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1
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Ruan C, Zhang J, Liao Y, Hang Y, Dong Y, Shi H, Wang X. CXCR4 expression in immunohistochemistry of gastrointestinal neuroendocrine neoplasms: a meta-analysis. J Immunoassay Immunochem 2025:1-9. [PMID: 40125935 DOI: 10.1080/15321819.2025.2482642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Abstract
OBJECTIVE C-X-C chemokine receptor type 4 (CXCR4) is significantly associated with the development of various malignant tumors. This meta-analysis aims to investigate the expression of CXCR4 in the immunohistochemistry of gastrointestinal neuroendocrine neoplasms (GI-NENs). METHODS A comprehensive literature search regarding gastrointestinal neuroendocrine neoplasms and CXCR4 was conducted using PubMed,Web of Science, and the Cochrane Library, with a cut off date of June 30, 2024.Two researchers independently screened the literature according to inclusion and exclusion criteria and assessed study quality using the Newcastle-OttawaScale. Meta-analysis was performed using Stata version 17.0. The pooled positive rate was employed to evaluate the expression of CXCR4 in the immunohistochemistry of GI-NENs. RESULTS A total of eight studies involving 501 patients were included in this research. The immunohistochemical analysis revealed positive CXCR4 expression in 174 patients. The meta-analysis calculated and summarized the combined positive rate (R: 0.41; 95% CI = 0.21-0.60, p = 0.00), indicating that the differences were statistically significant. CONCLUSION CXCR4 is highly expressed in the immunohistochemistry of GI-NENs, which may provide some evidence for the therapeutic application of CXCR4 antagonists in treating neuroendocrine neoplasms.
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Affiliation(s)
- Changlong Ruan
- Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Jiajia Zhang
- Nursing Department, Yunxi County People's Hospital, Shiyan, Hubei, China
| | - Yingying Liao
- Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Yujie Hang
- Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Yuan Dong
- Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Hanfeng Shi
- Department of Gastroenterology, Danjiangkou Municipal First Hospital, Shiyan, Hubei, China
| | - Xiaoya Wang
- Department of Cardiology,Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
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Kumar U. Somatostatin and Somatostatin Receptors in Tumour Biology. Int J Mol Sci 2023; 25:436. [PMID: 38203605 PMCID: PMC10779198 DOI: 10.3390/ijms25010436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/24/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
Somatostatin (SST), a growth hormone inhibitory peptide, is expressed in endocrine and non-endocrine tissues, immune cells and the central nervous system (CNS). Post-release from secretory or immune cells, the first most appreciated role that SST exhibits is the antiproliferative effect in target tissue that served as a potential therapeutic intervention in various tumours of different origins. The SST-mediated in vivo and/or in vitro antiproliferative effect in the tumour is considered direct via activation of five different somatostatin receptor subtypes (SSTR1-5), which are well expressed in most tumours and often more than one receptor in a single cell. Second, the indirect effect is associated with the regulation of growth factors. SSTR subtypes are crucial in tumour diagnosis and prognosis. In this review, with the recent development of new SST analogues and receptor-specific agonists with emerging functional consequences of signaling pathways are promising therapeutic avenues in tumours of different origins that are discussed.
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Affiliation(s)
- Ujendra Kumar
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada
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3
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Campana C, van Koetsveld PM, Feelders RA, de Herder WW, Iyer AM, van Velthuysen MLF, Veenstra MJ, van den Dungen ESR, Franck SE, Ferone D, Gatto F, Hofland LJ. Digital quantification of somatostatin receptor subtype 2a immunostaining: a validation study. Eur J Endocrinol 2022; 187:399-411. [PMID: 35895707 PMCID: PMC9346267 DOI: 10.1530/eje-22-0339] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/30/2022] [Indexed: 11/08/2022]
Abstract
OBJECTIVE The aim of this study was to develop an open-source and reproducible digital quantitative analysis (DIA) of somatostatin receptor subtype 2a (SST2) staining in formalin-fixed paraffin-embedded tissues of pancreatic neuroendocrine tumors (panNETs) and growth hormone (GH)-secreting pituitary adenomas (GHomas). DESIGN SST2 immunostaining of 18 panNETs and 39 GHomas was assessed using a novel DIA protocol and compared with a widely used semi-quantitative immunoreactivity score (IRS). METHODS The DIA software calculates the staining intensity/area and the percentage of positive cells (%PC). Four representative images were selected for each sample by two independent selectors (S1 and S2), with the analysis performed by two independent analyzers (A1 and A2). Agreement between observers was calculated using the concordance correlation coefficient (CCC). RESULTS In panNETs, the CCC ranged 0.935-0.977 for intensity/area and 0.942-0.983 for %PC. In GHomas, the CCC ranged 0.963-0.997 for intensity/area and 0.979-0.990 for %PC. In both panNETs and GHomas, the DIA staining intensity was strongly correlated with the IRS (Spearman rho: 0.916-0.969, P < 0.001), as well as the DIA %PC with the IRS %PC (Spearman rh: 0.826-0.881, P < 0.001). In GHomas, the biochemical response to somatostatin receptor ligands correlated with SST2 expression, evaluated both as DIA intensity/area (Spearman rho: -0.448 to -0.527, P = 0.007-0.004) and DIA %PC (Spearman rho: -0.558 to -0.644, P ≤ 0.001). CONCLUSIONS The DIA has an excellent inter-observer agreement and showed a strong correlation with the widely used semi-quantitative IRS. The DIA protocol is an open-source, highly reproducible tool and provides a reliable quantitative evaluation of SST2 immunohistochemistry.
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Affiliation(s)
- Claudia Campana
- Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties, School of Medical and Pharmaceutical Sciences, University of Genova, Genova, Italy
| | - Peter M van Koetsveld
- Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Richard A Feelders
- Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Wouter W de Herder
- Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Anand M Iyer
- Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Marie-Louise F van Velthuysen
- Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Marije J Veenstra
- Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Sanne E Franck
- Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Diego Ferone
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties, School of Medical and Pharmaceutical Sciences, University of Genova, Genova, Italy
| | - Federico Gatto
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Leo J Hofland
- Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
- Correspondence should be addressed to L J Hofland;
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Czajkowski M, Kaemmerer D, Sänger J, Sauter G, Wirtz RM, Schulz S, Lupp A. Comparative evaluation of somatostatin and CXCR4 receptor expression in different types of thyroid carcinoma using well-characterised monoclonal antibodies. BMC Cancer 2022; 22:740. [PMID: 35799158 PMCID: PMC9261050 DOI: 10.1186/s12885-022-09839-z] [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: 05/20/2022] [Accepted: 06/30/2022] [Indexed: 12/02/2022] Open
Abstract
Background Papillary and follicular thyroid carcinomas can be treated surgically and with radioiodine therapy, whereas therapeutic options for advanced stage IV medullary and for anaplastic tumours are limited. Recently, somatostatin receptors (SSTs) and the chemokine receptor CXCR4 have been evaluated for the treatment of thyroid carcinomas, however, with contradictory results. Methods The expression of the five SSTs and of CXCR4 was assessed in 90 samples from 56 patients with follicular, papillary, medullary, or anaplastic thyroid carcinoma by means of immunohistochemistry using well-characterised monoclonal antibodies. The stainings were evaluated using the Immunoreactivity Score (IRS) and correlated to clinical data. In order to further substantiate the immunohistochemistry results, in serial sections of a subset of the samples receptor expression was additionally examined at the mRNA level using qRT-PCR. Results Overall, SST and CXCR4 protein expression was low in all four entities. In single cases, however, very high IRS values for SST2 and CXCR4 were observed. SST2 was the most frequently expressed receptor, found in 38% of cases, followed by SST5 and SST4, found in 14 and 9% of tumours, respectively. SST1 and SST3 could not be detected to any significant extent. CXCR4 was present in 12.5% of medullary and 25% of anaplastic carcinomas. Expression SST3, SST4, SST5 and CXCR4 was positively correlated with expression of the proliferation marker Ki-67. Additionally, a negative interrelationship between SST4 or SST5 expression and patient survival and a positive association between SST3 expression and tumour diameter were observed. qRT-PCR revealed a similar receptor expression pattern to that seen at the protein level. However, probably due to the low overall expression, no correlation was found for the SSTs or the CXCR4 between the IRS and the mRNA values. Conclusions SST- or CXCR4-based diagnostics or therapy in thyroid carcinomas should not be considered in general but may be feasible in single cases with high levels of expression of these receptors.
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Affiliation(s)
- Max Czajkowski
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Str. 1, D-07747, Jena, Germany
| | - Daniel Kaemmerer
- Department of General and Visceral Surgery, Zentralklinik Bad Berka, Bad Berka, Germany
| | - Jörg Sänger
- Laboratory of Pathology and Cytology Bad Berka, Bad Berka, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center, Hamburg-Eppendorf, Germany
| | - Ralph M Wirtz
- STRATIFYER Molecular Pathology GmbH Köln, Köln, Germany
| | - Stefan Schulz
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Str. 1, D-07747, Jena, Germany
| | - Amelie Lupp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Str. 1, D-07747, Jena, Germany.
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Reassessment of SST4 Somatostatin Receptor Expression Using SST4-eGFP Knockin Mice and the Novel Rabbit Monoclonal Anti-Human SST4 Antibody 7H49L61. Int J Mol Sci 2021; 22:ijms222312981. [PMID: 34884783 PMCID: PMC8657703 DOI: 10.3390/ijms222312981] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 11/28/2021] [Accepted: 11/29/2021] [Indexed: 02/07/2023] Open
Abstract
Among the five somatostatin receptors (SST1–SST5), SST4 is the least characterized, which is in part due to the lack of specific monoclonal antibodies. We generated a knockin mouse model that expresses a carboxyl-terminal SST4-eGFP fusion protein. In addition, we extensively characterized the novel rabbit monoclonal anti-human SST4 antibody 7H49L61 using transfected cells and receptor-expressing tissues. 7H49L61 was then subjected to immunohistochemical staining of a series of formalin-fixed, paraffin-embedded normal and neoplastic human tissues. Characterization of SST4-eGFP mice revealed prominent SST4 expression in cortical pyramidal cells and trigeminal ganglion cells. In the human cortex, 7H49L61 disclosed a virtually identical staining pattern. Specificity of 7H49L61 was demonstrated by detection of a broad band migrating at 50–60 kDa in immunoblots. Tissue immunostaining was abolished by preadsorption of 7H49L61 with its immunizing peptide. In the subsequent immunohistochemical study, 7H49L61 yielded a predominant plasma membrane staining in adrenal cortex, exocrine pancreas, and placenta. SST4 was also found in glioblastomas, parathyroid adenomas, gastric and pancreatic adenocarcinomas, pheochromocytomas, and lymphomas. Altogether, we provide the first unequivocal localization of SST4 in normal and neoplastic human tissues. The monoclonal antibody 7H49L61 may also prove of great value for identifying SST4-expressing tumors during routine histopathological examinations.
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Si Y, Guan J, Xu Y, Chen K, Kim S, Zhou L, Jaskula-Sztul R, Liu XM. Dual-Targeted Extracellular Vesicles to Facilitate Combined Therapies for Neuroendocrine Cancer Treatment. Pharmaceutics 2020; 12:E1079. [PMID: 33187322 PMCID: PMC7696983 DOI: 10.3390/pharmaceutics12111079] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/28/2020] [Accepted: 11/09/2020] [Indexed: 12/18/2022] Open
Abstract
Neuroendocrine (NE) cancers arise from cells within the neuroendocrine system. Chemotherapies and endoradiotherapy have been developed, but their clinical efficacy is limited. The objective of this study was to develop a dual-targeted extracellular vesicles (EV)-delivered combined therapies to treat NE cancer. Specifically, we produced EV in stirred-tank bioreactors and surface tagged both anti-somatostatin receptor 2 (SSTR 2) monoclonal antibody (mAb) and anti-C-X-C motif chemokine receptor 4 (CXCR4) mAb to generate mAbs-EV. Both live-cell confocal microscopy imaging and In Vivo Imaging System (IVIS) imaging confirmed that mAbs-EV specifically targeted and accumulated in NE cancer cells and NE tumor xenografts. Then the highly potent natural cytotoxic marine compound verrucarin A (Ver-A) with IC50 of 2.2-2.8 nM and microtubule polymerization inhibitor mertansine (DM1) with IC50 of 3.1-4.2 nM were packed into mAbs-EV. The in vivo maximum tolerated dose study performed in non-tumor-bearing mice indicated minimal systemic toxicity of mAbs-EV-Ver-A/DM1. Finally, the in vivo anticancer efficacy study demonstrated that the SSTR2/CXCR4 dual-targeted EV-Ver-A/DM1 is more effective to inhibit NE tumor growth than the single targeting and single drug. The results from this study could expand the application of EV to targeting deliver the combined potent chemotherapies for cancer treatment.
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Affiliation(s)
- Yingnan Si
- Department of Biomedical Engineering, University of Alabama at Birmingham (UAB), 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (J.G.); (Y.X.); (K.C.); (S.K.)
| | - JiaShiung Guan
- Department of Biomedical Engineering, University of Alabama at Birmingham (UAB), 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (J.G.); (Y.X.); (K.C.); (S.K.)
| | - Yuanxin Xu
- Department of Biomedical Engineering, University of Alabama at Birmingham (UAB), 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (J.G.); (Y.X.); (K.C.); (S.K.)
| | - Kai Chen
- Department of Biomedical Engineering, University of Alabama at Birmingham (UAB), 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (J.G.); (Y.X.); (K.C.); (S.K.)
| | - Seulhee Kim
- Department of Biomedical Engineering, University of Alabama at Birmingham (UAB), 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (J.G.); (Y.X.); (K.C.); (S.K.)
| | - Lufang Zhou
- Department of Medicine, University of Alabama at Birmingham, 703 19th Street South, Birmingham, AL 35294, USA;
| | - Renata Jaskula-Sztul
- Department of Surgery, University of Alabama at Birmingham, 1808 7th Avenue South, Birmingham, AL 35294, USA;
| | - X. Margaret Liu
- Department of Biomedical Engineering, University of Alabama at Birmingham (UAB), 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (J.G.); (Y.X.); (K.C.); (S.K.)
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Mansi R, Nicolas GP, Del Pozzo L, Abid KA, Grouzmann E, Fani M. Evaluation of a New 177Lu-Labeled Somatostatin Analog for the Treatment of Tumors Expressing Somatostatin Receptor Subtypes 2 and 5. Molecules 2020; 25:E4155. [PMID: 32932783 PMCID: PMC7570871 DOI: 10.3390/molecules25184155] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/03/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022] Open
Abstract
Targeted radionuclide therapy of somatostatin receptor (SST)-expressing tumors is only partially addressed by the established somatostatin analogs having an affinity for the SST subtype 2 (SST2). Aiming to target a broader spectrum of tumors, we evaluated the bis-iodo-substituted somatostatin analog ST8950 ((4-amino-3-iodo)-d-Phe-c[Cys-(3-iodo)-Tyr-d-Trp-Lys-Val-Cys]-Thr-NH2), having subnanomolar affinity for SST2 and SST5, labeled with [177Lu]Lu3+ via the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). Human Embryonic Kidney (HEK) cells stably transfected with the human SST2 (HEK-SST2) and SST5 (HEK-SST5) were used for in vitro and in vivo evaluation on a dual SST2- and SST5-expressing xenografted mouse model. natLu-DOTA-ST8950 showed nanomolar affinity for both subtypes (IC50 (95% confidence interval): 0.37 (0.22-0.65) nM for SST2 and 3.4 (2.3-5.2) for SST5). The biodistribution of [177Lu]Lu-DOTA-ST8950 was influenced by the injected mass, with 100 pmol demonstrating lower background activity than 10 pmol. [177Lu]Lu-DOTA-ST8950 reached its maximal uptake on SST2- and SST5-tumors at 1 h p.i. (14.17 ± 1.78 and 1.78 ± 0.35%IA/g, respectively), remaining unchanged 4 h p.i., with a mean residence time of 8.6 and 0.79 h, respectively. Overall, [177Lu]Lu-DOTA-ST8950 targets SST2-, SST5-expressing tumors in vivo to a lower extent, and has an effective dose similar to clinically used radiolabeled somatostatin analogs. Its main drawbacks are the low uptake in SST5-tumors and the persistent kidney uptake.
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Affiliation(s)
- Rosalba Mansi
- Division of Radiopharmaceutical Chemistry, Clinic of Radiology and Nuclear Medicine, University Hospital Basel, 4031 Basel, Switzerland; (R.M.); (L.D.P.)
| | - Guillaume Pierre Nicolas
- Division of Nuclear Medicine, Clinic of Radiology and Nuclear Medicine, University Hospital Basel, 4031 Basel, Switzerland;
| | - Luigi Del Pozzo
- Division of Radiopharmaceutical Chemistry, Clinic of Radiology and Nuclear Medicine, University Hospital Basel, 4031 Basel, Switzerland; (R.M.); (L.D.P.)
| | - Karim Alexandre Abid
- Catecholamine and Peptides Laboratory, Department of Laboratories, University Hospital of Lausanne, 1011 Lausanne, Switzerland; (K.A.A.); (E.G.)
| | - Eric Grouzmann
- Catecholamine and Peptides Laboratory, Department of Laboratories, University Hospital of Lausanne, 1011 Lausanne, Switzerland; (K.A.A.); (E.G.)
| | - Melpomeni Fani
- Division of Radiopharmaceutical Chemistry, Clinic of Radiology and Nuclear Medicine, University Hospital Basel, 4031 Basel, Switzerland; (R.M.); (L.D.P.)
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Zhang MY, He D, Zhang S. Pancreatic neuroendocrine tumors G3 and pancreatic neuroendocrine carcinomas: Differences in basic biology and treatment. World J Gastrointest Oncol 2020; 12:705-718. [PMID: 32864039 PMCID: PMC7428799 DOI: 10.4251/wjgo.v12.i7.705] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 05/17/2020] [Accepted: 06/17/2020] [Indexed: 02/05/2023] Open
Abstract
In 2017 the World Health Organization revised the criteria for classification of pancreatic neuroendocrine neoplasms (pNENs) after a consensus conference at the International Agency for Research on Cancer. The major change in the new classification was to subclassify the original G3 group into well-differentiated pancreatic neuroendocrine tumors G3 (pNETs G3) and poorly differentiated pancreatic neuroendocrine carcinomas (pNECs), which have been gradually proven to be completely different in biological behavior and clinical manifestations in recent years. In 2019 this major change subsequently extended to NENs involving the entire digestive tract. The updated version of the pNENs grading system marks a growing awareness of these heterogeneous tumors. This review discusses the clinicopathological, genetic and therapeutic features of poorly differentiated pNECs and compare them to those of well-differentiated pNETs G3. For pNETs G3 and pNECs (due to their lower incidence), there are still many problems to be investigated. Previous studies under the new grading classification also need to be reinterpreted. This review summarizes the relevant literature from the perspective of the differences between pNETs G3 and pNECs in order to deepen understanding of these diseases and discuss future research directions.
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Affiliation(s)
- Ming-Yi Zhang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Du He
- Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Shuang Zhang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Werner C, Dirsch O, Dahmen U, Grimm MO, Schulz S, Lupp A. Evaluation of Somatostatin and CXCR4 Receptor Expression in a Large Set of Prostate Cancer Samples Using Tissue Microarrays and Well-Characterized Monoclonal Antibodies. Transl Oncol 2020; 13:100801. [PMID: 32460182 PMCID: PMC7249232 DOI: 10.1016/j.tranon.2020.100801] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 05/11/2020] [Accepted: 05/12/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND: Prostate cancer (PCa) is the most common type of cancer among men in Western countries. Despite numerous therapeutic options, few treatments are available for patients with end-stage disease. In the present study, different somatostatin receptors (SSTs) and the chemokine receptor CXCR4 were evaluated for their suitability as novel therapeutic targets in PCa. MATERIALS AND METHODS: The expression of SST subtypes 1, 2A, 3, and 5 and of CXCR4 was evaluated in 276 PCa tumor samples on a tissue microarray (TMA) in 23 whole-block tumor samples and in 3 PCa cell lines by immunohistochemistry using well-characterized monoclonal antibodies. RESULTS: Overall, the frequency and intensity of expression of SSTs and CXCR4 were very low among the PCa samples investigated. Specifically, SST5, SST2A, and SST3 were expressed, albeit at low intensity, in 10.5%, 9.1%, and 0.7% of the TMA samples, respectively. None of the TMA samples showed SST1 or CXCR4 expression. Only a single small-cell-type neuroendocrine carcinoma that was coincidentally included among the whole-block samples exhibited strong SST2A, SST5, and CXCR4 and moderate SST3 expression. Independent of the tumor cells, the tumor capillaries in many of the PCa samples were strongly positive for SST2A, SST3, SST5, or CXCR4 expression. SST expression in the tumor cells was associated with advanced tumor grade and stage. CONCLUSION: Overall, SST and CXCR4 expression levels are clearly of no therapeutic relevance in PCa. SST- or CXCR4-based therapy might be feasible, however, in rare cases of small-cell-type neuroendocrine carcinoma of the prostate.
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Affiliation(s)
- Christoph Werner
- Department of Internal Medicine III, Jena University Hospital, Jena, Germany; Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany
| | - Olaf Dirsch
- Institute of Pathology, Jena University Hospital, Jena, Germany; Institute of Pathology, Klinikum Chemnitz, Chemnitz, Germany
| | - Uta Dahmen
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany
| | | | - Stefan Schulz
- Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany
| | - Amelie Lupp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany.
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Chen W, Ding R, Tang J, Li H, Chen C, Zhang Y, Zhang Q, Zhu X. Knocking Out SST Gene of BGC823 Gastric Cancer Cell by CRISPR/Cas9 Enhances Migration, Invasion and Expression of SEMA5A and KLF2. Cancer Manag Res 2020; 12:1313-1321. [PMID: 32110105 PMCID: PMC7040191 DOI: 10.2147/cmar.s236374] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 01/22/2020] [Indexed: 12/18/2022] Open
Abstract
Background The impact and potential molecular mechanisms of SST in the occurrence and development of GC have not been determined. Materials and Methods Two pairs of sgRNA and reporter were designed according to targeting sequence of SST gene for double-nicking. Plasmids were transfected into 293T for selecting sgRNA with higher cutting efficiency. The subline which has knocked-out SST gene were selected by FACS and verified by sequencing and expression level. Moreover, the migration and invasion ability was evaluated by wound healing and transwell after knocking out SST. Besides, the protein expression of SEMA5A and KLF2 were observed by Western blotting and LSCM. Last, we detected the expression levels of SST, SEMA5A, and KLF2 in GC tissues by Western blotting. Results The results revealed that the new subline 1E9, which had knocked out SST gene, was established by CRISPR/Cas9. In addition, the knockout of SST in GC cells markedly increased migration and invasion ability. The results also demonstrated that the knockout of SST increased the expression of SEMA5A and KLF2. The expression level of SST was decreased in GC tissues, and its decrease was associated with overexpression of SEMA5A and KLF2. Conclusion SST plays an inhibitory role in the migration and invasion of GC cell BGC823. The protein expression levels of SEMA5A and KLF2 were enhanced in GC cells and tissues lacking SST expression.
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Affiliation(s)
- Wei Chen
- Department of Histology and Embryology, School of Basic Medical Sciences, Zhengzhou University, Henan, People's Republic of China
| | - Ruixian Ding
- Department of Histology and Embryology, School of Basic Medical Sciences, Zhengzhou University, Henan, People's Republic of China
| | - Jinlu Tang
- Department of Histology and Embryology, School of Basic Medical Sciences, Zhengzhou University, Henan, People's Republic of China
| | - Haodong Li
- Department of Clinical Medicine, School of Basic Medical Sciences, Zhengzhou University, Henan, People's Republic of China
| | - Chonghua Chen
- Department of Clinical Medicine, School of Basic Medical Sciences, Zhengzhou University, Henan, People's Republic of China
| | - Yaru Zhang
- Department of Histology and Embryology, School of Basic Medical Sciences, Zhengzhou University, Henan, People's Republic of China
| | - Qinxian Zhang
- Department of Histology and Embryology, School of Basic Medical Sciences, Zhengzhou University, Henan, People's Republic of China
| | - Xiaoyan Zhu
- Department of Histology and Embryology, School of Basic Medical Sciences, Zhengzhou University, Henan, People's Republic of China
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