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Pang C, Li Y, Shi M, Fan Z, Gao X, Meng Y, Liu S, Gao C, Su P, Wang X, Zhan H. Expression and clinical value of CXCR4 in high grade gastroenteropancreatic neuroendocrine neoplasms. Front Endocrinol (Lausanne) 2024; 15:1281622. [PMID: 38524630 PMCID: PMC10960360 DOI: 10.3389/fendo.2024.1281622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 02/23/2024] [Indexed: 03/26/2024] Open
Abstract
Background CXC chemokine receptor 4 (CXCR4) is associated with the progression and metastasis of numerous malignant tumors. However, its relationship with Gastroenteropancreatic Neuroendocrine Neoplasms Grade 3 (GEP-NENs G3) is unclear. The aim of this study was to characterize the expression of CXCR4 in GEP-NENS and to explore the clinical and prognostic value of CXCR4. Methods This study retrospectively collected clinical and pathological data from patients with GEP-NENs who receiving surgery in Qilu Hospital of Shandong University from January 2013 to April 2021, and obtained the overall survival of the patients based on follow-up. Immunohistochemistry (IHC) was performed on pathological paraffin sections to observe CXCR4 staining. Groups were made according to pathological findings. Kaplan-Meier (K-M) curve was used to evaluate prognosis. SPSS 26.0 was used for statistical analysis. Results 100 GEP-NENs G3 patients were enrolled in this study. There was a significant difference in primary sites (P=0.002), Ki-67 index (P<0.001), and Carcinoembryonic Antigen (CEA) elevation (P=0.008) between neuroendocrine tumor (NET) G3 and neuroendocrine carcinoma (NEC). CXCR4 was highly expressed only in tumors, low or no expressed in adjacent tissues (P<0.001). The expression level of CXCR4 in NEC was significantly higher than that in NET G3 (P=0.038). The K-M curves showed that there was no significant difference in overall survival between patients with high CXCR4 expression and patients with low CXCR4 expression, either in GEP-NEN G3 or NEC (P=0.920, P=0.842. respectively). Conclusion Differential expression of CXCR4 was found between tumor and adjacent tissues and between NET G3 and NEC. Our results demonstrated that CXCR4 can be served as a new IHC diagnostic indicator in the diagnosis and differential diagnosis of GEP-NENs G3. Further studies with multi-center, large sample size and longer follow-up are needed to confirm the correlation between CXCR4 expression level and prognosis.
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Affiliation(s)
- Chaoyu Pang
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yongzheng Li
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Ming Shi
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Zhiyao Fan
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Xin Gao
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yufan Meng
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Shujie Liu
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Changhao Gao
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Peng Su
- Department of Pathology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Xiao Wang
- Department of Pathology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Hanxiang Zhan
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
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Li Q, Wang J, Meng X, Chen W, Feng J, Mao J. Identification of autophagy-related gene and lncRNA signatures in the prognosis of HNSCC. Oral Dis 2023; 29:138-153. [PMID: 33901303 DOI: 10.1111/odi.13889] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 03/29/2021] [Accepted: 04/19/2021] [Indexed: 01/22/2023]
Abstract
OBJECTIVE The aim of this study was to identify prognostic autophagy-related genes and lncRNAs to predict clinical outcomes in head and neck squamous cell carcinoma (HNSCC). SUBJECTS AND METHODS Differentially expressed autophagy-related genes and autophagy-related lncRNAs were identified by comparing pare-carcinoma and carcinoma samples of HNSCC. And then, we constructed an ARG and an AR-lncRNA signature risk score. Receiver operating characteristic (ROC) curve analyses were performed to assess the prognostic prediction capacity. Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO) functional annotation were used to analysis the functions of ARGs and AR-lncRNAs. RESULTS Six ARGs and thirteen AR-lncRNAs were identified in the ARG and AR-lncRNA signatures, and overall survival (OS) in the high-risk group was significantly shorter than the low-risk group. ROC analysis showed the ARG and AR-lncRNA signatures have excellent ability of predicting the total OS of patients with HNSCC. What's more, GSEA and GO functional annotation proved that autophagy-related pathways are mainly enriched in the high-risk group. CONCLUSIONS These findings indicated that our ARG signature and AR-lncRNA signature could be considered to predict the prognosis of patients with HNSCC and provide a deep understanding of the biological mechanisms of autophagy in HNSCC.
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Affiliation(s)
- Qilin Li
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Wang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinyao Meng
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weimin Chen
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiexiong Feng
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Mao
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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The Expression and Prognostic Significance of VEGF and CXCR4 in Gastric Cancer: Correlation with Angiogenesis, Lymphangiogenesis and Progression. Curr Issues Mol Biol 2022; 44:3075-3088. [PMID: 35877436 PMCID: PMC9324442 DOI: 10.3390/cimb44070212] [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: 05/31/2022] [Revised: 06/27/2022] [Accepted: 07/04/2022] [Indexed: 12/24/2022] Open
Abstract
The cellular response to hypoxia includes the expression of hypoxia-inducible factor-1 (HIF-1) and its target genes: vascular endothelial growth factor (VEGF) and CXC chemokine receptor 4 (CXCR4). The aim of this study was to investigate the expression and prognostic significance of VEGF and CXCR4, which are responsible for angiogenesis and progression in gastric cancer. Twenty-eight gastric cancer patients were analyzed. The mRNA expression was examined in primary tumors and corresponding normal gastric mucosa by RT-PCR. The protein level was examined by immunohistochemistry staining. The high expression of VEGF and CXCR4 was found in 71.0 and 64.0% of tumors, respectively. The mean levels of VEGF and CXCR4 were upregulated in primary tumors compared to normal mucosa (p = 0.0007, p = 0.0052). A correlation between VEGF expression and tumor invasion (p = 0.0216) and stage (p = 0.0181) was found. CXCR4 expression correlated with lymph node metastases (p = 0.0237) and stage (p = 0.0054). The VEGF expression correlated with microvessel density (MVD) (p = 0.0491). The overall 3-year survival rate was 46.4% and correlated negatively with high CXCR4 mRNA expression (p = 0.0089). VEGF and CXCR4 play an important role in tumor progression. Their overexpression correlates with a bad prognosis and may improve high-risk patient selection, and these patients may obtain additional survival benefits if treated more aggressively.
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4
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Inflammation and Gastric Cancer. Diseases 2022; 10:diseases10030035. [PMID: 35892729 PMCID: PMC9326573 DOI: 10.3390/diseases10030035] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/16/2022] [Accepted: 06/19/2022] [Indexed: 11/17/2022] Open
Abstract
Gastric cancer remains a major killer globally, although its incidence has declined over the past century. It is the fifth most common cancer and the third most common reason for cancer-related deaths worldwide. Gastric cancer is the outcome of a complex interaction between environmental, host genetic, and microbial factors. There is significant evidence supporting the association between chronic inflammation and the onset of cancer. This association is particularly robust for gastrointestinal cancers in which microbial pathogens are responsible for the chronic inflammation that can be a triggering factor for the onset of those cancers. Helicobacter pylori is the most prominent example since it is the most widespread infection, affecting nearly half of the world’s population. It is well-known to be responsible for inducing chronic gastric inflammation progressing to atrophy, metaplasia, dysplasia, and eventually, gastric cancer. This review provides an overview of the association of the factors playing a role in chronic inflammation; the bacterial characteristics which are responsible for the colonization, persistence in the stomach, and triggering of inflammation; the microbiome involved in the chronic inflammation process; and the host factors that have a role in determining whether gastritis progresses to gastric cancer. Understanding these interconnections may improve our ability to prevent gastric cancer development and enhance our understanding of existing cases.
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Impact of Selected Serum Factors on Metastatic Potential of Gastric Cancer Cells. Diagnostics (Basel) 2022; 12:diagnostics12030700. [PMID: 35328253 PMCID: PMC8946911 DOI: 10.3390/diagnostics12030700] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/24/2022] [Accepted: 03/09/2022] [Indexed: 02/06/2023] Open
Abstract
(1) Background: stromal-derived factor-1 (SDF-1/CXCL12), hepatocyte and vascular-endothelial growth factors (HGF and VEGF) have been shown to facilitate cell motility, proliferation and promote local tumor progression and metastatic spread. Recent research shows the important role of these cytokines in gastric cancer (GC) progression. (2) Methods: 21 gastric cancer patients and 19 healthy controls were included in the study. SDF-1, HGF and VEGF levels were evaluated in sera by ELISA. Patients and control sera were used to stimulate CRL-1739 GC cell line, and chemotaxis, adhesion and proliferation potential were assessed. (3) Results: Concentrations of SDF-1, HGF and VEGF were significantly higher in patients than in controls. Chemotaxis and adhesion assays revealed a significant response of GC cells to patients’ serum. Furthermore, significant relationships were seen between chemotactic/adhesion response and tumor stage. Serum from intestinal early GC patients produced significantly stronger chemotactic response when compared to patients with metastatic spread. In turn, serum from patients with distal metastases significantly increased the adhesion of GC cells when compared to sera from the patients with no distal metastases. We also observed that HGF strongly stimulated the proliferation of CRL-1739 cells. (4) Conclusions: We observed that the sera from GC patients, but also SDF-1, HGF and VEGF used alone, have a strong pro-metastatic effect on CRL-1739 cells. We also demonstrated that the concentration of these cytokines is specifically elevated in the sera of patients in an early stage of malignancy. Our results indicate that SDF-1, HGF and VEGF are very important molecules involved in gastric cancer progression.
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6
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Jiang H, Yu D, Yang P, Guo R, Kong M, Gao Y, Yu X, Lu X, Fan X. Revealing the transcriptional heterogeneity of organ-specific metastasis in human gastric cancer using single-cell RNA Sequencing. Clin Transl Med 2022; 12:e730. [PMID: 35184420 PMCID: PMC8858624 DOI: 10.1002/ctm2.730] [Citation(s) in RCA: 130] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 01/22/2022] [Accepted: 01/25/2022] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Deciphering intra- and inter-tumoural heterogeneity is essential for understanding the biology of gastric cancer (GC) and its metastasis and identifying effective therapeutic targets. However, the characteristics of different organ-tropism metastases of GC are largely unknown. METHODS Ten fresh human tissue samples from six patients, including primary tumour and adjacent non-tumoural samples and six metastases from different organs or tissues (liver, peritoneum, ovary, lymph node) were evaluated using single-cell RNA sequencing. Validation experiments were performed using histological assays and bulk transcriptomic datasets. RESULTS Malignant epithelial subclusters associated with invasion features, intraperitoneal metastasis propensity, epithelial-mesenchymal transition-induced tumour stem cell phenotypes, or dormancy-like characteristics were discovered. High expression of the first three subcluster-associated genes displayed worse overall survival than those with low expression in a GC cohort containing 407 samples. Immune and stromal cells exhibited cellular heterogeneity and created a pro-tumoural and immunosuppressive microenvironment. Furthermore, a 20-gene signature of lymph node-derived exhausted CD8+ T cells was acquired to forecast lymph node metastasis and validated in GC cohorts. Additionally, although anti-NKG2A (KLRC1) antibody have not been used to treat GC patients even in clinical trials, we uncovered not only malignant tumour cells but one endothelial subcluster, mucosal-associated invariant T cells, T cell-like B cells, plasmacytoid dendritic cells, macrophages, monocytes, and neutrophils may contribute to HLA-E-KLRC1/KLRC2 interaction with cytotoxic/exhausted CD8+ T cells and/or natural killer (NK) cells, suggesting novel clinical therapeutic opportunities in GC. Additionally, our findings suggested that PD-1 expression in CD8+ T cells might predict clinical responses to PD-1 blockade therapy in GC. CONCLUSIONS This study provided insights into heterogeneous microenvironment of GC primary tumours and organ-specific metastases and provide support for precise diagnosis and treatment.
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Affiliation(s)
- Haiping Jiang
- Department of Medical OncologyThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Dingyi Yu
- Pharmaceutical Informatics InstituteCollege of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
| | - Penghui Yang
- Pharmaceutical Informatics InstituteCollege of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
| | - Rongfang Guo
- Pharmaceutical Informatics InstituteCollege of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
| | - Mei Kong
- Department of PathologyThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yuan Gao
- Department of Gastro‐Intestinal SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiongfei Yu
- Department of Surgical OncologyThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiaoyan Lu
- Pharmaceutical Informatics InstituteCollege of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
- State Key Laboratory of Component‐Based Chinese MedicineInnovation Center in Zhejiang UniversityHangzhouChina
| | - Xiaohui Fan
- Pharmaceutical Informatics InstituteCollege of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
- State Key Laboratory of Component‐Based Chinese MedicineInnovation Center in Zhejiang UniversityHangzhouChina
- Westlake Laboratory of Life Sciences and BiomedicineHangzhouChina
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7
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Jiang S, Luo M, Bai X, Nie P, Zhu Y, Cai H, Li B, Luo P. Cellular crosstalk of glomerular endothelial cells and podocytes in diabetic kidney disease. J Cell Commun Signal 2022; 16:313-331. [PMID: 35041192 DOI: 10.1007/s12079-021-00664-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetic kidney disease (DKD) is a serious microvascular complication of diabetes and is the leading cause of end-stage renal disease (ESRD). Persistent proteinuria is an important feature of DKD, which is caused by the destruction of the glomerular filtration barrier (GFB). Glomerular endothelial cells (GECs) and podocytes are important components of the GFB, and their damage can be observed in the early stages of DKD. Recently, studies have found that crosstalk between cells directly affects DKD progression, which has prospective research significance. However, the pathways involved are complex and largely unexplored. Here, we review the literature on cellular crosstalk of GECs and podocytes in the context of DKD, and highlight specific gaps in the field to propose future research directions. Elucidating the intricates of such complex processes will help to further understand the pathogenesis of DKD and develop better prevention and treatment options.
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Affiliation(s)
- Shan Jiang
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China
| | - Manyu Luo
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China
| | - Xue Bai
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China
| | - Ping Nie
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China
| | - Yuexin Zhu
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China
| | - Hangxi Cai
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China
| | - Bing Li
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China.
| | - Ping Luo
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China.
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Saxena S, Singh RK. Chemokines orchestrate tumor cells and the microenvironment to achieve metastatic heterogeneity. Cancer Metastasis Rev 2021; 40:447-476. [PMID: 33959849 PMCID: PMC9863248 DOI: 10.1007/s10555-021-09970-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/22/2021] [Indexed: 01/26/2023]
Abstract
Chemokines, a subfamily of the cell cytokines, are low molecular weight proteins known to induce chemotaxis in leukocytes in response to inflammatory and pathogenic signals. A plethora of literature demonstrates that chemokines and their receptors regulate tumor progression and metastasis. With these diverse functionalities, chemokines act as a fundamental link between the tumor cells and their microenvironment. Recent studies demonstrate that the biology of chemokines and their receptor in metastasis is complex as numerous chemokines are involved in regulating site-specific tumor growth and metastasis. Successful treatment of disseminated cancer is a significant challenge. The most crucial problem for treating metastatic cancer is developing therapy regimes capable of overcoming heterogeneity problems within primary tumors and among metastases and within metastases (intralesional). This heterogeneity of malignant tumor cells can be related to metastatic potential, response to chemotherapy or specific immunotherapy, and many other factors. In this review, we have emphasized the role of chemokines in the process of metastasis and metastatic heterogeneity. Individual chemokines may not express the full potential to address metastatic heterogeneity, but chemokine networks need exploration. Understanding the interplay between chemokine-chemokine receptor networks between the tumor cells and their microenvironment is a novel approach to overcome the problem of metastatic heterogeneity. Recent advances in the understanding of chemokine networks pave the way for developing a potential targeted therapeutic strategy to treat metastatic cancer.
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Affiliation(s)
- Sugandha Saxena
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE, 68198-5900, USA
| | - Rakesh K Singh
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE, 68198-5900, USA.
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9
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Yang P, Hu Y, Zhou Q. The CXCL12-CXCR4 Signaling Axis Plays a Key Role in Cancer Metastasis and is a Potential Target for Developing Novel Therapeutics against Metastatic Cancer. Curr Med Chem 2020; 27:5543-5561. [PMID: 31724498 DOI: 10.2174/0929867326666191113113110] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 10/07/2019] [Accepted: 10/25/2019] [Indexed: 12/12/2022]
Abstract
Metastasis is the main cause of death in cancer patients; there is currently no effective treatment for cancer metastasis. This is primarily due to our insufficient understanding of the metastatic mechanisms in cancer. An increasing number of studies have shown that the C-X-C motif chemokine Ligand 12 (CXCL12) is overexpressed in various tissues and organs. It is a key niche factor that nurtures the pre-metastatic niches (tumorigenic soil) and recruits tumor cells (oncogenic "seeds") to these niches, thereby fostering cancer cell aggression and metastatic capabilities. However, the C-X-C motif chemokine Receptor 4 (CXCR4) is aberrantly overexpressed in various cancer stem/progenitor cells and functions as a CXCL12 receptor. CXCL12 activates CXCR4 as well as multiple downstream multiple tumorigenic signaling pathways, promoting the expression of various oncogenes. Activation of the CXCL12-CXCR4 signaling axis promotes Epithelial-Mesenchymal Transition (EMT) and mobilization of cancer stem/progenitor cells to pre-metastatic niches. It also nurtures cancer cells with high motility, invasion, and dissemination phenotypes, thereby escalating multiple proximal or distal cancer metastasis; this results in poor patient prognosis. Based on this evidence, recent studies have explored either CXCL12- or CXCR4-targeted anti-cancer therapeutics and have achieved promising results in the preclinical trials. Further exploration of this new strategy and its potent therapeutics effect against metastatic cancer through the targeting of the CXCL12- CXCR4 signaling axis may lead to a novel therapy that can clean up the tumor microenvironment ("soil") and kill the cancer cells, particularly the cancer stem/progenitor cells ("seeds"), in cancer patients. Ultimately, this approach has the potential to effectively treat metastatic cancer.
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Affiliation(s)
- Ping Yang
- Department of Pathophysiology, School of Medicine (School of Nursing), Nantong University, Nantong, Jiangsu 226000, China
| | - Yae Hu
- Department of Pathophysiology, School of Medicine (School of Nursing), Nantong University, Nantong, Jiangsu 226000, China
| | - Quansheng Zhou
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University; Suzhou, Jiangsu 215123, China
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10
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Yashiro M, Kinoshita H, Tsujio G, Fukuoka T, Yamamoto Y, Sera T, Sugimoto A, Nishimura S, Kushiyama S, Togano S, Kuroda K, Toyokawa T, Ohira M. SDF1α/CXCR4 axis may be associated with the malignant progression of gastric cancer in the hypoxic tumor microenvironment. Oncol Lett 2020; 21:38. [PMID: 33262830 PMCID: PMC7693388 DOI: 10.3892/ol.2020.12299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 10/22/2020] [Indexed: 12/28/2022] Open
Abstract
Stromal cell-derived factor 1α (SDF1α) and its receptor C-X-C chemokine receptor type 4 (CXCR4) have been reported to form an important chemokine signaling pathway. Our previous study reported that SDF1α from tumor stromal cells may stimulate the proliferation of gastric cancer (GC) cells through the CXCR4 axis in a hypoxic microenvironment. However, a limited number of studies have addressed the clinicopathological significance of the expression of SDF1α and CXCR4 in GC, particularly at hypoxic regions. Immunohistochemistry was used to investigate the expression levels of SDF1α, CXCR4 and the hypoxic marker carbonic anhydrase 9 (CA9) in 185 patients with stage II and III GC. The results demonstrated that CA9 was expressed on cancer and stromal cells in hypoxic lesions, CXCR4 was mainly expressed in cancer cells, and SDFα was mainly expressed in stromal cells. CXCR4 expression in cancer cells and SDFα expression in stromal cells were associated with the hypoxic regions with CA9 expression. The CA9 and CXCR4 expression in the cancer cells, and the SDF1α expression in the stromal cells (CA9/CXCR4/SDF1α) was significantly associated with macroscopic type 4 tumor (P=0.012) and the pattern of tumor infiltration into the surrounding tissue (P<0.001). The prognosis of the all CA9/CXCR4/SDF1α-positive patients was significantly poorer compared with that of patients with CA9-, CXCR4- or SDF1α-negative GC at Stage III (P=0.041). These results indicated that hypoxia may upregulate SDFα production in stromal cells and CXCR4 expression in cancer cells. The SDF1α/CXCR4 axis may serve an important role in the progression of GC.
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Affiliation(s)
- Masakazu Yashiro
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Haruhito Kinoshita
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Gen Tsujio
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Tatsunari Fukuoka
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Yurie Yamamoto
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Tomohiro Sera
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Atsushi Sugimoto
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Sadaaki Nishimura
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Shuhei Kushiyama
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Shingo Togano
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Kenji Kuroda
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Takahiro Toyokawa
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Masaichi Ohira
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
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11
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Dong XZ, Zhao ZR, Hu Y, Lu YP, Liu P, Zhang L. LncRNA COL1A1-014 is involved in the progression of gastric cancer via regulating CXCL12-CXCR4 axis. Gastric Cancer 2020; 23:260-272. [PMID: 31650323 DOI: 10.1007/s10120-019-01011-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 10/03/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND The aberrant expression of long noncoding RNAs (lncRNAs) is found in various types of cancers and also showed its association with the occurrence and development of gastric cancer (GC). We found lncRNA COL1A1-014 was frequently upregulated in GC. METHODS This study investigated COL1A1-014 for its biological function at both cellular and animal levels, using MTT, flow cytometry, colony formation and transwell assays. The expression levels of COL1A1-014 and other genes were detected by RT-PCR and western blot. Luciferase reporter assay was used to detect the potential binding of miR-1273h-5p to COL1A1-014 and CXCL12. RESULTS We found that COL1A1-014 was frequently upregulated in GC tissues as well as cells. COL1A1-014 increased cell proliferation, colony forming efficiency, migration ability, invasion ability, and weight and volume of grafted tumors, while reduced cell apoptosis. Overexpression of COL1A1-014 increased the mRNA expression of chemokine (CXCmotif) ligand (CXCL12) and high levels of CXCL12 and CXCR4 proteins in GC cells. The levels of miR-1273h-5p showed an inverse correlation with COL1A1-014 and CXCL12 in GC cells transfected with miR-1273h-5p. The mRNAs of wild-type COL1A1-014 and CXCL12 showed reduction in HEK293 cells transfected with miR-1273h-5p. This suggested that COL1A1-014 functions as an efficient miR-1273h-5p sponge and as a competing endogenous RNA (ceRNA) to regulate CXCL12. The proliferative activity of COL1A1-014 on GC cells was blocked by CXCL12-CXCR4 axis inhibitor AMD-3100. CONCLUSIONS These findings demonstrated that COL1A1-014 play an important regulatory role in GC development by functioning as a ceRNA in regulating the CXCL12/CXCR4 axis via sponging miR-1273h-5p.
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Affiliation(s)
- Xian-Zhe Dong
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, 45 Changchun Road, Xicheng District, Beijing, 100053, China
| | - Zi-Run Zhao
- Renaissance School of Medicine at Stony Brook University, NY, 11794, USA
| | - Yuan Hu
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, 100853, China
| | - Yu-Pan Lu
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, 100853, China
| | - Ping Liu
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, 100853, China. .,Department of Clinical Pharmacology, General Hospital of Chinese PLA, 28 Fuxing Road, Haidian District, Beijing, 100853, China.
| | - Lan Zhang
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, 45 Changchun Road, Xicheng District, Beijing, 100053, 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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Xiao J, Lai H, Wei S, Ye Z, Gong F, Chen L. lncRNA HOTAIR promotes gastric cancer proliferation and metastasis via targeting miR-126 to active CXCR4 and RhoA signaling pathway. Cancer Med 2019; 8:6768-6779. [PMID: 31517442 PMCID: PMC6825996 DOI: 10.1002/cam4.1302] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Revised: 11/02/2017] [Accepted: 11/26/2017] [Indexed: 12/30/2022] Open
Abstract
HOTAIR, a well-known long noncoding RNAs (lncRNA), has been recognized to contribute to the tumor metastasis in several tumors. But its role in gastric cancer remains elusive. Here, we reported an increase in HOTAIR promoted proliferation and metastasis of gastric cancer cell lines. The HOTAIR and miR-126 level was determined in 15 paired primary gastric cancer tissues and their adjacent noncancerous gastric tissues. Over-expression or downregulation HOTAIR was conducted in AGS or BGC-823 cells to investigate the impact of HOTAIR in proliferation and metastasis. Then dual luciferase reporter assay was utilized to study the interaction between CXCR4 and miR-126. Cells transfected with shHOTAIR or miR-126 mimic were subjected to western blot to investigate the role of SDF-1/CXCR4 signaling in HOTAIR mediated proliferation and metastasis. HOTAIR was highly expressed in gastric cancer tissues and several gastric cancer cell lines. Overexpressed HOTAIR facilitated proliferation and metastasis in vitro while HOTAIR knockdown inhibit proliferation and metastasis. A negative correlation was observed between miR-126 and HOTAIR. And, we also confirmed the decrease in miR-126 in clinic specimen. Furthermore, HOTAIR and miR-126 negatively regulated each other and then increase or decrease CXCR4 expression and downstream pathway, respectively. CXCR4 was confirmed as a direct target of miR-126. Our study demonstrated that high HOTAIR expression promote proliferation and metastasis in gastric cancer via miR-126/CXCR4 axis and downstream signaling pathways.
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Affiliation(s)
- Jun Xiao
- Department of Gastrointestinal SurgeryFujian Cancer HospitalFujian Medical University Cancer HospitalFuzhou350001China
| | - Hao Lai
- Department of Gastrointestinal SurgeryGuangxi Cancer HospitalGuangxi Medical University Cancer HospitalNanning530001China
| | - Sheng‐Hong Wei
- Department of Gastrointestinal SurgeryFujian Cancer HospitalFujian Medical University Cancer HospitalFuzhou350001China
| | - Zai‐Sheng Ye
- Department of Gastrointestinal SurgeryFujian Cancer HospitalFujian Medical University Cancer HospitalFuzhou350001China
| | - Fu‐Sheng Gong
- Department of Molecular immune laboratoryFujian Cancer HospitalFujian Medical University Cancer HospitalFuzhou350001China
| | - Lu‐Chuan Chen
- Department of Gastrointestinal SurgeryFujian Cancer HospitalFujian Medical University Cancer HospitalFuzhou350001China
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14
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Altered Expression of CD44, SIRT1, CXCR4, miR-21, miR-34a, and miR-451 Genes in MKN-45 Cell Line After Docetaxel Treatment. J Gastrointest Cancer 2019; 51:520-526. [DOI: 10.1007/s12029-019-00274-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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15
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Gadalla R, Hassan H, Ibrahim SA, Abdullah MS, Gaballah A, Greve B, El-Deeb S, El-Shinawi M, Mohamed MM. Tumor microenvironmental plasmacytoid dendritic cells contribute to breast cancer lymph node metastasis via CXCR4/SDF-1 axis. Breast Cancer Res Treat 2019; 174:679-691. [PMID: 30632021 DOI: 10.1007/s10549-019-05129-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 01/03/2019] [Indexed: 12/11/2022]
Abstract
PURPOSE Plasmacytoid dendritic cells (PDCs) infiltration into breast cancer tissues is associated with poor prognosis. Also, CXCR4 shows compelling evidences to be exploited by cancer cells to migrate to distant sites. The present study investigated lymph node metastasis in the light of PDCs infiltration and the potential cross talk with CXCR4/SDF-1 chemokine axis. METHODS We assessed circulating PDCs proportions drained from the axillary tributaries, and the in situ expression of both CD303 and CXCR4 in breast cancer patients with positive lymph nodes (pLN) and negative lymph nodes (nLN) using immunohistochemistry and flow cytometry. We also analyzed the expression of SDF-1 in lymph nodes of pLN and nLN patients. We studied the effect of the secretome of PDCs of pLN and nLN patients on the expression of CXCR4 and activation of NF-κB in human breast cancer cell lines SKBR3 and MCF-7. TNF-α mRNA expression level in PDCs from both groups was determined by qPCR. RESULTS Our findings indicate increased infiltration of PDCs in breast cancer tissues of pLN patients than nLN patients, which correlates with CXCR4+ cells percentage. Interestingly, SDF-1 is highly immunostained in lymph nodes of pLN patients compared to nLN patients. Our in vitro experiments demonstrate an upregulation of NF-κB expression and CXCR4 cells upon stimulation with PDCs secretome of pLN patients than those of nLN patients. Also, PDCs isolated from pLN patients exhibited a higher TNF-α mRNA expression than nLN patients. Treatment of MCF-7 cell lines with TNF-α significantly upregulates CXCR4 expression. CONCLUSIONS Our findings suggest a potential role for microenvironmental PDCs in breast cancer lymph node metastasis via CXCR4/SDF-1 axis.
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Affiliation(s)
- Ramy Gadalla
- Department of Zoology, Faculty of Science, Cairo University, 12613, Giza, Egypt. .,Princess Margaret Cancer Center, University Health Network, 610 University Ave, Toronto, ON, M5G 2M9, Canada.
| | - Hebatallah Hassan
- Department of Zoology, Faculty of Science, Cairo University, 12613, Giza, Egypt
| | | | | | - Ahmed Gaballah
- Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
| | - Burkhard Greve
- Department of Radiotherapy-Radiooncology, University Hospital Münster, Münster, Germany
| | - Somaya El-Deeb
- Department of Zoology, Faculty of Science, Cairo University, 12613, Giza, Egypt
| | - Mohamed El-Shinawi
- Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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16
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Chemokines and Chemokine Receptors: Orchestrating Tumor Metastasization. Int J Mol Sci 2018; 20:ijms20010096. [PMID: 30591657 PMCID: PMC6337330 DOI: 10.3390/ijms20010096] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 12/20/2018] [Accepted: 12/23/2018] [Indexed: 12/14/2022] Open
Abstract
Metastasis still represents the primary cause of cancer morbidity and mortality worldwide. Chemokine signalling contributes to the overall process of cancer growth and metastasis, and their expression in both primary tumors and metastatic lesions correlate with prognosis. Chemokines promote tumor metastasization by directly supporting cancer cell survival and invasion, angiogenesis, and by indirectly shaping the pre-metastatic niches and antitumor immunity. Here, we will focus on the relevant chemokine/chemokine receptor axes that have been described to drive the metastatic process. We elaborate on their role in the regulation of tumor angiogenesis and immune cell recruitment at both the primary tumor lesions and the pre-metastatic foci. Furthermore, we also discuss the advantages and limits of current pharmacological strategies developed to target chemokine networks for cancer therapy.
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17
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Haji Mansor M, Najberg M, Contini A, Alvarez-Lorenzo C, Garcion E, Jérôme C, Boury F. Development of a non-toxic and non-denaturing formulation process for encapsulation of SDF-1α into PLGA/PEG-PLGA nanoparticles to achieve sustained release. Eur J Pharm Biopharm 2018; 125:38-50. [DOI: 10.1016/j.ejpb.2017.12.020] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 12/12/2017] [Accepted: 12/29/2017] [Indexed: 12/28/2022]
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18
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Lecavalier-Barsoum M, Chaudary N, Han K, Koritzinsky M, Hill R, Milosevic M. Targeting the CXCL12/CXCR4 pathway and myeloid cells to improve radiation treatment of locally advanced cervical cancer. Int J Cancer 2018; 143:1017-1028. [PMID: 29417588 DOI: 10.1002/ijc.31297] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 01/10/2018] [Accepted: 02/01/2018] [Indexed: 12/17/2022]
Abstract
Cervical cancer is the fourth most commonly diagnosed cancer and the fourth leading cause of cancer death in women worldwide. Approximately half of cervical cancer patients present with locally advanced disease, for which surgery is not an option. These cases are nonetheless potentially curable with radiotherapy and cisplatin chemotherapy. Unfortunately, some tumours are resistant to treatment, and lymph node and distant recurrences are major problems in patients with advanced disease at diagnosis. New targeted treatments that can overcome treatment resistance and reduce metastases are urgently needed. The CXCL12/CXCR4 chemokine pathway is ubiquitously expressed in many normal tissues and cancers, including cervical cancer. Emerging evidence indicates that it plays a central role in cervical cancer pathogenesis, malignant progression, the development of metastases and radiation treatment response. Pre-clinical studies of standard-of-care fractionated radiotherapy and concurrent weekly cisplatin plus the CXCR4 inhibitor Plerixafor (AMD3100) in patient-derived orthotopic cervical cancer xenografts have shown improved primary tumour response and reduced lymph node metastases with no increase in early or late side effects. These studies have pointed the way forward to future clinical trials of radiotherapy/cisplatin plus Plerixafor or other newly emerging CXCL12 or CXCR4 inhibitors in women with cervical cancer.
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Affiliation(s)
- Magali Lecavalier-Barsoum
- Department of Oncology, Segal Cancer Centre, Jewish General Hospital, McGill University, Montréal, Canada
| | - Naz Chaudary
- Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Canada
| | - Kathy Han
- Radiation Medicine Program, University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Canada.,Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Marianne Koritzinsky
- Radiation Medicine Program, University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Canada.,Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Richard Hill
- Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Canada.,Radiation Medicine Program, University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Michael Milosevic
- Radiation Medicine Program, University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Canada.,Institute of Medical Science, University of Toronto, Toronto, Canada
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19
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Deng QJ, Xu XF, Ren J. Effects of SDF-1/CXCR4 on the Repair of Traumatic Brain Injury in Rats by Mediating Bone Marrow Derived Mesenchymal Stem Cells. Cell Mol Neurobiol 2018; 38:467-477. [PMID: 28484859 PMCID: PMC11481861 DOI: 10.1007/s10571-017-0490-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 03/24/2017] [Indexed: 12/16/2022]
Abstract
Our study aims to investigate the effects of the SDF-1/CXCR4 axis on the repair of traumatic brain injury (TBI) in rats by mediating bone marrow derived from mesenchymal stem cells (BMSCs). Healthy male SD rats were collected, their tibiofibulars were removed, cultured, and BMSCs were collected. The expression of cell-surface molecular proteins was examined using flow cytometry. The mRNA and protein expression of CXCR4 in cells were tested using qRT-PCR and western blotting analysis. An electronic brain injury instrument was utilized to build TBI rat models and each rat was assigned into the experiment, positive control and control groups (10 rats in each group). The morris water maze was used to calculate the escape latency and number of times rats in each group crossed the platform. Neurological severity scores (NSS) was calculated to evaluate the recovery of neurological functioning. The distribution of neuronal nuclear antigens was detected using double-labeling immunohistochemistry. The morphological changes in the hippocampal neuronal and the number of BrdU-positive cells were observed through Nissl's staining and high magnification. The mRNA and protein expressions of CXCR4 were gradually increased as SDF-1 concentration increased. NGF and BDNF positive cells were expressed in each group. The distribution of neuronal nuclear antigens in the experiment group was elevated compared to the control and positive control groups. Among the three groups, the experimental group had the shortest escape latency and the highest number platform crossings. The difference in NSS among the three groups was significant. The experimental group had better cell morphology and a higher number of BrdU-positive cells than the other groups. The present study demonstrates that transplanting BMSCs with SDF-1-induced CXCR4 expression can promote the repair of TBI. This is expected to become a new treatment regimen for TBI.
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Affiliation(s)
- Quan-Jun Deng
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, People's Republic of China
| | - Xiao-Feng Xu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, 200032, People's Republic of China
| | - Jing Ren
- Department of Medical Laboratory, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, Tianjin, 300052, People's Republic of China.
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20
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SRF promotes gastric cancer metastasis through stromal fibroblasts in an SDF1-CXCR4-dependent manner. Oncotarget 2018; 7:46088-46099. [PMID: 27323859 PMCID: PMC5216783 DOI: 10.18632/oncotarget.10024] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 05/28/2016] [Indexed: 01/28/2023] Open
Abstract
It has been suggested that the overexpression of serum response factor (SRF) in cancer cells may promote cancer metastasis. However, the exact pathway by which SRF promotes metastasis has not been clarified. Here we showed that SRF promotes gastric cancer (GC) metastasis through stromal fibroblasts in an SDF1-CXCR4-dependent manner. SRF expression was significantly increased in metastatic GCs compared with the non-metastatic GCs (n=50, p=0.013). Immuno-staining indicated that SRF was primarily expressed in a-smooth muscle actin (αSMA)-expressing periglandular fibroblasts in GCs. The conditioned medium (CM) from CCD18Co fibroblasts stably transfected with the SRF vector (CCD18Co-SRF) significantly enhanced migration of MKN45 gastric cancer cells. In contrast, the CM from CCD18Co fibroblasts, in which SRF was downregulated, inhibited mobility of MKN45 cells. Similar results were observed in cultured BGC823 cells even when they were treated with the NIH3T3-SRF CM. When MKN45 cells and SRF-upregulated or downregulated CCD18Co cells were simultaneously co-injected into the tail veins of NOD-SCID mice, a significant increase or decrease was, respectively, observed in the experimental pulmonary metastasis of cancer cells. Furthermore, SRF overexpression significantly upregulated `SMA and stromal cell derived factor1 (SDF1) expression in these fibroblasts, and an anti-SDF1 antibody or the SDF1 receptor CXCR4-specific inhibitor AMD3100 treatment completely reversed the SRF-enhanced migration of cancer cells. Quantitative RT-PCR demonstrated that the expression level of SRF was positively correlated with that of SDF1 in 92 GC samples (r=0.63, p<0.001). In conclusion, SRF promote GC metastasis by facilitating myofibroblast-cancer cell crosstalk in an SDF1-CXCR4 dependent manner, and maybe a therapeutic target.
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21
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Nazari A, Khorramdelazad H, Hassanshahi G. Biological/pathological functions of the CXCL12/CXCR4/CXCR7 axes in the pathogenesis of bladder cancer. Int J Clin Oncol 2017; 22:991-1000. [PMID: 29022185 DOI: 10.1007/s10147-017-1187-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 08/21/2017] [Indexed: 12/14/2022]
Abstract
CXC chemokine ligand 12 (CXCL12) is an important member of the CXC subfamily of chemokines, and has been extensively studied in various human body organs and systems, both in physiological and clinical states. Ligation of CXCL12 to CXCR4 and CXCR7 as its receptors on peripheral immune cells gives rise to pleiotropic activities. CXCL12 itself is a highly effective chemoattractant which conservatively attracts lymphocytes and monocytes, whereas there exists no evidence to show attraction for neutrophils. CXCL12 regulates inflammation, neo-vascularization, metastasis, and tumor growth, phenomena which are all pivotally involved in cancer development and further metastasis. Generation and secretion of CXCL12 by stromal cells facilitate attraction of cancer cells, acting through its cognate receptor, CXCR4, which is expressed by both hematopoietic and non-hematopoietic tumor cells. CXCR4 stimulates tumor progression by different mechanisms and is required for metastatic spread to organs where CXCL12 is expressed, thereby allowing tumor cells to access cellular niches, such as the marrow, which favor tumor cell survival and proliferation. It has also been demonstrated that CXCL12 binds to another seven-transmembrane G-protein receptor or G-protein-coupled receptor, namely CXCR7. These studies indicated critical roles for CXCR4 and CXCR7 mediation of tumor metastasis in several types of cancers, suggesting their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Furthermore, CXCL12 itself has the capability to stimulate survival and growth of neoplastic cells in a paracrine fashion. CXCL12 is a supportive chemokine for tumor neovascularization via attracting endothelial cells to the tumor microenvironment. It has been suggested that elevated protein and mRNA levels of CXCL12/CXCR4/CXCR7 are associated with human bladder cancer (BC). Taken together, mounting evidence suggests a role for CXCR4, CXCR7, and their ligand CXCL12 during the genesis of BC and its further development. However, a better understanding is still required before exploring CXCL12/CXCR4/CXCR7 targeting in the clinic.
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Affiliation(s)
- Alireza Nazari
- Department of Surgery, School of Medicine, Rafsanjan University of Medical Science, Rafsanjan, Iran.,Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Hossein Khorramdelazad
- Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Gholamhossein Hassanshahi
- Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. .,Department of Immunology, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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22
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Guo W, Chen X, Zhu L, Wang Q. A six-mRNA signature model for the prognosis of head and neck squamous cell carcinoma. Oncotarget 2017; 8:94528-94538. [PMID: 29212247 PMCID: PMC5706893 DOI: 10.18632/oncotarget.21786] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 09/22/2017] [Indexed: 12/14/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC), one of the most common cancers with high morbidity and mortality rates worldwide, has a poor prognosis. The transcriptome sequencing data of 500 patients with HNSCC in the TCGA dataset were assessed to find biomarkers associated with HNSCC prognosis so as to improve the prognosis of patients with HNSCC. The patients were divided into the training and testing sets. A model of six mRNAs (FRMD5, PCMT1, PDGFA, TMC8, YIPF4, ZNF324B) that could predict patient prognosis was identified in the training set using the Cox regression analysis. According to this model, the patients were divided into high-risk and low-risk groups. The Kaplan-Meier analysis showed that the high-risk group showed significantly shorter overall survival time compared with the low-risk group in both training and testing sets. The receiver operating characteristic analysis further confirmed high sensitivity and specificity for the model, which was more accurate compared with some known biomarkers in predicting HNSCC prognosis. Moreover, the model was applicable to patients of different ages, genders, clinical stages, tumor locations, smoking history, and human papillomavirus (HPV) status, as well as to microarray dataset. This model could be used as a novel biomarker for the prognosis of HNSCC and a significant tool for guiding the clinical treatment of HNSCC. The risk score acquired from the model might contribute to improving outcome prediction and management for patients with HNSCC, indicating its clinical significance.
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Affiliation(s)
- Wenna Guo
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Xijia Chen
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Liucun Zhu
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Qiang Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
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23
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Xue L, Mao X, Ren L, Chu X. Inhibition of CXCL12/CXCR4 axis as a potential targeted therapy of advanced gastric carcinoma. Cancer Med 2017; 6:1424-1436. [PMID: 28544785 PMCID: PMC5463074 DOI: 10.1002/cam4.1085] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Revised: 02/09/2017] [Accepted: 02/11/2017] [Indexed: 01/30/2023] Open
Abstract
The whole outcome for patients with gastric carcinoma (GC) is very poor because most of them remain metastatic disease during survival even at diagnosis or after surgery. Despite many improvements in multiple strategies of chemotherapy, immunotherapy, and targeted therapy, exploration of novel alternative therapeutic targets is still warranted. Chemokine receptor 4 (CXCR4) and its chemokine ligand 12 (CXCL12) have been identified with significantly elevated levels in various malignancies including GC, which correlates with the survival, proliferation, angiogenesis, and metastasis of tumor cells. Increasing experimental evidence suggests an implication of inhibition of CXCL12/CXCR4 axis as a promising targeted therapy, although there are rare trials focused on the therapeutic efficacy of CXCR4 inhibitors in GC until recently. Therefore, it is reasonable to infer that specific antagonists or antibodies targeting CXCL12/CXCR4 axis alone or combined with chemotherapy will be effective and worthy of further translational studies as a potential treatment strategy in advanced GC.
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Affiliation(s)
- Li‐Jun Xue
- Department of Medical OncologyJinling HospitalNanjing University Clinical School of MedicineNanjing210002China
| | - Xiao‐Bei Mao
- Department of Medical OncologyJinling HospitalNanjing University Clinical School of MedicineNanjing210002China
| | - Li‐Li Ren
- Department of Medical OncologyJinling HospitalNanjing University Clinical School of MedicineNanjing210002China
| | - Xiao‐Yuan Chu
- Department of Medical OncologyJinling HospitalNanjing University Clinical School of MedicineNanjing210002China
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24
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Xin Q, Zhang N, Yu HB, Zhang Q, Cui YF, Zhang CS, Ma Z, Yang Y, Liu W. CXCR7/CXCL12 axis is involved in lymph node and liver metastasis of gastric carcinoma. World J Gastroenterol 2017; 23:3053-3065. [PMID: 28533662 PMCID: PMC5423042 DOI: 10.3748/wjg.v23.i17.3053] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 01/17/2017] [Accepted: 03/20/2017] [Indexed: 02/07/2023] Open
Abstract
AIM To investigate the role of CXC chemokine receptor (CXCR)-7 and CXCL12 in lymph node and liver metastasis of gastric carcinoma. METHODS In 160 cases of gastric cancer, the expression of CXCR7 and CXCL12 in tumor and matched tumor-adjacent non-cancer tissues, in the lymph nodes around the stomach and in the liver was detected using immunohistochemistry to analyze the relationship between CXCR7/CXCL12 expression and clinicopathological features and to determine whether CXCR7 and CXCL12 constitute a biological axis to promote lymph node and liver metastasis of gastric cancer. Furthermore, the CXCR7 gene was silenced and overexpressed in human gastric cancer SGC-7901 cells, and cell proliferation, migration and invasiveness were measured by the MTT, wound healing and Transwell assays, respectively. RESULTS CXCR7 expression was up-regulated in gastric cancer tissues (P = 0.011). CXCR7/CXCL12 expression was significantly related to high tumor stage and lymph node (r = 0.338, P = 0.000) and liver metastasis (r = 0.629, P = 0.000). The expression of CXCL12 in lymph node and liver metastasis was higher than that in primary gastric cancer tissues (χ2 = 6.669, P = 0.010; χ2 = 25379, P = 0.000), and the expression of CXCL12 in lymph node and liver metastasis of gastric cancer was consistent with the positive expression of CXCR7 in primary gastric cancer (r = 0.338, P = 0.000; r = 0.629, P = 0.000). Overexpression of the CXCR7 gene promoted cell proliferation, migration and invasion. Silencing of the CXCR7 gene suppressed SGC-7901 cell proliferation, migration and invasion. Human gastric cancer cell lines expressed CXCR7 and showed vigorous proliferation and migratory responses to CXCL12. CONCLUSION The CXCR7/CXCL12 axis is involved in lymph node and liver metastasis of gastric cancer. CXCR7 is considered a potential therapeutic target for the treatment of gastric cancer.
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Saeed AI, Qeadan F, Sood A, VanderJagt DJ, Mishra SI, Hill DA, Peikert T, Sopori ML. A novel cytokine profile associated with cancer metastasis to mediastinal and hilar lymph nodes identified using fine needle aspiration biopsy - A pilot study. Cytokine 2016; 89:98-104. [PMID: 27599390 DOI: 10.1016/j.cyto.2016.08.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Revised: 08/10/2016] [Accepted: 08/14/2016] [Indexed: 12/14/2022]
Abstract
Cancer metastasis to the lymph nodes is indicative of a poor prognosis. An endobronchial ultrasound-guided fine needle aspiration (EBUS-FNA) biopsy is increasingly being used to sample paratracheal lymph nodes for simultaneous cancer diagnosis and staging. In this prospective, single-center study, we collected dedicated EBUS-FNA biopsies from 27 patients with enlarged paratracheal and hilar lymph nodes. Cytokines were assayed using Bio-Plex Pro human cancer biomarker panels (34 cytokines), in a Bio-Rad 200 suspension array system. A mean cytokine value was taken from each subject with more than 1 lymph node station EBUS-FNA biopsies. Malignant and benign histologic diagnoses were established in 16 and 12 patients, respectively. An initial analysis using the Kruskal-Wallis test with Sidak correction for multiple comparisons, showed significant elevation of sVEGFR-1, IL-6, VEGF-A, Angiopoeintin-2, uPA, sHER-2/neu and PLGF in malignant lymph node samples compared to benign samples. The univariate logistic regression analyses revealed that 6 cytokines were significant predictors and 1 cytokine (PLGF) was marginally significant for discrimination between benign and malignant samples. The prediction power of these cytokines as biomarkers were very high according to the area under the ROC curve. Multiple logistic regression for subsets of the seven cytokine combined; provided an almost complete discrimination between benign and malignant samples (AUC=0.989). For screening and diagnostic purposes, we presented the optimal discrimination cut-off for each cytokine: sVEGFR-1 (2124.5pg/mL), IL-6 (40.2pg/mL), VEGF-A (1060.1pg/mL), Angiopoeintin-2 (913.7pg/mL), uPA (248.1pg/mL), sHER-2/neu (5010pg/mL) and PLGF (93.4pg/mL). For the very first time, a novel cytokine profile associated with cancer metastasis to the paratracheal lymph nodes were reported.
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Affiliation(s)
- Ali I Saeed
- Department of Internal Medicine, Pulmonary Critical Care and Sleep Medicine, University of New Mexico, Albuquerque, NM, United States; Department of Internal Medicine, Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, United States.
| | - Fares Qeadan
- Department of Internal Medicine, Division of Epidemiology, Biostatistics and Preventive Medicine, University of New Mexico, Albuquerque, NM, United States
| | - Akshay Sood
- Department of Internal Medicine, Pulmonary Critical Care and Sleep Medicine, University of New Mexico, Albuquerque, NM, United States
| | - Dorothy J VanderJagt
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM, United States
| | - Shiraz I Mishra
- Departments of Pediatrics and Family and Community Medicine, University of New Mexico, University of New Mexico Cancer Center, Albuquerque, NM, United States
| | - Deirdre A Hill
- Cancer Research and Treatment Center, Departments of Internal Medicine, Division of Epidemiology, University of New Mexico, Albuquerque, NM, United States
| | - Tobias Peikert
- Department of Internal Medicine, Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, United States
| | - Mohan L Sopori
- Lovelace Respiratory Research Institute, Albuquerque, NM, United States
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Łukaszewicz-Zając M, Szmitkowski M, Litman-Zawadzka A, Mroczko B. Matrix Metalloproteinases and Their Tissue Inhibitors in Comparison to Other Inflammatory Proteins in Gastric Cancer (GC). Cancer Invest 2016; 34:305-12. [PMID: 27414231 DOI: 10.1080/07357907.2016.1197237] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Gastric cancer (GC) remains a major cause of cancer-related deaths worldwide. The lack of management strategies for the diagnosis of GC in patients gives rise to the challenging questions about the new tumor markers for GC. Developing malignant process may induce local and systemic inflammatory responses. Cancer-associated inflammation is characterized by the infiltration of immune cells. Thus, the inflammation-related proteins, such as cytokines, chemokines, and selected matrix metalloproteinases, may facilitate the growth, proliferation, and migration of tumor cells, including GC. Based on our previous findings, we assessed the significance of various inflammatory mediators as candidates for tumor markers of GC.
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Affiliation(s)
| | - Maciej Szmitkowski
- a Department of Biochemical Diagnostics , Medical University of Białystok , Poland
| | - Ala Litman-Zawadzka
- b Department of Neurodegeneration Diagnostics , Medical University of Białystok , Białystok , Poland
| | - Barbara Mroczko
- b Department of Neurodegeneration Diagnostics , Medical University of Białystok , Białystok , Poland
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Xiong QQ, Wang DR, Liang Y. Liver metastases of gastric cancer: Molecular mechanisms and comprehensive therapy. Shijie Huaren Xiaohua Zazhi 2016; 24:2823-2829. [DOI: 10.11569/wcjd.v24.i18.2823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The liver is the main target organ of metastasis for gastric cancer. Gastric cancer with liver metastases (GCLM) has a poor prognosis and is a challenge for treatment of patients with gastric cancer. At present the mechanism of liver metastases of gastric cancer is unclear, and there have been no unified treatment guidelines. This paper mainly discusses the molecular mechanism and comprehensive therapy of liver metastases of gastric cancer.
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Huang J, Lin H, En Lin M. EVALUATION THE EXPRESSION OF THREE GENES TO EPITHELIAL OVARIAN CANCER RISK IN CHINESE POPULATION. AFRICAN JOURNAL OF TRADITIONAL, COMPLEMENTARY, AND ALTERNATIVE MEDICINES : AJTCAM 2016; 13:81-87. [PMID: 28852723 PMCID: PMC5566156 DOI: 10.21010/ajtcam.v13i4.12] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Ovarian cancer is associated with poor survival, because patients are diagnosed at an advanced stage of the disease, and in addition, tumors develop chemoresistance, which carries a poor prognosis for the patient. MATERIAL AND METHODS We hypothesize that high expression of SDF-1, survivin and smac is associated with ovarian cancers development and could be used as a biomarker to identify this disease. The expressions of SDF-1, survivin and smac in normal ovarian (NO) tissue, benign tumor (BT) tissue and epithelial ovarian cancer (EOC) tissue were immunohistochemically analysed. RESULTS Positive expressions of SDF-1, survivin and smac were significantly higher in EOC tissue than those in NO and BT tissues. SDF-1 expressions were significantly more weaker in advanced ovarian carcinomas (FIGO stage III-IV), and in high-grade carcinomas. There was a positive correlation between EOC patients with lymph node metastasis and with ascites and SDF-1 positivity (P < 0.05). Survivin expressions were significantly more stronger in advanced ovarian carcinomas (FIGO stage III-IV), and in high-grade carcinomas. There was a positive correlation between EOC patients with lymph node metastasis and with ascites and surviving positivity (P < 0.05). Smac expressions were significantly more stronger in advanced ovarian carcinomas (FIGO stage III-IV), and in high-grade carcinomas. There was a positive correlation between EOC patients with lymph node metastasis and with ascites and smac positivity (P < 0.05). CONCLUSION These results indicate that SDF-1, surviving and smac are closely associated with EOC metastasis.
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Affiliation(s)
- Ju Huang
- Department of Gynaecology, The First Affiliated Hospital of Shantou University Medical College, Shantou, PR China
| | - Hao Lin
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University
| | - Ming En Lin
- Department of Urology, The First Affiliated Hospital of Shantou University Medical College, Shantou, PR China
- Corresponding author E-mail: (ME Lin)
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Błogowski W, Zuba-Surma E, Sałata D, Budkowska M, Dołęgowska B, Starzyńska T. Peripheral trafficking of bone-marrow-derived stem cells in patients with different types of gastric neoplasms. Oncoimmunology 2015; 5:e1099798. [PMID: 27141380 DOI: 10.1080/2162402x.2015.1099798] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 09/18/2015] [Accepted: 09/18/2015] [Indexed: 02/06/2023] Open
Abstract
Recently, there has been a growing interest in the importance of stem cells (SCs) in the development/progression of gastric neoplasms. In this study, we performed a comprehensive analysis of different populations of bone-marrow-derived stem cells (BMSCs) in patients with various types of gastric malignancies, including gastric cancer, gastrointestinal stromal tumors (GISTs), neuroendocrine neoplasms (NENs), and lymphomas. We found significantly lower numbers of circulating Lin-/CD45 +/ CD133 + hematopoietic stem/progenitor cells (HSPCs), and intensified peripheral trafficking of both Lin-/CD45-/CXCR4+/CD34+/CD133+ very small embryonic/epiblast-like stem cells (VSELs) and CD105 + /STRO-1 +/ CD45- mesenchymal SCs (MSCs) in patients with gastric cancer, but not in those with other types of gastric neoplasms. No significant differences in the absolute numbers of circulating CD34 +/ KDR +/ CD31 +/ CD45- endothelial progenitor cells (EPCs) were observed between the groups. This abnormal balance in the peripheral trafficking of BMSCs in patients with gastric cancer was neither associated with clinical stage of the disease nor with systemic levels of stromal-derived factor-1 (SDF-1), as these were comparable to the values observed in control individuals. Interestingly, the absolute numbers of circulating BMSCs correlated with the concentrations of complement cascade-derived anaphylatoxins/molecules (mainly C5b-9/membrane attack complex-MAC) and sphingosine-1-phosphate (S1P). In summary, our translational study revealed that abnormal peripheral trafficking of BMSCs occurs in patients with gastric cancer, but not in those with other types of gastric neoplasms. Further, our findings indicate that highlighted complement cascade-derived molecules and S1P, but not SDF-1, are significant players associated with this phenomenon.
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Affiliation(s)
- Wojciech Błogowski
- Department of Internal Medicine, University of Zielona Góra, Zielona Góra, Poland; Department of Gastroenterology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Ewa Zuba-Surma
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Kraków, Poland
| | - Daria Sałata
- Department of Medical Analytics, Pomeranian Medical University in Szczecin , Szczecin, Poland
| | - Marta Budkowska
- Department of Medical Analytics, Pomeranian Medical University in Szczecin , Szczecin, Poland
| | - Barbara Dołęgowska
- Department of Medical Analytics, Pomeranian Medical University in Szczecin , Szczecin, Poland
| | - Teresa Starzyńska
- Department of Gastroenterology, Pomeranian Medical University in Szczecin , Szczecin, Poland
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Gravina GL, Mancini A, Muzi P, Ventura L, Biordi L, Ricevuto E, Pompili S, Mattei C, Di Cesare E, Jannini EA, Festuccia C. CXCR4 pharmacogical inhibition reduces bone and soft tissue metastatic burden by affecting tumor growth and tumorigenic potential in prostate cancer preclinical models. Prostate 2015; 75:1227-46. [PMID: 26073897 DOI: 10.1002/pros.23007] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 03/25/2015] [Indexed: 12/22/2022]
Abstract
BACKGROUND The majority of prostate cancer (Pca) patient morbidity can be attributed to bone metastatic events, which poses a significant clinical obstacle. Therefore, a better understanding of this phenomenon is imperative and might help to develop novel therapeutic strategies. Stromal cell-derived factor 1α (SDF-1α) and its receptor CXCR4 have been implicated as regulators of bone resorption and bone metastatic development, suggesting that agents able to suppress this signaling pathway may be used as pharmacological treatments. In this study we studied if two CXCR4 receptor antagonists, Plerixafor and CTE9908, may affect bone metastatic disease induced by Pca in preclinical experimental models METHODS To verify the hypothesis that CXCR4 inhibition affects Pca metastatic disease, selective CXCR4 compounds, Plerixafor, and CTE9908, were tested in preclinical models known to generate bone lesions. Additionally, the expression levels of CXCR4 and SDF-1α were analyzed in a number of human tissues derived from primary tumors, lymph-nodes and osseous metastases of Pca as well as in a wide panel of human Pca cell lines to non-tumorigenic and tumorigenic phenotype. RESULTS Bone-derived Pca cells express higher CXCR4 levels than other Pca cell lines. This differential expression was also observed in human Pca samples. In vitro evidence supports the hypothesis that factors produced by bone microenvironment differentially sustain CXCR4 and SDF1-α expression with respect to prostate microenvironment determining increased efficacy toward Plerixafor. The use of SDF1-α neutralizing antibodies greatly reduced the increase of CXCR4 expression in cells co-cultured with bone stromal cells (BMSc) and to a lesser extent in cells co-cultured with prostate stromal cells (HPSc) and partially reduced SDF1-α Plerixafor efficacy. SDF-1α induced tumor cell migration and invasion, as well as MMP-9, MMP-2, and uPA expression, which were reduced by Plerixafor. The incidence of X-ray detectable bone lesions was significantly reduced following Plerixafor and CTE9908 treatment Kaplan-Meier probability plots showed a significant improvement in the overall survival of mice treated with Plerixafor and CTE9908. The reduced intra-osseous growth of PC3 and PCb2 tumor cells after intratibial injection, as a result of Plerixafor and CTE9908 treatment, correlated with decreased osteolysis and serum levels of both mTRAP and type I collagen fragments (CTX), which were significantly lower with respect to controls. CONCLUSIONS Our report provides novel information on the potential activity of CXCR4 inhibitors on the formation and progression of Pca bone and soft tissue metastases and supports a biological rationale for the use of these inhibitors in men at high risk to develop clinically evident bone lesions.
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Affiliation(s)
- Giovanni Luca Gravina
- Division of Radiation Oncology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
- Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy
| | - Andrea Mancini
- Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy
| | - Paola Muzi
- Department of Life, Health and Environmental Sciences, L'Aquila, Italy
| | - Luca Ventura
- Pathology Department, San Salvatore Hospital L'Aquila, L'Aquila, Italy
| | - Leda Biordi
- Department of Biotechnological and Applied Clinical Sciences, Laboratory of Molecular Pathology, University of L'Aquila, L'Aquila, Italy
| | - Enrico Ricevuto
- Department of Biotechnological and Applied Clinical Sciences, Laboratory of Molecular Pathology, University of L'Aquila, L'Aquila, Italy
| | - Simona Pompili
- Department of Biotechnological and Applied Clinical Sciences, Laboratory of Human Anatomy, L'Aquila, Italy
| | - Claudia Mattei
- Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy
| | - Ernesto Di Cesare
- Division of Radiation Oncology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
- Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy
| | | | - Claudio Festuccia
- Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy
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Hu F, Miao L, Zhao Y, Xiao YY, Xu Q. A meta-analysis for C-X-C chemokine receptor type 4 as a prognostic marker and potential drug target in hepatocellular carcinoma. Drug Des Devel Ther 2015. [PMID: 26203228 PMCID: PMC4507792 DOI: 10.2147/dddt.s86032] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Chemokines (CKs), small proinflammatory chemoattractant cytokines that bind to specific G-protein coupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. C-X-C chemokine receptor type 4 (CXCR4) has gained tremendous attention over the last decade, since it was found to be upregulated in a wide variety of cancer types, including hepatocellular carcinoma (HCC). The clinical relevance of expression of CXCR4 in HCC remains controversial; our aim was to identify the precise relationship of CXCR4 to prognosis and clinicopathological features. We searched the database from MEDLINE, PubMed, Web of Science, Scopus and Embase and then conducted a meta-analysis from publications met the inclusion criteria for the qualitative study. Our data showed that 1) CXCR4 is overexpressed in HCC tissues but not in normal hepatic tissue, OR =84.26, 95% confidence interval (CI) =11.86–598.98, P<0.0001. CXCR4 expression is higher in HCC than those in cirrhosis as well, OR =20.71, 95% CI =7.61–56.34, P<0.00001. 2) The expression levels of CXCR4 does not increase during local progression, however, CXCR4 expression increases the risk of distant metastases in HCC, OR =5.84, 95% CI =2.84–12.00, P<0.00001. 3) High levels of CXCR4 gene expression are associated with worse survival in HCC, HR =0.18, 95% CI =0.10–0.32, Z=5.77, P<0.00001. These data indicate that CXCR4 expression correlates with an increased risk and worse survival in HCC patients. The aberrant CXCR4 expression plays an important role in the carcinogenesis and metastasis of HCC. Our conclusion also supports that the promise of CXCR4 signaling pathway blockade as a potential strategy for HCC patients.
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Affiliation(s)
- Fei Hu
- Department of Medical Oncology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, People's Republic of China
| | - Lin Miao
- Department of Medical Oncology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, People's Republic of China
| | - Yu Zhao
- Department of Medical Oncology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, People's Republic of China
| | - Yuan-Yuan Xiao
- Department of Medical Oncology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, People's Republic of China
| | - Qing Xu
- Department of Medical Oncology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, People's Republic of China
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Wei LM, Cao S, Yu WD, Liu YL, Wang JT. Overexpression of CX3CR1 is associated with cellular metastasis, proliferation and survival in gastric cancer. Oncol Rep 2015; 33:615-624. [PMID: 25482732 DOI: 10.3892/or.2014.3645] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 09/30/2014] [Indexed: 11/05/2022] Open
Abstract
The CX3CR1/CX3CL1 axis is involved in the metastasis and prognosis of many types of cancer; however, whether CX3CR1 is expressed in gastric cancer cells and whether it participates in gastric cancer metastasis remain unknown. We investigated the expression of CX3CR1 in gastric cancer tissues and non‑neoplastic gastric tissues in vivo and in gastric cancer cell lines and a gastric epithelial cell line in vitro, and then the functional roles of CX3CR1 in cellular metastasis, proliferation and survival were explored. We observed that CX3CR1 was highly expressed in gastric cancer tissues in vivo and was related to lymph node metastasis, higher clinical TNM stage and larger tumor size. In vitro, CX3CR1 overexpression promoted gastric cancer cell migration, invasion, proliferation and survival. Additionally, different from several chemokine receptors, CX3CR1 was also expressed in non-neoplastic gastric tissues and in gastric epithelial cells and played a functional role in vitro. Notably, gastric cancer tissues expressed higher CX3CR1 compared with that in the non-neoplastic gastric tissues in vivo, while in vitro, CX3CR1 expresssion in the gastric cancer cell lines was equivalent or significantly lower than that in the gastric epithelial cell line, which suggests that the high expression of CX3CR1 in gastric cancer in vivo might be induced, not constitutive. Altogether, our findings suggest that on the one hand overexpression of CX3CR1 promoted gastric cancer metastasis, proliferation and survival; on the other hand, appropriate expression of CX3CR1 in normal gastric tissues may play a physiological role in tissue remodeling after injury and/or epithelial renewal. Additionally, the tumor microenvironment may play an important role in the high expression of CX3CR1 in gastric cancer cells.
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Affiliation(s)
- Lu-Min Wei
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, P.R. China
| | - Shan Cao
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, P.R. China
| | - Wei-Dong Yu
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, P.R. China
| | - Yu-Lan Liu
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, P.R. China
| | - Jing-Tong Wang
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, P.R. China
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Sarvaiya PJ, Guo D, Ulasov I, Gabikian P, Lesniak MS. Chemokines in tumor progression and metastasis. Oncotarget 2014; 4:2171-85. [PMID: 24259307 PMCID: PMC3926818 DOI: 10.18632/oncotarget.1426] [Citation(s) in RCA: 268] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Chemokines play a vital role in tumor progression and metastasis. Chemokines are involved in the growth of many cancers including breast cancer, ovarian cancer, pancreatic cancer, melanoma, lung cancer, gastric cancer, acute lymphoblastic leukemia, colon cancer, non-small lung cancer, non-hodgkin's lymphoma, etc. The expression of chemokines and their receptors is altered in many malignancies and leads to aberrant chemokine receptor signaling. This review focuses on the role of chemokines in key processes that facilitate tumor progression including proliferation, senescence, angiogenesis, epithelial mesenchymal transition, immune evasion and metastasis.
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Affiliation(s)
- Purvaba J Sarvaiya
- The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA
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Schlereth SL, Refaian N, Iden S, Cursiefen C, Heindl LM. Impact of the prolymphangiogenic crosstalk in the tumor microenvironment on lymphatic cancer metastasis. BIOMED RESEARCH INTERNATIONAL 2014; 2014:639058. [PMID: 25254213 PMCID: PMC4165560 DOI: 10.1155/2014/639058] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Accepted: 08/14/2014] [Indexed: 02/08/2023]
Abstract
Lymphangiogenesis is a very early step in lymphatic metastasis. It is regulated and promoted not only by the tumor cells themselves, but also by cells of the tumor microenvironment, including cancer associated fibroblasts, mesenchymal stem cells, dendritic cells, or macrophages. Even the extracellular matrix as well as cytokines and growth factors are involved in the process of lymphangiogenesis and metastasis. The cellular and noncellular components influence each other and can be influenced by the tumor cells. The knowledge about mechanisms behind lymphangiogenesis in the tumor microenvironmental crosstalk is growing and offers starting points for new therapeutic approaches.
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Affiliation(s)
- Simona L. Schlereth
- Department of Ophthalmology, University of Cologne, Kerpener Straße 62, 50937 Cologne, Germany
| | - Nasrin Refaian
- Department of Ophthalmology, University of Cologne, Kerpener Straße 62, 50937 Cologne, Germany
| | - Sandra Iden
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, University of Cologne, Kerpener Straße 62, 50937 Cologne, Germany
| | - Ludwig M. Heindl
- Department of Ophthalmology, University of Cologne, Kerpener Straße 62, 50937 Cologne, Germany
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Zhou J, Xiang Y, Yoshimura T, Chen K, Gong W, Huang J, Zhou Y, Yao X, Bian X, Wang JM. The role of chemoattractant receptors in shaping the tumor microenvironment. BIOMED RESEARCH INTERNATIONAL 2014; 2014:751392. [PMID: 25110692 PMCID: PMC4119707 DOI: 10.1155/2014/751392] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 06/17/2014] [Indexed: 12/13/2022]
Abstract
Chemoattractant receptors are a family of seven transmembrane G protein coupled receptors (GPCRs) initially found to mediate the chemotaxis and activation of immune cells. During the past decades, the functions of these GPCRs have been discovered to not only regulate leukocyte trafficking and promote immune responses, but also play important roles in homeostasis, development, angiogenesis, and tumor progression. Accumulating evidence indicates that chemoattractant GPCRs and their ligands promote the progression of malignant tumors based on their capacity to orchestrate the infiltration of the tumor microenvironment by immune cells, endothelial cells, fibroblasts, and mesenchymal cells. This facilitates the interaction of tumor cells with host cells, tumor cells with tumor cells, and host cells with host cells to provide a basis for the expansion of established tumors and development of distant metastasis. In addition, many malignant tumors of the nonhematopoietic origin express multiple chemoattractant GPCRs that increase the invasiveness and metastasis of tumor cells. Therefore, GPCRs and their ligands constitute targets for the development of novel antitumor therapeutics.
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Affiliation(s)
- Jiamin Zhou
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
- Endoscopic Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yi Xiang
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
- Department of Pulmonary Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Teizo Yoshimura
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Keqiang Chen
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Wanghua Gong
- Basic Research Program, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA
| | - Jian Huang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Ye Zhou
- Department of Gastric Cancer and Soft Tissue Surgery, Fudan University Cancer Center, Shanghai 200032, China
| | - Xiaohong Yao
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Xiuwu Bian
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Ji Ming Wang
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
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Thomaidis T, Maderer A, Al-Batran SE, Kany J, Pauligk C, Steinmetz K, Schad A, Hofheinz R, Schmalenberg H, Homann N, Galle PR, Moehler M. VEGFR-3 and CXCR4 as predictive markers for treatment with fluorouracil, leucovorin plus either oxaliplatin or cisplatin in patients with advanced esophagogastric cancer: a comparative study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). BMC Cancer 2014; 14:476. [PMID: 24981311 PMCID: PMC4094395 DOI: 10.1186/1471-2407-14-476] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Accepted: 06/18/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Combination of fluoropyrimidines and a platinum derivative are currently standards for systemic chemotherapy in advanced adenocarcinoma of the stomach and gastroesophageal junction (GEJ). Nevertheless, individual likelihood for response to these therapeutic regimes remains uncertain. Even more, no predictive markers are available to determine which patients may benefit more from oxaliplatin versus cisplatin or vice versa. The new invasion and stem cell markers VEGFR-3 and CXCR4 have been linked prognostically with more aggressive esophagogastric cancer types. Thus, we aimed to assess correlations of VEGFR-3 and CXCR4 expression levels with clinical outcome in a randomized phase III study of patients with oxaliplatin/leucovorin/5-FU (FLO) versus cisplatin/leucovorin/5-FU (FLP). METHODS The patients data examined in this study (n = 72) were from the collective of the FLO vs. FLP phase III AIO trial. Tumour tissues were stained via immunohistochemistry for VEGFR-3 and CXCR4 expression and results were evaluated by two independent, blinded investigators.Outcome parameter: Survival analysis was calculated for patients receiving FLO vs. FLP in relation to VEGFR-3 and CXCR4 expression. RESULTS 54% and 36% of the examined tumour tissues showed strong positive expression of VEGFR-3 and CXCR4 respectively. No superiority of each regime was detected in terms of overall survival (OS) in the whole population. Patients with strong expression of CXCR4 on their tumour tissues profited more in terms of OS under the treatment of FLP (mOS: 28 vs 15 months, p = 0.05 respectively). Patients with negative VEGFR-3 and CXCR4 expression had a trend to live longer when FLO regime was applied (mOS: 22 vs. 9 months, p = 0.099 and 20 vs. 10 months, p = 0.073 respectively). In an exploratory analysis of patients older than 60 years at diagnosis, we observed a significant benefit in overall survival for VEGFR-3 and CXCR4-positive patients when treated with FLP (p = 0.002, p = 0.021 respectively). CONCLUSIONS CXCR4 positive patients profited in terms of OS from FLP, whereas FLO proved to be more effective in CXCR4 and VEGFR-3 negative patients. Our results suggest, despite the limited size of the study, a predictive value of these biomarkers concerning chemotherapy with FLP or FLO in advanced esophagogastric cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Markus Moehler
- I, Medical Department, Johannes-Gutenberg University of Mainz, Langenbeckstr,1, 55131 Mainz, Germany.
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CXC and CC chemokines as angiogenic modulators in nonhaematological tumors. BIOMED RESEARCH INTERNATIONAL 2014; 2014:768758. [PMID: 24971349 PMCID: PMC4058128 DOI: 10.1155/2014/768758] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Accepted: 04/08/2014] [Indexed: 12/26/2022]
Abstract
Chemokines are a superfamily of structurally homologous heparin-binding proteins that includes potent inducers and inhibitors of angiogenesis. The imbalance between angiogenic and angiostatic chemokine activities can lead to abnormalities, such as chronic inflammation, dysplastic transformation, and even tumor development and spreading. In this review, we summarize the current literature regarding the role of chemokines as modulators of tumor angiogenesis and their potential role as therapeutic targets in patients with nonhaematological tumors.
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Chang WJ, Du Y, Zhao X, Ma LY, Cao GW. Inflammation-related factors predicting prognosis of gastric cancer. World J Gastroenterol 2014; 20:4586-4596. [PMID: 24782611 PMCID: PMC4000495 DOI: 10.3748/wjg.v20.i16.4586] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/24/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC), which is mainly induced by Helicobacter pylori (H. pylori) infection, is one of the leading causes of cancer-related death in the developing world. Active inflammation initiated by H. pylori infection and maintained by inherent immune disorders promotes carcinogenesis and postoperative recurrence. However, the presence with H. pylori in tumors has been linked to a better prognosis, possibly due to the induction of antitumor immunity. Tumor infiltrations of tumor-associated macrophages, myeloid-derived suppressor cells, neutrophils, Foxp3+ regulatory T cells are correlated with poor prognosis. Tumor infiltrating CD8+ cytotoxic T lymphocytes, dendritic cells, and CD45RO T cells are generally associated with good prognosis of GC, although some subsets of these immune cells have inverse prognosis prediction values. High ratios of Foxp3+/CD4+ and Foxp3+/CD8+ in tumors are associated with a poor prognosis; whereas high Th1/Th2 ratio in tumors predicts a good prognosis. High levels of interleukin (IL)-6, IL-10, IL-32, and chemokine C-C motif ligands (CCL)7 and CCL21 in circulation, high expression of CXC chemokine receptor 4, chemokine C-C motif receptor (CCR)3, CCR4, CCR5, CCR7, hypoxia-inducible factor-1α, signal transducer activator of transcription-3, cyclooxygenase-2, and orphan nuclear receptor 4A2 in tumors are associated with an unfavorable prognosis. Increased serum levels of matrix metalloproteinases (MMP)-3, MMP-7, and MMP-11 and increased levels of MMP-9, MMP-12, and MMP-21 in tumors are consistently associated with poor survival of GC. Further emphasis should be put on the integration of these biomarkers and validation in large cohorts for personalized prediction of GC postoperative prognosis.
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Lee HJ, Song IC, Yun HJ, Jo DY, Kim S. CXC chemokines and chemokine receptors in gastric cancer: from basic findings towards therapeutic targeting. World J Gastroenterol 2014; 20:1681-1693. [PMID: 24587647 PMCID: PMC3930968 DOI: 10.3748/wjg.v20.i7.1681] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Revised: 10/01/2013] [Accepted: 11/12/2013] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is the fourth most common cancer, and the second-highest cause of cancer-related deaths worldwide. Despite extensive research to identify novel diagnostic and therapeutic agents, patients with advanced gastric cancer suffer from a poor quality of life and poor prognosis, and treatment is dependent mainly on conventional cytotoxic chemotherapy. To improve the quality of life and survival of gastric cancer patients, a better understanding of the underlying molecular pathologies, and their application towards the development of novel targeted therapies, is urgently needed. Chemokines are a group of small proteins associated with cytoskeletal rearrangements, the directional migration of several cell types during development and physiology, and the host immune response via interactions with G-protein coupled receptors. There is also growing evidence to suggest that chemokines not only play a role in the immune system, but are also involved in the development and progression of tumors. In gastric cancer, CXC chemokines and chemokine receptors regulate the trafficking of cells in and out of the tumor microenvironment. CXC chemokines and their receptors can also directly influence tumorigenesis by modulating tumor transformation, survival, growth, invasion and metastasis, as well as indirectly by regulating angiogenesis, and tumor-leukocyte interactions. In this review, we will focus on the roles of CXC chemokines and their receptors in the development, progression, and metastasis of gastric tumors, and discuss their therapeutic potential for gastric cancer.
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Chung HW, Lim JB. Role of the tumor microenvironment in the pathogenesis of gastric carcinoma. World J Gastroenterol 2014; 20:1667-1680. [PMID: 24587646 PMCID: PMC3930967 DOI: 10.3748/wjg.v20.i7.1667] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 11/22/2013] [Accepted: 12/06/2013] [Indexed: 02/06/2023] Open
Abstract
Gastric carcinoma (GC) is the 4th most prevalent cancer and has the 2nd highest cancer-related mortality rate worldwide. Despite the incidence of GC has decreased over the past few decades, it is still a serious health problem. Chronic inflammatory status of the stomach, caused by the infection of Helicobacter pylori (H. pylori) and through the production of inflammatory mediators within the parenchyma is suspected to play an important role in the initiation and progression of GC. In this review, the correlation between chronic inflammation and H. pylori infection as an important factor for the development of GC will be discussed. Major components, including tumor-associated macrophages, lymphocytes, cancer-associated fibroblasts, angiogenic factors, cytokines, and chemokines of GC microenvironment and their mechanism of action on signaling pathways will also be discussed. Increasing our understanding of how the components of the tumor microenviroment interact with GC cells and the signaling pathways involved could help identify new therapeutic and chemopreventive targets.
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Nuclear pattern of CXCR4 expression is associated with a better overall survival in patients with gastric cancer. JOURNAL OF ONCOLOGY 2014; 2014:808012. [PMID: 24659999 PMCID: PMC3934579 DOI: 10.1155/2014/808012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 12/10/2013] [Accepted: 12/19/2013] [Indexed: 12/19/2022]
Abstract
Introduction. Previous studies have shown that stromal-derived factor-1 (CXCL12) and its receptor, CXCR4, play a crucial role in metastasis of various tumors. Similarly, it has been cleared that CXCR4 is expressed on the cell surface of gastric cancers. However, nuclear expression of CXCR4 and its clinical importance have not been yet studied. Materials and Methods. Herein, we studied the expression of CXCR4 in gastric samples from patients with gastric adenocarcinoma as well as human gastric carcinoma cell line, AGS, by employing RT-PCR, immunohistochemistry, and flow cytometry techniques. Results. RT-PCR data showed that CXCR4 is highly expressed on AGS cells. This was confirmed by IHC and FACS as CXCR4 was detected on cell membrane, in cytoplasm, and in nucleus of AGS cells. Moreover, we found that both cytoplasmic and nuclear CXCR4 are strongly expressed in primary gastric cancer and the cytoplasmic pattern of CXCR4 tends to be associated with a shorter overall survival than nuclear staining. In conclusion, we present evidence for the first time that both cytoplasmic and nuclear expression of CXCR4 are detectable in gastric cancer tissues. However, the role of both cytoplasmic and nuclear CXCR4 needs to be further elucidated.
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The prognosis and clinicopathology of CXCR4 in gastric cancer patients: a meta-analysis. Tumour Biol 2014; 35:4589-97. [DOI: 10.1007/s13277-013-1603-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 12/30/2013] [Indexed: 12/29/2022] Open
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Xiao Z, Luo G, Liu C, Wu C, Liu L, Liu Z, Ni Q, Long J, Yu X. Molecular mechanism underlying lymphatic metastasis in pancreatic cancer. BIOMED RESEARCH INTERNATIONAL 2014; 2014:925845. [PMID: 24587996 PMCID: PMC3919106 DOI: 10.1155/2014/925845] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Accepted: 11/10/2013] [Indexed: 02/07/2023]
Abstract
As the most challenging human malignancies, pancreatic cancer is characterized by its insidious symptoms, low rate of surgical resection, high risk of local invasion, metastasis and recurrence, and overall dismal prognosis. Lymphatic metastasis, above all, is recognized as an early adverse event in progression of pancreatic cancer and has been described to be an independent poor prognostic factor. It should be noted that the occurrence of lymphatic metastasis is not a casual or stochastic but an ineluctable and designed event. Increasing evidences suggest that metastasis-initiating cells (MICs) and the microenvironments may act as a double-reed style in this crime. However, the exact mechanisms on how they function synergistically for this dismal clinical course remain largely elusive. Therefore, a better understanding of its molecular and cellular mechanisms involved in pancreatic lymphatic metastasis is urgently required. In this review, we will summarize the latest advances on lymphatic metastasis in pancreatic cancer.
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Affiliation(s)
- Zhiwen Xiao
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Guopei Luo
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Chen Liu
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Chuntao Wu
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Liang Liu
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Zuqiang Liu
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Quanxing Ni
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Jiang Long
- Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
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Gosalbez M, Hupe MC, Lokeshwar SD, Yates TJ, Shields J, Veerapen MK, Merseburger AS, Rosser CJ, Soloway MS, Lokeshwar VB. Differential expression of SDF-1 isoforms in bladder cancer. J Urol 2013; 191:1899-1905. [PMID: 24291546 DOI: 10.1016/j.juro.2013.11.053] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2013] [Indexed: 10/26/2022]
Abstract
PURPOSE SDF-1 is a ligand of the chemokine receptors CXCR4 and 7. The 6 known SDF-1 isoforms are generated by alternative mRNA splicing. While SDF-1 expression has been detected in various malignancies, only few groups have reported differential expression of SDF-1 isoforms and its clinical significance. We evaluated the expression of 3 SDF-1 isoforms (α, β and γ) in bladder cancer. MATERIALS AND METHODS Using quantitative polymerase chain reaction we measured SDF-1α, β and γ mRNA levels in 25 normal and 44 bladder cancer tissues, and in 210 urine specimens (28 normal, 74 benign, 57 bladder cancer, 35 bladder cancer history, 8 other cancer history and 8 other cancer) from consecutive patients. Levels were correlated with clinical outcome. RESULTS Of the SDF-1 isoforms only SDF-1β mRNA was significantly over expressed 2.5-fold to sixfold in bladder cancer compared to normal bladder tissues. SDF-1α was expressed in bladder tissues but SDF-1γ was undetectable. On multivariate analysis SDF-1β was an independent predictor of metastasis and disease specific mortality (p=0.017 and 0.043, respectively). In exfoliated urothelial cells only SDF-1β mRNA levels were differentially expressed with 91.2% sensitivity and 73.8% specificity for detecting bladder cancer. In patients with a bladder cancer history increased SDF-1β levels indicated a 4.3-fold increased risk of recurrence within 6 months (p=0.0001). CONCLUSIONS SDF-1 isoforms are differentially expressed in bladder tissues and exfoliated urothelial cells. SDF-1β mRNA levels in bladder cancer tissues predict a poor prognosis. Furthermore, SDF-1β mRNA levels in exfoliated cells detect bladder cancer with high sensitivity and they are a potential predictor of future recurrence.
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Affiliation(s)
- Miguel Gosalbez
- Department of Urology University of Miami - Miller School of Medicine, Miami, Florida, 33101
| | - Marie C Hupe
- Department of Urology University of Miami - Miller School of Medicine, Miami, Florida, 33101.,Department of Urology and Urologic Oncology Hannover Medical School (MHH), Hannover Germany
| | - Soum D Lokeshwar
- Sylvester Comprehensive Cancer Center, University of Miami - Miller School of Medicine, Miami, Florida, 33101
| | - Travis J Yates
- Department of Urology University of Miami - Miller School of Medicine, Miami, Florida, 33101
| | - John Shields
- Department of Urology University of Miami - Miller School of Medicine, Miami, Florida, 33101
| | - Muthu K Veerapen
- Department of Human Genetics and Hussman Institute of Human Genetics, University of Miami - Miller School of Medicine, Miami, Florida 33136
| | - Axel S Merseburger
- Department of Urology and Urologic Oncology Hannover Medical School (MHH), Hannover Germany
| | - Charles J Rosser
- University of Central Florida College of Medicine, Orlando, Florida
| | - Mark S Soloway
- Department of Urology University of Miami - Miller School of Medicine, Miami, Florida, 33101
| | - Vinata B Lokeshwar
- Department of Urology University of Miami - Miller School of Medicine, Miami, Florida, 33101.,Sylvester Comprehensive Cancer Center, University of Miami - Miller School of Medicine, Miami, Florida, 33101
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Tan XY, Chang S, Liu W, Tang HH. Silencing of CXCR4 inhibits tumor cell proliferation and neural invasion in human hilar cholangiocarcinoma. Gut Liver 2013; 8:196-204. [PMID: 24672662 PMCID: PMC3964271 DOI: 10.5009/gnl.2014.8.2.196] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 03/24/2013] [Accepted: 04/16/2013] [Indexed: 12/25/2022] Open
Abstract
Background/Aims To evaluate the expression of CXC motif chemokine receptor 4 (CXCR4) in the tissues of patients with hilar cholangiocarcinoma (hilar-CCA) and to investigate the cell proliferation and frequency of neural invasion (NI) influenced by RNAi-mediated CXCR4 silencing. Methods An immunohistochemical technique was used to detect the expression of CXCR4 in 41 clinical tissues, including hilar-CCA, cholangitis, and normal bile duct tissues. The effects of small interference RNA (siRNA)-mediated CXCR4 silencing were detected in the hilar-CCA cell line QBC939. Cell proliferation was determined by MTT. Expression of CXCR4 was monitored by quantitative real time polymerase chain reaction and Western blot analysis. The NI ability of hilar-CCA cells was evaluated using a perineural cell and hilar-CCA cell coculture migration assay. Results The expression of CXCR4 was significantly induced in clinical hilar-CCA tissue. There was a positive correlation between the expression of CXCR4 and lymph node metastasis/NI in hilar-CCA patients (p<0.05). Silencing of CXCR4 in tumor cell lines by siRNA led to significantly decreased NI (p<0.05) and slightly decreased cell proliferation. Conclusions CXCR4 is likely correlated with clinical recurrence of hilar-CCA. CXCR4 is involved in the invasion and proliferation of human hilar-CCA cell line QBC939, indicating that CXCR4 could be a promising therapeutic target for hilar-CCA.
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Affiliation(s)
- Xin-Yu Tan
- Department of Emergency, Xiangya Hospital, Central-South University, Changsha, China
| | - Shi Chang
- Department of General Surgery, Xiangya Hospital, Central-South University, Changsha, China
| | - Wei Liu
- Department of Intensive Care Unit, Xiangya Hospital, Central-South University, Changsha, China
| | - Hui-Huan Tang
- Department of General Surgery, Xiangya Hospital, Central-South University, Changsha, China
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Langhammer S. Rationale for the design of an oncology trial using a generic targeted therapy multi‑drug regimen for NSCLC patients without treatment options (Review). Oncol Rep 2013; 30:1535-41. [PMID: 23877481 PMCID: PMC3810357 DOI: 10.3892/or.2013.2631] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Accepted: 07/05/2013] [Indexed: 01/07/2023] Open
Abstract
Despite more than 70 years of research concerning medication for cancer treatment, the disease still remains one of the leading causes of mortality worldwide. Many cancer types lead to death within a period of months to years. The original class of chemotherapeutics is not selective for tumor cells and often has limited efficacy, while treated patients suffer from adverse side‑effects. To date, the concept of tumor‑specific targeted therapy drugs has not fulfilled its expectation to provide a key for a cure. Today, many oncology trials are designed using a combination of chemotherapeutics with targeted therapy drugs. However, these approaches have limited outcomes in most cancer indications. This perspective review provides a rationale to combine targeted therapy drugs for cancer treatment based on observations of evolutionary principles of tumor development and HIV infections. In both diseases, the mechanisms of immune evasion and drug resistance can be compared to some extent. However, only for HIV is a breakthrough treatment available, which is the highly active antiretroviral therapy (HAART). The principles of HAART and recent findings from cancer research were employed to construct a hypothetical model for cancer treatment with a multi‑drug regimen of targeted therapy drugs. As an example of this hypothesis, it is proposed to combine already marketed targeted therapy drugs against VEGFRs, EGFR, CXCR4 and COX2 in an oncology trial for non‑small cell lung cancer patients without further treatment options.
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Miyazaki H, Takabe K, Yeudall WA. Chemokines, chemokine receptors and the gastrointestinal system. World J Gastroenterol 2013; 19:2847-2863. [PMID: 23704819 PMCID: PMC3660811 DOI: 10.3748/wjg.v19.i19.2847] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Revised: 11/13/2012] [Accepted: 04/27/2013] [Indexed: 02/06/2023] Open
Abstract
The biological properties of tumor cells are known to be regulated by a multitude of cytokines and growth factors, which include epidermal growth factor receptor agonists and members of the transforming growth factor β family. Furthermore, the recent explosion of research in the field of chemokine function as mediators of tumor progression has led to the possibility that these small, immunomodulatory proteins also play key roles in carcinogenesis and may, therefore, be potential targets for novel therapeutic approaches. In this review, we will summarize recently reported findings in chemokine biology with a focus on the gastrointestinal tract.
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Abstract
PURPOSE OF REVIEW Stem cell-based therapies for preventing and treating chronic end-organ dysfunction have captured the imagination of the lay public and spurred scientific and clinical development in multiple disciplines and disease states. The goal of this review is to build a framework around the different approaches being deployed to heal or treat end-organ dysfunction and discuss how within this framework future developments may occur. RECENT FINDINGS In this review, we divide the development of regenerative therapies into two broad categories. The first 'Stem Cells as the Student' focuses on the fact that we need to coax/teach the stem cells to differentiate in an efficient manner into the cells of interest, then using tissue engineering, we need to integrate them in an appropriate delivery system/matrix, and then generate a blood supply, sufficient to allow for their survival following engraftment. In the second category 'Stem Cells as the Teacher,' we learn from studies on stem cell biology, critical pathways that are dysregulated in tissue repair. By identifying these critical pathways, we can develop drug and biologics that can enhance tissue repair and end-organ function. SUMMARY Regenerative therapies have exciting potential to improve patient outcomes in a variety of acute and chronic disease states. There is significant excitement in general public, and the scientific and clinical communities. Early studies have been variably successful. As we move forward and understand the biology and engineering principles involved, significant advances with greater chances of success and efficacy will come.
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Gene therapy of gastric cancer using LIGHT-secreting human umbilical cord blood-derived mesenchymal stem cells. Gastric Cancer 2013; 16:155-66. [PMID: 22850801 DOI: 10.1007/s10120-012-0166-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Accepted: 05/11/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have the ability to migrate into tumors and therefore are potential vehicles for the therapy of malignant diseases. In this study, we investigated the use of umbilical cord blood mesenchymal stem cells (UCB-MSCs) as carriers for a constant source of transgenic LIGHT (TNFSF14) to target tumor cells in vivo. METHODS Lentiviral vectors carrying LIGHT genes were constructed, producing viral particles with a titer of 2 × 10(8) TU/L. Fourteen days after UCB-MSCs transfected by LIGHT gene packaged lentivirus had been injected into mouse gastric cancer models, the expression levels of LIGHT mRNA and protein were detected by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Then the tumors' approximate volumes were measured. RESULTS The treatment with MSC-LIGHT demonstrated a strong suppressive effect on tumor growth compared to treatment with MSC and NaCl (p < 0.001). Examination of pathological sections of the tumor tissues showed that the areas of tumor necrocis in the MSC-LIGHT group were larger than those in the MSC group. Moreover, we found that MSCs with LIGHT were able to significantly induce apoptosis of tumor cells. The expression levels of LIGHT mRNA and protein were significantly higher in the UCB-MSCs with the LIGHT gene than the levels in UCB-MSCs (p < 0.001). CONCLUSION These results suggest that UCB-MSCs carrying the LIGHT gene have the potential to be used as effective delivery vehicles in the treatment of gastric cancers.
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Liarmakopoulos E, Theodoropoulos G, Vaiopoulou A, Rizos S, Aravantinos G, Kouraklis G, Nikiteas N, Gazouli M. Effects of stromal cell-derived factor-1 and survivin gene polymorphisms on gastric cancer risk. Mol Med Rep 2013; 7:887-892. [PMID: 23258739 DOI: 10.3892/mmr.2012.1247] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Accepted: 11/07/2012] [Indexed: 11/06/2022] Open
Abstract
Stromal-cell derived factor-1 (SDF-1), a CXC chemokine, is important for growth, angiogenesis and metastasis of tumor cells. The SDF1-3'A polymorphism has been investigated in various types of cancer; however, no information is currently available on its role in gastric cancer. Survivin is a member of the inhibitor of apoptosis family of proteins and has a genetic polymorphism (-31G/C) located in the CDE/CHR repressor element of its promoter. In this study, 88 gastric cancer patients and 480 normal healthy control subjects were investigated for the genotype and allelic SDF1-3'A and survivin -31G/C frequencies using polymerase chain reaction‑restriction fragment length polymorphism. The SDF1-3'A genotype frequencies for GG, GA and AA were 44.32, 48.86 and 6.92% in patients and 42.71, 47.71 and 9.58% in healthy subjects, respectively. GA+AA genotype frequency and A allele distribution were not identified as significantly different between gastric cancer cases and controls. The survivin frequencies for GG, GC and CC were 20.45, 50 and 29.54% in patients and 33.96, 45 and 21.04% in healthy subjects, respectively. The C carriers (GC+CC genotype) and the C allele were over-represented among the gastric cancer cases (P=0.013 and P=0.0083, respectively). Overall, no statistically significant association was identified for SDF-1 and survivin gene examined alleles and genotypes and any parameter investigated, (e.g., stage, differentiation status and survival). The survivin promoter -31G/C polymorphism may confer an increased susceptibility to gastric cancer, while the SDF1-3'A polymorphism may not be a candidate genetic variant to select individuals at higher risk of developing gastric cancer.
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