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2013] [Accepted: 11/24/2013] [Indexed: 02/07/2023]
Abstract
Toll-like receptor 4 (TLR4) is an important trigger of the immune response against hepatitis B virus (HBV) infection and liver injuries. The roles of HBV reactivation versus TLR4-dependant immune response may be critical factors in preventing radiation-induced liver diseases (RILDs) after liver cancer radiotherapy. This study consists of three phases. In the primary phase, livers of mutant TLR4 (TLR4(-)) mice were irradiated with 30 Gy in either the absence or presence of HBV infection. The latter was done by introduction of plasmid pAAV/HBV 1.2. In the advanced phase, RILDs were compared in normal TLR4 (TLR4(+)) versus TLR4(-) mice. In the validation phase, 28 liver cancer patients who had undergone radiotherapy before hepatectomy were enrolled. Liver biopsies near tumors, irradiated with 35-48 Gy, were used to construct tissue microarrays. HBV reactivation, TLR4 expression, and severity of RILDs were studied in both mouse and human. More HBV reactivation, without significant RILD, was observed in irradiated versus unirradiated TLR4(-) mice. RILD scores of TLR4(+) mice were higher than TLR4(-) mice. In humans, serious RILDs tended to develop in patients with high TLR4 expression, but not in patients with low TLR4 or high HBV surface antigen expression. High TLR4 expression was seen in only 2 of 12 HBV-reactive patients, but in HBV-nonreactive patients, it was seen in 6 of 9 (P < 0.03). In summary, RILDs correlated with high TLR4 expression, but not with HBV reactivation, which is inhibited in liver with high TLR4 expression after liver cancer radiotherapy.
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Affiliation(s)
- Zhi-Feng Wu
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032 China
| | - Xiao-Hui Zhou
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yun-Wen Hu
- Key Laboratory of Medical Molecular Virology of the Ministries of Education, Fudan University, Shanghai, China
| | - Le-Yuan Zhou
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032 China
| | - Ya-Bo Gao
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032 China
| | - Xiu-Hua Peng
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xiao-Hua Yang
- Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Jian-Ying Zhang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032 China
| | - Yong Hu
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032 China
| | - Zhao-Chong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032 China
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Berahovich RD, Zabel BA, Lewén S, Walters MJ, Ebsworth K, Wang Y, Jaen JC, Schall TJ. Endothelial expression of CXCR7 and the regulation of systemic CXCL12 levels. Immunology 2014; 141:111-22. [PMID: 24116850 DOI: 10.1111/imm.12176] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Revised: 09/13/2013] [Accepted: 09/27/2013] [Indexed: 12/24/2022] Open
Abstract
The concentration of CXCL12/SDF-1 in the bloodstream is tightly regulated, given its central role in leucocyte and stem/progenitor cell egress from bone marrow and recruitment to sites of inflammation or injury. The mechanism responsible for this regulation is unknown. Here we show that both genetic deletion and pharmacological inhibition of CXCR7, a high-affinity CXCL12 receptor, caused pronounced increases in plasma CXCL12 levels. The rise in plasma CXCL12 levels was associated with an impairment in the ability of leucocytes to migrate to a local source of CXCL12. Using a set of complementary and highly sensitive techniques, we found that CXCR7 protein is expressed at low levels in multiple organs in both humans and mice. In humans, CXCR7 was detected primarily on venule endothelium and arteriole smooth muscle cells. CXCR7 expression on venule endothelium was also documented in immunodeficient mice and CXCR7(+/lacZ) mice. The vascular expression of CXCR7 therefore gives it immediate access to circulating CXCL12. These studies suggest that endothelial CXCR7 regulates circulating CXCL12 levels and that CXCR7 inhibitors might be used to block CXCL12-mediated cell migration for therapeutic purposes.
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D'Alterio C, Avallone A, Tatangelo F, Delrio P, Pecori B, Cella L, Pelella A, D'Armiento FP, Carlomagno C, Bianco F, Silvestro L, Pacelli R, Napolitano M, Iaffaioli RV, Scala S. A prognostic model comprising pT stage, N status, and the chemokine receptors CXCR4 and CXCR7 powerfully predicts outcome in neoadjuvant resistant rectal cancer patients. Int J Cancer 2014; 135:379-90. [PMID: 24375277 DOI: 10.1002/ijc.28689] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Revised: 12/03/2013] [Accepted: 12/12/2013] [Indexed: 01/15/2023]
Abstract
Despite the optimization of the local treatment of advanced rectal cancer (LARC), combination of preoperative chemoradiotherapy (CRT) and surgery, approximately one third of patients will develop distant metastases. Since the chemokine receptor CXCR4 has been implicated in metastasis development and prognosis in colorectal cancer, the role of the entire axis CXCR4-CXCL12-CXCR7 was evaluated to identify high relapse risk rectal cancer patients. Tumor specimens of 68 LARC patients undergoing surgery after neoadjuvant-CRT were evaluated for CXCR4, CXCR7, and CXCL12 expression through immunohistochemistry. Multivariable prognostic model was developed using classical prognostic factors along with chemokine receptor expression profiles. High CXCR4 correlated with a shorter relapse-free survival (RFS) (p = 0.0006) and cancer specific survival (CSS) (p = 0.0004). Concomitant high CXCR4-negative/low CXCR7 or high CXCR4-negative/low CXCL12 significantly impaired RFS (p = 0.0003 and p = 0.0043) and CSS (p = 0.0485 and p = 0.0026). High CXCR4/N+ identified the worst prognostic category for RFS (p < 0.0001) and CSS (p = 0.0003). The optimal multivariable predictive model for RFS was a five-variable model consisting of gender, pT stage, N status, CXCR4, and CXCR7 (AUC = 0.92, 95% CI = 0.77-0.98). The model is informative and supportive for adjuvant treatment and identifies CXCR4 as a new therapeutic target in rectal cancer.
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Affiliation(s)
- Crescenzo D'Alterio
- Department of Oncological Immunology, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"-IRCCS-ITALIA, via M. Semmola, 80131, Naples, Italy
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Stimulation of TLR4 by LMW-HA induces metastasis in human papillary thyroid carcinoma through CXCR7. Clin Dev Immunol 2013; 2013:712561. [PMID: 24363762 PMCID: PMC3865734 DOI: 10.1155/2013/712561] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Accepted: 10/12/2013] [Indexed: 12/13/2022]
Abstract
In inflammatory sites, high molecular weight hyaluronan fragments are degraded into lower molecular weight hyaluronan fragments (LMW-HA) to regulate immune responses. However, the function of LMW-HA in PTC progression remains to be elucidated. In this study, we found that receptor of LMW-HA, TLR4, was aberrantly overexpressed in PTC tissues and cell line W3. Exposure of W3 cells to LMW-HA promoted cell proliferation and migration via TLR4. Knockdown of TLR4 has provided evidence that TLR4 is essential for LMW-HA-induced CXCR7 expression, which is responsible for LMW-HA-induced proliferation and migration of W3 cells. In tumor-bearing adult nude mice, stimulation of LMW-HA on W3 cells promotes CXCR7 expression in tumor masses (P = 0.002) and tumor growth (P < 0.001). To further confirm our findings, we investigated the clinicopathologic significance of TLR4 and CXCR7 expression using immumohistochemistry in 135 human PTC tissues and 56 normal thyroid tissue samples. Higher rates of TLR4 (53%) and CXCR7 (24%) expression were found in PTC tissues than in normal tissues. Expression of TLR4 or CXCR7 is associated with tumor size and lymph node metastasis. Therefore, LMW-HA may contribute to the development of PTC via TLR4/CXCR7 pathway, which may be a novel target for PTC immunomodulatory therapy.
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36
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The peculiarities of the SDF-1/CXCL12 system: in some cells, CXCR4 and CXCR7 sing solos, in others, they sing duets. Cell Tissue Res 2013; 355:239-53. [DOI: 10.1007/s00441-013-1747-y] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 10/17/2013] [Indexed: 12/26/2022]
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37
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Maussang D, Mujić-Delić A, Descamps FJ, Stortelers C, Vanlandschoot P, Stigter-van Walsum M, Vischer HF, van Roy M, Vosjan M, Gonzalez-Pajuelo M, van Dongen GAMS, Merchiers P, van Rompaey P, Smit MJ. Llama-derived single variable domains (nanobodies) directed against chemokine receptor CXCR7 reduce head and neck cancer cell growth in vivo. J Biol Chem 2013; 288:29562-72. [PMID: 23979133 PMCID: PMC3795254 DOI: 10.1074/jbc.m113.498436] [Citation(s) in RCA: 121] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Revised: 08/23/2013] [Indexed: 12/22/2022] Open
Abstract
The chemokine receptor CXCR7, belonging to the membrane-bound G protein-coupled receptor superfamily, is expressed in several tumor types. Inhibition of CXCR7 with either small molecules or small interference (si)RNA has shown promising therapeutic benefits in several tumor models. With the increased interest and effectiveness of biologicals inhibiting membrane-bound receptors we made use of the "Nanobody platform" to target CXCR7. Previously we showed that Nanobodies, i.e. immunoglobulin single variable domains derived from naturally occurring heavy chain-only camelids antibodies, represent new biological tools to efficiently tackle difficult drug targets such as G protein-coupled receptors. In this study we developed and characterized highly selective and potent Nanobodies against CXCR7. Interestingly, the CXCR7-targeting Nanobodies displayed antagonistic properties in contrast with previously reported CXCR7-targeting agents. Several high affinity CXCR7-specific Nanobodies potently inhibited CXCL12-induced β-arrestin2 recruitment in vitro. A wide variety of tumor biopsies was profiled, showing for the first time high expression of CXCR7 in head and neck cancer. Using a patient-derived CXCR7-expressing head and neck cancer xenograft model in nude mice, tumor growth was inhibited by CXCR7-targeting Nanobody therapy. Mechanistically, CXCR7-targeting Nanobodies did not inhibit cell cycle progression but instead reduced secretion of the angiogenic chemokine CXCL1 from head and neck cancer cells in vitro, thus acting here as inverse agonists, and subsequent angiogenesis in vivo. Hence, with this novel class of CXCR7 inhibitors, we further substantiate the therapeutic relevance of targeting CXCR7 in head and neck cancer.
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Affiliation(s)
- David Maussang
- From the Amsterdam Institute for Molecules Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Azra Mujić-Delić
- From the Amsterdam Institute for Molecules Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
| | | | | | | | - Marijke Stigter-van Walsum
- the Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Henry F. Vischer
- From the Amsterdam Institute for Molecules Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
| | | | - Maria Vosjan
- the Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | | | - Guus A. M. S. van Dongen
- the Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | | | | | - Martine J. Smit
- From the Amsterdam Institute for Molecules Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
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38
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Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma. Oncogene 2013; 32:5541-50. [PMID: 23851494 DOI: 10.1038/onc.2013.264] [Citation(s) in RCA: 102] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2012] [Revised: 05/01/2013] [Accepted: 05/24/2013] [Indexed: 12/18/2022]
Abstract
G-protein-coupled receptor 120 (GPR120) functions as a receptor for unsaturated long-chain free fatty acids and has an important role in regulating lipid and glucose metabolism. However, a role for GPR120 in the development of tumors has not yet been clarified. Here, we show that GPR120 signaling promotes angiogenic switching and motility of human colorectal carcinoma (CRC) cells. We show that the expression of GPR120 is significantly induced in CRC tissues and cell lines, which is associated with tumor progression. Activation of GPR120 signaling in human CRC promotes angiogenesis in vitro and in vivo, largely by inducing the expression and secretion of proangiogenic mediators such as vascular endothelial growth factor (VEGF), interleukin-8 and cyclooxygenase-2-derived prostaglandin E2. The PI3K/Akt-NF-κB pathway is activated by GPR120 signaling and is required for GPR120 signaling-induced angiogenic switching in CRC cells. And, GPR120 activation enhances the motility of CRC cells and induces epithelial-mesenchymal transition. Furthermore, in vivo study shows that activation of GPR120 promotes angiogenesis and tumor growth. Finally, we find that GPR120 expression is positively correlated with VEGF expression and inversely correlated with the epithelial marker E-cadherin in CRC tissues. Collectively, our results demonstrate that GPR120 functions as a tumor-promoting receptor in CRC and, therefore, shows promise as a new potential target for cancer therapeutics.
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39
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Yan L, Cai Q, Xu Y. The ubiquitin-CXCR4 axis plays an important role in acute lung infection-enhanced lung tumor metastasis. Clin Cancer Res 2013; 19:4706-16. [PMID: 23690484 DOI: 10.1158/1078-0432.ccr-13-0011] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE Our goals were to test the effect of acute lung infection on tumor metastasis and to investigate the underlying mechanisms. EXPERIMENTAL DESIGN We combined bacteria-induced and lipopolysaccharide (LPS)-induced acute lung injury/inflammation (ALI) mouse models with mouse metastatic models to study the effect of acute inflammation on lung metastasis in mice. The mechanisms were investigated in ex vivo, in vitro, and in vivo studies. RESULTS Both bacteria- and LPS-induced ALI significantly enhanced lung metastasis of four tail vein-injected mouse tumor cell lines. Bacteria also enhanced lung metastasis when 4T1 cells were orthotopically injected. The bronchoalveolar lavage fluid (BALF) from LPS- or bacteria-injected mice stimulated migration of tumor cells. In vivo tracking of metastatic RM-9 cells showed that bacterial injection enhanced early dissemination of tumor cells to the lung. The majority of the BALF migratory activity could be blocked by AMD3100, a chemokine receptor 4 (CXCR4) inhibitor. All tested cell lines expressed CXCR4. The levels of extracellular ubiquitin, but not stromal cell-derived factor-1, in BALF were significantly increased by LPS. Ubiquitin was able to induce AMD3100-sensitive migration of tumor cells. Finally, the antibacterial agent amoxicillin and the CXCR4 inhibitor AMD3100 blocked the enhancement effect of bacterial infection on tumor metastasis. CONCLUSIONS Acute lung infection dramatically increased cancer cell homing to the lung and lung metastasis. This change may be due to an alteration of the lung microenvironment and preparation of a favorable metastatic "niche." This effect was seen in multiple cancer types and thus may have broad applications for cancer patients in prevention and/or treatment of metastasis.
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Affiliation(s)
- Libo Yan
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
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40
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Moossavi S, Rezaei N. Toll-like receptor signalling and their therapeutic targeting in colorectal cancer. Int Immunopharmacol 2013; 16:199-209. [PMID: 23602501 DOI: 10.1016/j.intimp.2013.03.017] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2012] [Revised: 02/13/2013] [Accepted: 03/13/2013] [Indexed: 12/16/2022]
Abstract
Intestinal homeostasis is dependent on the proper host/microbiota interaction via pattern recognition receptors. Toll-like receptors are a specialised group of membrane receptors which detect pathogen-associated conserved structures. They are present in the intestinal tract and are required for intestinal homeostasis. Dysregulation in the Toll-like receptor signalling can conceivably result in a dysregulated immune response which could contribute to major intestinal pathologies including colorectal cancer. Evidence for the role of microbiota and toll-like receptors in colorectal cancer is emerging. In this report the evidence for the contribution of toll-like receptors to the pathogenesis of colorectal cancer; potential mechanisms affecting toll-like receptor signalling; and their therapeutic targeting in colorectal cancer are reviewed.
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Affiliation(s)
- Shirin Moossavi
- Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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41
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Huang WS, Chen CN, Sze CI, Teng CC. Visfatin induces stromal cell-derived factor-1 expression by β1 integrin signaling in colorectal cancer cells. J Cell Physiol 2013; 228:1017-24. [PMID: 23042611 DOI: 10.1002/jcp.24248] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 09/26/2012] [Indexed: 12/11/2022]
Abstract
Obesity has been shown to be associated with the risk of colorectal cancer (CRC). Adipokines produced by the adipose tissue are linked to some malignancies, including CRC. Visfatin is an adipokine shown to be a biomarker of CRC malignant potential. In addition, the stromal cell-derived factor-1 (SDF-1) has been reported to play a role in CRC progression. Although the relationship between visfatin and CRC has been established, the underlying mechanism has not been clarified. We investigated the molecular mechanism governing the interaction between visfatin stimulation and SDF-1 expression in human CRC cell lines. We found that visfatin stimulation led to an increase in the expression and secretion of SDF-1 in CRC DLD-1 and SW48 cells. Experiments involving specific inhibitors and small interfering RNA demonstrated that the activation of ERK and p38 mitogen-activated protein kinase (MAPK) pathways are critical for visfatin-induced SDF-1 expression. Analysis of transcription factor binding using ELISA and luciferase reporter assays revealed that visfatin increased NF-κB- and AP-1-DNA-binding activities in DLD-1 cells. Inhibition of NF-κB and AP-1 activation blocked the visfatin-induced expression and activity of the SDF-1 promoter. The effect of visfatin on DLD-1 signaling and SDF-1 expression was mediated by β1 integrin. In summary, these findings provide novel insights pertaining to the pathophysiological role of visfatin in CRC.
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Affiliation(s)
- Wen-Shih Huang
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
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42
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Rega A, Terlizzi M, Luciano A, Forte G, Crother TR, Arra C, Arditi M, Pinto A, Sorrentino R. Plasmacytoid dendritic cells play a key role in tumor progression in lipopolysaccharide-stimulated lung tumor-bearing mice. THE JOURNAL OF IMMUNOLOGY 2013; 190:2391-402. [PMID: 23355734 DOI: 10.4049/jimmunol.1202086] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The antitumor activity of LPS was first described by Dr. William Coley. However, its role in lung cancer remains unclear. The aim of our study was to elucidate the dose-dependent effects of LPS (0.1-10 μg/mouse) in a mouse model of B16-F10-induced metastatic lung cancer. Lung tumor growth increased at 3 and 7 d after the administration of low-dose LPS (0.1 μg/mouse) compared with control mice. This was associated with an influx of plasmacytoid dendritic cells (pDCs), regulatory T cells, myeloid-derived suppressor cells, and CD8(+) regulatory T cells. In contrast, high-dose LPS (10 μg/mouse) reduced lung tumor burden and was associated with a greater influx of pDCs, as well as a stronger Th1 and Th17 polarization. Depletion of pDCs during low-dose LPS administration resulted in a decreased lung tumor burden. Depletion of pDCs during high-dose LPS treatment resulted in an increased tumor burden. The dichotomy in LPS effects was due to the phenotype of pDCs, which were immunosuppressive after the low-dose LPS, and Th1- and T cytotoxic-polarizing cells after the high-dose LPS. Adoptive transfer of T cells into nude mice demonstrated that CD8(+) T cells were responsible for pDC recruitment following low-dose LPS administration, whereas CD4(+) T cells were required for pDC influx after the high-dose LPS. In conclusion, our data suggest differential effects of low-dose versus high-dose LPS on pDC phenotype and tumor progression or regression in the lungs of mice.
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Affiliation(s)
- Alessia Rega
- Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Fisciano 84084, Italy.
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43
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Yu L, Wang L, Chen S. Dual character of Toll-like receptor signaling: pro-tumorigenic effects and anti-tumor functions. Biochim Biophys Acta Rev Cancer 2012; 1835:144-54. [PMID: 23232186 DOI: 10.1016/j.bbcan.2012.10.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2012] [Revised: 10/29/2012] [Accepted: 10/30/2012] [Indexed: 01/01/2023]
Abstract
As a major class of pattern-recognition receptors, Toll-like receptors (TLRs) play a critical role in defense against invading pathogens. Increasing evidence demonstrates that, in addition to infection, TLRs are involved in other important pathological processes, such as tumorigenesis. Activation of TLRs results in opposing outcomes, pro-tumorigenic effects and anti-tumor functions. TLR signaling can inhibit apoptosis and promote chronic inflammation-induced tumorigenesis. TLR activation in tumor cells and immune cells can induce production of cytokines, increase tumor cell proliferation and apoptosis resistance, promote invasion and metastasis, and inhibit immune cell activity resulting in tumor immune escape. In contrast, the engagement of other TLRs directly induces growth inhibition and apoptosis of tumor cells and triggers activation of immune cells enhancing anti-tumor immune responses. Thus, the interpretation of the precise function of each TLR in tumors is very important for targeting TLRs and using TLR agonists in tumor therapy. We review the role of TLR signaling in tumors and discuss the factors that affect outcomes of TLR activation.
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Affiliation(s)
- Li Yu
- Department of Pathology, Sun Yat-sen University, Guangzhou, Republic of China.
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44
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Tung SY, Chang SF, Chou MH, Huang WS, Hsieh YY, Shen CH, Kuo HC, Chen CN. CXC chemokine ligand 12/stromal cell-derived factor-1 regulates cell adhesion in human colon cancer cells by induction of intercellular adhesion molecule-1. J Biomed Sci 2012; 19:91. [PMID: 23098564 PMCID: PMC3488341 DOI: 10.1186/1423-0127-19-91] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 10/22/2012] [Indexed: 02/06/2023] Open
Abstract
Background The CXC chemokine ligand 12 (CXCL12)/stromal cell-derived factor-1 (SDF-1) and CXC receptor 4 (CXCR4) axis is involved in human colorectal cancer (CRC) carcinogenesis and can promote the progression of CRC. Interaction between CRC cells and endothelium is a key event in tumor progression. The aim of this study was to investigate the effect of SDF-1 on the adhesion of CRC cells. Methods Human CRC DLD-1 cells were used to study the effect of SDF-1 on intercellular adhesion molecule-1 (ICAM-1) expression and cell adhesion to endothelium. Results SDF-1 treatment induced adhesion of DLD-1 cells to the endothelium and increased the expression level of the ICAM-1. Inhibition of ICAM-1 by small interfering RNA (siRNA) and neutralizing antibody inhibited SDF-1-induced cell adhesion. By using specific inhibitors and short hairpin RNA (shRNA), we demonstrated that the activation of ERK, JNK and p38 pathways is critical for SDF-1-induced ICAM-1 expression and cell adhesion. Promoter activity and transcription factor ELISA assays showed that SDF-1 increased Sp1-, C/EBP-β- and NF-κB-DNA binding activities in DLD-1 cells. Inhibition of Sp1, C/EBP-β and NF-κB activations by specific siRNA blocked the SDF-1-induced ICAM-1 promoter activity and expression. The effect of SDF-1 on cell adhesion was mediated by the CXCR4. Conclusion Our findings support the hypothesis that ICAM-1 up-regulation stimulated by SDF-1 may play an active role in CRC cell adhesion.
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Affiliation(s)
- Shui-Yi Tung
- Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Chiayi, Taiwan
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Basith S, Manavalan B, Yoo TH, Kim SG, Choi S. Roles of toll-like receptors in cancer: a double-edged sword for defense and offense. Arch Pharm Res 2012; 35:1297-316. [PMID: 22941474 DOI: 10.1007/s12272-012-0802-7] [Citation(s) in RCA: 148] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Revised: 06/21/2012] [Accepted: 06/25/2012] [Indexed: 12/18/2022]
Abstract
Toll-like receptors (TLRs) belong to a class of pattern-recognition receptors that play an important role in host defense against pathogens by recognizing a wide variety of pathogen-associated molecular patterns (PAMPs). Besides driving inflammatory responses, TLRs also regulate cell proliferation and survival by expanding useful immune cells and integrating inflammatory responses and tissue repair processes. TLR signaling, which is centrally involved in the initiation of both innate and adaptive immune responses, has been thought to be restricted to immune cells. However, recent studies have shown that functional TLRs are expressed not only on immune cells, but also on cancer cells, thus implicating a role of TLRs in tumor biology. Increasing bodies of evidence have suggested that TLRs act as a double-edged sword in cancer cells because uncontrolled TLR signaling provides a microenvironment that is necessary for tumor cells to proliferate and evade the immune response. Alternatively, TLRs can induce an antitumor immune response in order to inhibit tumor progression. In this review, we summarize the dual roles of TLRs in tumor cells and, more importantly, delve into the therapeutic potential of TLRs in the context of tumorigenesis.
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Affiliation(s)
- Shaherin Basith
- Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea
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Involvement of the CXCR7/CXCR4/CXCL12 axis in the malignant progression of human neuroblastoma. PLoS One 2012; 7:e43665. [PMID: 22916293 PMCID: PMC3423387 DOI: 10.1371/journal.pone.0043665] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2012] [Accepted: 07/23/2012] [Indexed: 12/30/2022] Open
Abstract
Neuroblastoma (NB) is a typical childhood and heterogeneous neoplasm for which efficient targeted therapies for high-risk tumors are not yet identified. The chemokine CXCL12, and its receptors CXCR4 and CXCR7 have been involved in tumor progression and dissemination. While CXCR4 expression is associated to undifferentiated tumors and poor prognosis, the role of CXCR7, the recently identified second CXCL12 receptor, has not yet been elucidated in NB. In this report, CXCR7 and CXCL12 expressions were evaluated using a tissue micro-array including 156 primary and 56 metastatic NB tissues. CXCL12 was found to be highly associated to NB vascular and stromal structures. In contrast to CXCR4, CXCR7 expression was low in undifferentiated tumors, while its expression was stronger in matured tissues and specifically associated to differentiated neural tumor cells. As determined by RT-PCR, CXCR7 expression was mainly detected in N-and S-type NB cell lines, and was slightly induced upon NB cell differentiation in vitro. The relative roles of the two CXCL12 receptors were further assessed by overexpressing CXCR7 or CXCR4 receptor alone, or in combination, in the IGR-NB8 and the SH-SY5Y NB cell lines. In vitro functional analyses indicated that, in response to their common ligand, both receptors induced activation of ERK1/2 cascade, but not Akt pathway. CXCR7 strongly reduced in vitro growth, in contrast to CXCR4, and impaired CXCR4/CXCL12-mediated chemotaxis. Subcutaneous implantation of CXCR7-expressing NB cells showed that CXCR7 also significantly reduced in vivo growth. Moreover, CXCR7 affected CXCR4-mediated orthotopic growth in a CXCL12-producing environment. In such model, CXCR7, in association with CXCR4, did not induce NB cell metastatic dissemination. In conclusion, the CXCR7 and CXCR4 receptors revealed specific expression patterns and distinct functional roles in NB. Our data suggest that CXCR7 elicits anti-tumorigenic functions, and may act as a regulator of CXCR4/CXCL12-mediated signaling in NB.
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Li M, Hale JS, Rich JN, Ransohoff RM, Lathia JD. Chemokine CXCL12 in neurodegenerative diseases: an SOS signal for stem cell-based repair. Trends Neurosci 2012; 35:619-28. [PMID: 22784557 DOI: 10.1016/j.tins.2012.06.003] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2012] [Revised: 06/12/2012] [Accepted: 06/12/2012] [Indexed: 12/20/2022]
Abstract
The dynamic relation between stem cells and their niche governs self-renewal and progenitor cell deployment. The chemokine CXCL12 (C-X-C motif ligand 12) and its signaling receptor CXCR4 (C-X-C motif receptor 4) represent an important pathway that regulates homing and maintenance of stem cells in neural niches. Neural stem cells (NSCs) reside in specific niches where communication with blood vessels is regulated by CXCL12. In neurodegenerative diseases and brain tumors, reactive vasculature forms in response to diseased tissues to create new niches that secrete CXCL12, enhancing the recruitment of neural progenitor cells (NPCs) to lesion sites via long-range migration. These observations suggest that the CXCL12-CXCR4 axis maintains NSCs and serves as an emergent salvage signal for initiating endogenous stem cell-based tissue repair.
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Affiliation(s)
- Meizhang Li
- Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
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Yates TJ, Knapp J, Gosalbez M, Lokeshwar SD, Gomez CS, Benitez A, Ekwenna OO, Young EE, Manoharan M, Lokeshwar VB. C-X-C chemokine receptor 7: a functionally associated molecular marker for bladder cancer. Cancer 2012; 119:61-71. [PMID: 22736438 DOI: 10.1002/cncr.27661] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2011] [Revised: 04/11/2012] [Accepted: 04/16/2012] [Indexed: 11/06/2022]
Abstract
BACKGROUND C-X-C chemokine receptor 4 (CXCR4) and CXCR7 are 7-transmembrane chemokine receptors of the stroma-derived factor (SDF-1). CXCR4, but not CXCR7, has been examined in bladder cancer (BCa). This study examined the functional and clinical significance of CXCR7 in BCa. METHODS CXCR4 and CXCR7 levels were measured in BCa cell lines, tissues (normal = 25; BCa = 44), and urine specimens (n = 186) by quantitative polymerase chain reaction and/or immunohistochemistry. CXCR7 function in BCa cells were examined by transient transfections using a CXCR7 expression vector or small interfering RNA. RESULTS In BCa cell lines, CXCR7 messenger RNA levels were 5- to 37-fold higher than those for CXCR4. Transient overexpression of CXCR7 in BCa cell lines promoted growth and chemotactic motility. CXCR7 colocalized and formed a functional complex with epidermal growth factor receptor, phosphoinositide 3-kinase/Akt, Erk, and src and induced their phosphorylation. CXCR7 also induced up-regulation of cyclin-D1 and bcl-2. Suppression of CXCR7 expression reversed these effects and induced apoptosis. CXCR7 messenger RNA levels and CXCR7 staining scores were significantly (5- to 10-fold) higher in BCa tissues than in normal tissues (P < .001). CXCR7 expression independently associated with metastasis (P = .019) and disease-specific mortality (P = .03). CXCR7 was highly expressed in endothelial cells in high-grade BCa tissues when compared to low-grade BCa and normal bladder. CXCR7 levels were elevated in exfoliated urothelial cells from high-grade BCa patients (P = .0001; 90% sensitivity; 75% specificity); CXCR4 levels were unaltered. CONCLUSIONS CXCR7 promotes BCa cell proliferation and motility plausibly through epidermal growth factor receptor receptor and Akt signaling. CXCR7 expression is elevated in BCa tissues and exfoliated cells and is associated with high-grade and metastasis.
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Affiliation(s)
- Travis J Yates
- Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Florida, USA
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Heinrich EL, Lee W, Lu J, Lowy AM, Kim J. Chemokine CXCL12 activates dual CXCR4 and CXCR7-mediated signaling pathways in pancreatic cancer cells. J Transl Med 2012; 10:68. [PMID: 22472349 PMCID: PMC3342892 DOI: 10.1186/1479-5876-10-68] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Accepted: 04/02/2012] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Previously assumed to be a select ligand for chemokine receptor CXCR4, chemokine CXCL12 is now known to activate both CXCR4 and CXCR7. However, very little is known about the co-expression of these receptors in cancer cells. METHODS We used immunohistochemistry to determine the extent of co-expression in pancreatic cancer tissue samples and immunoblotting to verify expression in pancreatic cancer cell lines. In cell culture studies, siRNA was used to knock down expression of CXCR4, CXCR7, K-Ras and β-arrestin -2 prior to stimulating the cells with CXCL12. Activation of the mitogen-activated protein kinase pathway (MAPK) was assessed using both a Raf-pull down assay and western blotting. The involvement of the receptors in CXCL12-mediated increases in cell proliferation was examined via an ATP-based proliferation assay. RESULTS First, we discovered frequent CXCR4/CXCR7 co-expression in human pancreatic cancer tissues and cell lines. Next, we observed consistent increases in ERK1/2 phosphorylation after exposure to CXCL12 or CXCL11, a CXCR7 agonist, in pancreatic cancer cell lines co-expressing CXCR4/CXCR7. To better characterize the receptor-mediated pathway(s), we knocked down CXCR4 or CXCR7, exposed the cells to CXCL12 and examined subsequent effects on ERK1/2. We observed that CXCR7 mediates the CXCL12-driven increase in ERK1/2 phosphorylation. Knockdown of CXCR4 expression however, decreased levels of K-Ras activity. Conversely, KRAS knockdown greatly reduced CXCL12-mediated increases in ERK1/2 phosphorylation. We then evaluated the role of β-arrestin-2, a protein directly recruited by chemokine receptors. We observed that β-arrestin-2 knockdown also inhibited increases in ERK1/2 phosphorylation mediated by both CXCR4 and CXCR7. Finally, we investigated the mechanism for CXCL12-enhanced cell proliferation and found that either receptor can modulate cell proliferation. CONCLUSIONS In summary, our data demonstrate that CXCR4 and CXCR7 are frequently co-expressed in human pancreatic cancer tissues and cell lines. We show that β-arrestin-2 and K-Ras dependent pathways coordinate the transduction of CXCL12 signals. Our results suggest that the development of therapies based on inhibiting CXCL12 signaling to halt the growth of pancreatic cancer should be focused at the ligand level in order to account for the contributions of both receptors to this signaling pathway.
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Affiliation(s)
- Eileen L Heinrich
- Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
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