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1
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Lehmann J, Thelen M, Kreer C, Schran S, Garcia-Marquez MA, Cisic I, Siepmann K, Hagen EM, Eckel HNC, Lohneis P, Kruger S, Boeck S, Ormanns S, Rudelius M, Werner J, Popp F, Klein F, von Bergwelt-Baildon MS, Bruns CJ, Quaas A, Wennhold K, Schlößer HA. Tertiary Lymphoid Structures in Pancreatic Cancer are Structurally Homologous, Share Gene Expression Patterns and B-cell Clones with Secondary Lymphoid Organs, but Show Increased T-cell Activation. Cancer Immunol Res 2025; 13:323-336. [PMID: 39661055 DOI: 10.1158/2326-6066.cir-24-0299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 07/02/2024] [Accepted: 12/06/2024] [Indexed: 12/12/2024]
Abstract
Tertiary lymphoid structures (TLS) in cancer are considered ectopic hotspots for immune activation that are similar to lymphoid follicles in secondary lymphoid organs (SLO). This study elucidates shared and TLS/SLO-specific features in pancreatic ductal adenocarcinoma (PDAC). TLS abundance was related to superior survival and T-cell abundance in 110 treatment-naïve PDAC samples, underlining their clinical relevance. Immunofluorescence microscopy identified structural homologies between TLSs and SLOs. In RNA expression analyses of laser-microdissected TLSs and paired SLOs, we observed largely overlapping expression patterns of immune-related gene clusters but distinct expression patterns of T-cell and complement-associated genes. Immune cells in TLS expressed essential markers of germinal center formation. Increased activation of tumor-draining lymph nodes in patients with high numbers of TLSs highlights the relevance of these tumor-related structures to systemic immune response. In line with this, we identified an overlap of expanded B-cell receptor clonotypes in TLSs and SLOs, which suggests a vivid cross-talk between the two compartments. We conclude that combined therapeutic approaches exploiting TLS-mediated antitumor immune responses may improve susceptibility of PDAC to immunotherapy.
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Affiliation(s)
- Jonas Lehmann
- Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Martin Thelen
- Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Christoph Kreer
- Laboratory of Experimental Immunology, Faculty of Medicine and University Hospital Cologne, Institute of Virology, University of Cologne Cologne, Germany
| | - Simon Schran
- Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Maria A Garcia-Marquez
- Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Igor Cisic
- Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Klara Siepmann
- Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Elena M Hagen
- Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Hans Nikolaus Caspar Eckel
- Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, Cologne, Germany
| | - Philipp Lohneis
- Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Stephan Kruger
- Department of Internal Medicine III, University Hospital, Ludwig Maximilians University, Munich, Germany
| | - Stefan Boeck
- Department of Internal Medicine III, University Hospital, Ludwig Maximilians University, Munich, Germany
- Department of Hematology and Oncology, München Klinik Neuperlach, Munich, Germany
| | - Steffen Ormanns
- Faculty of Medicine, Institute of Pathology, Ludwig Maximilians University, Munich, Germany
- Innpath Institute of Pathology, Tirol Kliniken, Innsbruck, Austria
| | - Martina Rudelius
- Faculty of Medicine, Institute of Pathology, Ludwig Maximilians University, Munich, Germany
| | - Jens Werner
- Department of General, Visceral and Transplant Surgery, University Hospital, Ludwig Maximilians University, Munich, Germany
| | - Felix Popp
- Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Florian Klein
- Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Laboratory of Experimental Immunology, Faculty of Medicine and University Hospital Cologne, Institute of Virology, University of Cologne Cologne, Germany
- German Center for Infection Research (DZIF), Partner site Bonn-Cologne, Cologne, Germany
| | - Michael S von Bergwelt-Baildon
- Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Department of Internal Medicine III, University Hospital, Ludwig Maximilians University, Munich, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Christiane J Bruns
- Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Alexander Quaas
- Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Kerstin Wennhold
- Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Hans A Schlößer
- Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
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Valdivia A, Isac AM, Cardenas H, Zhao G, Zhang Y, Huang H, Wei JJ, Cuello-Fredes M, Kato S, Gómez-Valenzuela F, Gourronc F, Klingelhutz A, Matei D. Complement activation at the interface between adipocytes and cancer cells drives tumor progression. JCI Insight 2025; 10:e184935. [PMID: 39964754 PMCID: PMC11949041 DOI: 10.1172/jci.insight.184935] [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: 07/17/2024] [Accepted: 02/07/2025] [Indexed: 02/20/2025] Open
Abstract
The omentum is the primary site of metastasis for ovarian cancer (OC). Interactions between cancer cells and adipocytes drive an invasive and prometastatic phenotype. Here we studied cancer cell-adipocyte crosstalk by using a direct coculture model with immortalized human visceral nondiabetic pre-adipocytes (VNPADs) and OC cells. We demonstrated increased proliferation, invasiveness, and resistance to cisplatin of cocultured compared with monocultured OC cells. RNA sequencing of OC cells from coculture versus monoculture revealed significant transcriptomic changes, identifying over 200 differentially expressed genes common to OVCAR5 and OVCAR8 cell lines. Enriched pathways included PI3K/AKT and complement activation. Lipid transfer into OC cells from adipocytes induced upregulation of complement C3 and C5 proteins. Inhibiting C3 or C5 reversed the invasive phenotype and C3 knockdown reduced tumor progression in vivo. Increased C3 expression was observed in omental implants compared with primary ovarian tumors and C3 secretion was higher in OC ascites from high-BMI versus low-BMI patients. C3 upregulation in OC cells involved activation of the ATF4-mediated integrated stress response (ISR). Overall, adipocyte-cancer cell interactions promoted invasiveness and tumorigenesis via lipid transfer, activating the ISR, and upregulating complement proteins C3 and C5.
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Affiliation(s)
| | | | | | | | | | - Hao Huang
- Department of Obstetrics and Gynecology
| | - Jian-Jun Wei
- Department of Obstetrics and Gynecology
- Robert H. Lurie Comprehensive Cancer Center, and
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Mauricio Cuello-Fredes
- Department of Gynecology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Sumie Kato
- Department of Gynecology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Fernán Gómez-Valenzuela
- Department of Gynecology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Francoise Gourronc
- Department of Microbiology and Immunology, College of Medicine, The University of Iowa, Iowa City, Iowa, USA
| | - Aloysius Klingelhutz
- Department of Microbiology and Immunology, College of Medicine, The University of Iowa, Iowa City, Iowa, USA
| | - Daniela Matei
- Department of Obstetrics and Gynecology
- Robert H. Lurie Comprehensive Cancer Center, and
- Jesse Brown VA Medical Center, Chicago, Illinois, USA
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3
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Xiao G, Xie R, Gu J, Huang Y, Ding M, Shen D, Yan J, Yuan J, Yang Q, He W, Xiao S, Chen H, Xu D, Wu J, Fei J. Single-cell RNA-sequencing and spatial transcriptomic analysis reveal a distinct population of APOE - cells yielding pathological lymph node metastasis in papillary thyroid cancer. Clin Transl Med 2025; 15:e70172. [PMID: 39810624 PMCID: PMC11733439 DOI: 10.1002/ctm2.70172] [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: 10/08/2024] [Revised: 12/19/2024] [Accepted: 12/24/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Thyroid cancer is one of the most common endocrine tumors worldwide, especially among women and the metastatic mechanism of papillary thyroid carcinoma remains poorly understood. METHODS Thyroid cancer tissue samples were obtained for single-cell RNA-sequencing and spatial transcriptomics, aiming to intratumoral and antimetastatic heterogeneity of advanced PTC. The functions of APOE in PTC cell proliferation and invasion were confirmed through in vivo and in vitro assays. Pseudotime analysis and CellChat were performed to explore the the molecular mechanisms of the APOE in PTC progression. RESULTS We identified a subpopulation of tumor cells with lower expression levels of APOE, associated with advanced stages of PTC and cervical metastasis. APOE overexpression significantly reduced tumor cell proliferation and invasion, both in vitro and in vivo, by activating the ABCA1-LXR axis. APOE- tumor cells may promote tumor growth by interacting with dendritic cells and CD4+ T cells via CD99- rather than CD6-regulated signaling. We established a machine learning-based scRNA-seq data, 13-gene signature predictive of lymph node metastasis. CONCLUSIONS We identified a distinct APOE- tumor cell population associated with cervical metastasis and poor prognosis. Our results and models have potential clinical, prognostic, and therapeutic implications for advanced PTC. KEY POINTS A subpopulation of tumor cells with lower expression levels of APOE was strongly associated with more advanced stages and metastasis of PTC. APOE-negative (APOE-) cellsoverall exhibited weaker interactions with immune cells. A machine-learning bioinformatics model based on scRNA-seq data of in-situ thyroid cancer tissue was established to predict lymph node metastasis.
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Affiliation(s)
- Guohui Xiao
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Rongli Xie
- Department of General SurgeryRuijin Hospital Luwan BranchShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jianhua Gu
- Department of Thyroid and Breast SurgeryPunan Branch of Renji HospitalShanghai Jiaotong University School of MedicineShanghaiChina
| | - Yishu Huang
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Min Ding
- Department of General SurgeryRuijin Hospital Luwan BranchShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Dongjie Shen
- Department of General SurgeryRuijin Hospital Luwan BranchShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jiqi Yan
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jianming Yuan
- Department of General SurgeryRuijin Hospital Luwan BranchShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Qiong Yang
- Department of General SurgeryShanghai Changhang HospitalShanghaiChina
| | - Wen He
- Department of General SurgeryShanghai International Medical CenterShanghaiChina
| | - Siyu Xiao
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Haizhen Chen
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Dan Xu
- Department of Emergency MedicineRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jian Wu
- Department of PathologyPunan Branch of Renji HospitalJiaotong University School of MedicineShanghaiChina
| | - Jian Fei
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesShanghaiChina
- Institute of Translational MedicineShanghai Jiao Tong UniversityShanghaiChina
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4
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Eisenblätter R, Seifert F, Schürmann P, Beckhaus T, Hanel P, Jentschke M, Böhmer G, Strauß HG, Hirchenhain C, Schmidmayr M, Müller F, Hein A, Stuebs F, Koch M, Ruebner M, Beckmann MW, Fasching PA, Luyten A, Häfner N, Hillemanns P, Dörk T, Ramachandran D. Validation and functional follow-up of cervical cancer risk variants at the HLA locus. HLA 2024; 104:e15597. [PMID: 39101335 DOI: 10.1111/tan.15597] [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: 04/17/2024] [Revised: 06/19/2024] [Accepted: 07/02/2024] [Indexed: 08/06/2024]
Abstract
Cervical cancer is the fourth most common cancer in females. Genome-wide association studies (GWASs) have proposed cervical cancer susceptibility variants at the HLA locus on chromosome 6p21. To corroborate these findings and investigate their functional impact in cervical tissues and cell lines, we genotyped nine variants from cervical cancer GWASs (rs17190106, rs535777, rs1056429, rs2763979, rs143954678, rs113937848, rs3117027, rs3130214, and rs9477610) in a German hospital-based series of 1122 invasive cervical cancers, 1408 dysplasias, and 1196 healthy controls. rs17190106, rs1056429 and rs143954678/rs113937848 associated with cervical malignancies overall, while rs17190106 and rs535777 associated specifically with invasive cancer (OR = 0.69, 95% CI = 0.55-0.86, p = 0.001) or adenocarcinomas (OR = 1.63, 95%CI = 1.17-2.27, p = 0.004), respectively. We tested these and one previously genotyped GWAS variant, rs9272117, for potential eQTL effects on 36 gene transcripts at the HLA locus in 280 cervical epithelial tissues. The strongest eQTL pairs were rs9272117 and HLA-DRB6 (p = 1.9x10E-5), rs1056429 and HLA-DRB5 (p = 2.5x10E-4), and rs535777 and HLA-DRB1 (p = 2.7x10E-4). We also identified transcripts that were specifically upregulated (DDX39B, HCP5, HLA-B, LTB, NFKBIL1) or downregulated (HLA-C, HLA-DPB2) in HPV+ or HPV16+ samples. In comparison, treating cervical epithelial cells with proinflammatory cytokine γ-IFN led to a dose-dependent induction of HCP5, HLA-B, HLA-C, HLA-DQB1, HLA-DRB1, HLA-DRB6, and repression of HSPA1L. Taken together, these results identify relevant genes from both the MHC class I and II regions that are inflammation-responsive in cervical epithelium and associate with HPV (HCP5, HLA-B, HLA-C) and/or with genomic cervical cancer risk variants (HLA-DRB1, HLA-DRB6). They may thus constitute important contributors to the immune escape of precancerous cells after HPV-infection.
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Affiliation(s)
- Rieke Eisenblätter
- Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany
| | - Finja Seifert
- Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany
| | - Peter Schürmann
- Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany
| | - Theresa Beckhaus
- Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany
| | - Patricia Hanel
- Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany
| | - Matthias Jentschke
- Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany
| | | | - Hans-Georg Strauß
- Department of Gynaecology, University Clinics, Martin-Luther University, Halle-Wittenberg, Germany
| | - Christine Hirchenhain
- Department of Gynaecology, Clinics Carl Gustav Carus, University of Dresden, Dresden, Germany
| | - Monika Schmidmayr
- Department of Gynaecology, Technische Universität München, Munich, Germany
| | - Florian Müller
- Martin-Luther Hospital, Charite University, Berlin, Germany
| | - Alexander Hein
- Department of Gynaecology and Obstetrics, Klinikum Esslingen, Esslingen am Neckar, Germany
| | - Frederik Stuebs
- Department of Gynaecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander, University of Erlangen-Nuremberg (FAU), Erlangen, Germany
- Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Martin Koch
- Department of Gynaecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander, University of Erlangen-Nuremberg (FAU), Erlangen, Germany
- Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Matthias Ruebner
- Department of Gynaecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander, University of Erlangen-Nuremberg (FAU), Erlangen, Germany
- Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Matthias W Beckmann
- Department of Gynaecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander, University of Erlangen-Nuremberg (FAU), Erlangen, Germany
- Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Peter A Fasching
- Department of Gynaecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander, University of Erlangen-Nuremberg (FAU), Erlangen, Germany
- Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Alexander Luyten
- Dysplasia Unit, Department of Gynecology and Obstetrics, Mare Klinikum, Kronshagen, Germany
- Department of Gynaecology, Wolfsburg Hospital, Wolfsburg, Germany
| | - Norman Häfner
- Department of Gynaecology, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany
| | - Peter Hillemanns
- Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany
| | - Thilo Dörk
- Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany
| | - Dhanya Ramachandran
- Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany
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Gao B, Zhou P, Wang L, Wang Z, Yi Y, Li X, Zhou J, Fan J, Qiu S, Xu Y. Effects of the subtypes of apolipoprotein E on immune inhibition and prognosis in patients with Hepatocellular Carcinoma. J Cancer Res Clin Oncol 2024; 150:341. [PMID: 38976030 PMCID: PMC11230970 DOI: 10.1007/s00432-024-05856-6] [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: 04/13/2024] [Accepted: 06/17/2024] [Indexed: 07/09/2024]
Abstract
PURPOSE To investigate whether prognosis of patients with hepatocellular carcinoma (HCC) is affected by the abundance and subgroups of myeloid-derived suppressor cells (MDSCs) as well as subtypes and expression of apolipoprotein E (apoE). METHODS 31 HCC patients were divided into three groups according to blood total apoE level for detecting the abundance of immunoregulatory cells by flow cytometry. Tumour tissue microarrays from 360 HCC patients were evaluated about the abundance and subgroups of MDSCs and the expression of apoE2, apoE3, apoE4 by immunofluorescence staining and immunohistochemistry staining. Survival analysis by means of univariate, multivariate COX regression and Kaplan-Meier methods of the 360 patients was performed based on clinical and pathological examinations along with 10 years' follow-up data. RESULTS The lower apoE group presented higher abundance of MDSCs in the peripheral blood of HCC patients than higher apoE group. The abundance of monocyte-like MDSCs (M-MDSCs) was higher in the apoE low level group than high level group (p = 0.0399). Lower H-score of apoE2 (HR = 6.140, p = 0.00005) and higher H-score of apoE4 (HR = 7.001, p = 0.009) in tumour tissue were significantly associated with shorter overall survival (OS). The higher infiltration of polymorphonuclear granulocyte-like MDSCs (PMN-MDSCs, HR = 3.762, p = 0.000009) and smaller proportion of M-MDSCs of total cells (HR = 0.454, p = 0.006) in tumour tissue were independent risk factors for shorter recurrence-free survival (RFS). CONCLUSION The abundance of MDSCs in HCC patients' plasma negatively correlates with the level of apoE. The expression of apoE4 in HCC tissue indicated a poor prognosis while apoE2 might be a potential protective factor.
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Affiliation(s)
- Bowen Gao
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Peiyun Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Fudan University, Shanghai, 200032, China
- Shanghai Cancer Centre, Fudan University, Shanghai, 200032, China
| | - Li Wang
- Institutes of Biomedical Science, Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Zhutao Wang
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Yong Yi
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Xian Li
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Shuangjian Qiu
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Yang Xu
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Fudan University, Shanghai, 200032, China.
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Anwar MA, Keshteli AH, Yang H, Wang W, Li X, Messier HM, Cullis PR, Borchers CH, Fraser R, Wishart DS. Blood-Based Multiomics-Guided Detection of a Precancerous Pancreatic Tumor. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2024; 28:182-192. [PMID: 38634790 DOI: 10.1089/omi.2023.0278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/19/2024]
Abstract
Over a decade ago, longitudinal multiomics analysis was pioneered for early disease detection and individually tailored precision health interventions. However, high sample processing costs, expansive multiomics measurements along with complex data analysis have made this approach to precision/personalized medicine impractical. Here we describe in a case report, a more practical approach that uses fewer measurements, annual sampling, and faster decision making. We also show how this approach offers promise to detect an exceedingly rare and potentially fatal condition before it fully manifests. Specifically, we describe in the present case report how longitudinal multiomics monitoring (LMOM) helped detect a precancerous pancreatic tumor and led to a successful surgical intervention. The patient, enrolled in an annual blood-based LMOM since 2018, had dramatic changes in the June 2021 and 2022 annual metabolomics and proteomics results that prompted further clinical diagnostic testing for pancreatic cancer. Using abdominal magnetic resonance imaging, a 2.6 cm lesion in the tail of the patient's pancreas was detected. The tumor fluid from an aspiration biopsy had 10,000 times that of normal carcinoembryonic antigen levels. After the tumor was surgically resected, histopathological findings confirmed it was a precancerous pancreatic tumor. Postoperative omics testing indicated that most metabolite and protein levels returned to patient's 2018 levels. This case report illustrates the potentials of blood LMOM for precision/personalized medicine, and new ways of thinking medical innovation for a potentially life-saving early diagnosis of pancreatic cancer. Blood LMOM warrants future programmatic translational research with the goals of precision medicine, and individually tailored cancer diagnoses and treatments.
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Affiliation(s)
| | | | - Haiyan Yang
- Molecular You Corporation, Vancouver, British Columbia, Canada
| | - Windy Wang
- Molecular You Corporation, Vancouver, British Columbia, Canada
| | - Xukun Li
- Molecular You Corporation, Vancouver, British Columbia, Canada
| | - Helen M Messier
- Molecular You Corporation, Vancouver, British Columbia, Canada
- Fountain Life, Naples, Florida, USA
| | - Pieter R Cullis
- Molecular You Corporation, Vancouver, British Columbia, Canada
- Life Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Christoph H Borchers
- Gerald Bronfman Department of Oncology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
- Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
- Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
- Department of Pathology, McGill University, Montreal, Quebec, Canada
| | - Robert Fraser
- Molecular You Corporation, Vancouver, British Columbia, Canada
| | - David S Wishart
- Molecular You Corporation, Vancouver, British Columbia, Canada
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
- Department of Computing Science, University of Alberta, Edmonton, Alberta, Canada
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
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7
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Bhandari K, Kong JS, Morris K, Xu C, Ding WQ. Protein Arginine Methylation Patterns in Plasma Small Extracellular Vesicles Are Altered in Patients with Early-Stage Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2024; 16:654. [PMID: 38339405 PMCID: PMC10854811 DOI: 10.3390/cancers16030654] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 01/30/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024] Open
Abstract
Small extracellular vesicles (sEVs) contain lipids, proteins and nucleic acids, which often resemble their cells of origin. Therefore, plasma sEVs are considered valuable resources for cancer biomarker development. However, previous efforts have been largely focused on the level of proteins and miRNAs in plasma sEVs, and the post-translational modifications of sEV proteins, such as arginine methylation, have not been explored. Protein arginine methylation, a relatively stable post-translational modification, is a newly described molecular feature of PDAC. The present study examined arginine methylation patterns in plasma sEVs derived from patients with early-stage PDAC (n = 23) and matched controls. By utilizing the arginine methylation-specific antibodies for western blotting, we found that protein arginine methylation patterns in plasma sEVs are altered in patients with early-stage PDAC. Specifically, we observed a reduction in the level of symmetric dimethyl arginine (SDMA) in plasma sEV proteins derived from patients with early- and late-stage PDAC. Importantly, immunoprecipitation followed by proteomics analysis identified a number of arginine-methylated proteins exclusively present in plasma sEVs derived from patients with early-stage PDAC. These results indicate that arginine methylation patterns in plasma sEVs are potential indicators of PDAC, a new concept meriting further investigation.
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Affiliation(s)
- Kritisha Bhandari
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (K.B.); (J.S.K.)
| | - Jeng Shi Kong
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (K.B.); (J.S.K.)
| | - Katherine Morris
- Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Chao Xu
- Department of Biostatistics & Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Wei-Qun Ding
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (K.B.); (J.S.K.)
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8
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Gu X, Shen H, Zhu G, Li X, Zhang Y, Zhang R, Su F, Wang Z. Prognostic Model and Tumor Immune Microenvironment Analysis of Complement-Related Genes in Gastric Cancer. J Inflamm Res 2023; 16:4697-4711. [PMID: 37872955 PMCID: PMC10590588 DOI: 10.2147/jir.s422903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 10/12/2023] [Indexed: 10/25/2023] Open
Abstract
Introduction The complement system is integral to the innate and adaptive immune response, helping antibodies eliminate pathogens. However, the potential role of complement and its modulators in the tumor microenvironment (TME) of gastric cancer (GC) remains unclear. Methods This study assessed the expression, frequency of somatic mutations, and copy number variations of complement family genes in GC derived from The Cancer Genome Atlas (TCGA). Lasso and Cox regression analyses were conducted to develop a prognostic model based on the complement genes family, with the training and validation sets taken from the TCGA-GC cohort (n=371) and the International Gene Expression Omnibus (GEO) cohort (n=433), correspondingly. The nomogram assessment model was used to predict patient outcomes. Additionally, the link between immune checkpoints, immune cells, and the prognostic model was investigated. Results In contrast to patients at low risk, those at high risk had a less favorable outcome. The prognostic model-derived risk score was shown to serve as a prognostic marker of GC independently, as per the multivariate Cox analysis. Nomogram assessment showed that the model had high reliability for predicting the survival of patients with GC in the 1, 3, 5 years. Additionally, the risk score was positively linked to the expression of immune checkpoints, notably CTLA4, LAG3, PDCD1, and CD274, according to an analysis of immune processes. The core gene C5aR1 in the prognostic model was found to be upregulated in GC tissues in contrast to adjoining normal tissues, and patients with elevated expressed levels of C5aR1 had lower 10-year overall survival (OS) rates. Conclusion Our work reveals that complement genes are associated with the diversity and complexity of TME. The complement prognosis model help improves our understanding of TME infiltration characteristics and makes immunotherapeutic strategies more effective.
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Affiliation(s)
- Xianhua Gu
- Department of Gynecology Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, People’s Republic of China
| | - Honghong Shen
- Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, People’s Republic of China
| | - Guangzheng Zhu
- Department of Surgical Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, People’s Republic of China
| | - Xinwei Li
- Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, People’s Republic of China
| | - Yue Zhang
- Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, People’s Republic of China
| | - Rong Zhang
- Department of Gynecology Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, People’s Republic of China
| | - Fang Su
- Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, People’s Republic of China
| | - Zishu Wang
- Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, People’s Republic of China
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9
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Guan SW, Lin Q, Yu HB. Intratumour microbiome of pancreatic cancer. World J Gastrointest Oncol 2023; 15:713-730. [PMID: 37275446 PMCID: PMC10237023 DOI: 10.4251/wjgo.v15.i5.713] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/26/2023] [Accepted: 04/04/2023] [Indexed: 05/12/2023] Open
Abstract
Pancreatic cancer is a high mortality malignancy with almost equal mortality and morbidity rates. Both normal and tumour tissues of the pancreas were previously considered sterile. In recent years, with the development of technologies for high-throughput sequencing, a variety of studies have revealed that pancreatic cancer tissues contain small amounts of bacteria and fungi. The intratumour microbiome is being revealed as an influential contributor to carcinogenesis. The intratumour microbiome has been identified as a crucial factor for pancreatic cancer progression, diagnosis, and treatment, chemotherapy resistance, and immune response. A better understanding of the biology of the intratumour microbiome of pancreatic cancer contributes to the establishment of better early cancer screening and treatment strategies. This review focuses on the possible origins of the intratumour microbiome in pancreatic cancer, the intratumour localization, the interaction with the tumour microenvironment, and strategies for improving the outcome of pancreatic cancer treatment. Thus, this review offers new perspectives for improving the prognosis of pancreatic cancer.
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Affiliation(s)
- Shi-Wei Guan
- Department of Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Quan Lin
- Department of Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Hai-Bo Yu
- Department of Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
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10
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Complement and Fungal Dysbiosis as Prognostic Markers and Potential Targets in PDAC Treatment. Curr Oncol 2022; 29:9833-9854. [PMID: 36547187 PMCID: PMC9777542 DOI: 10.3390/curroncol29120773] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/02/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is still hampered by a dismal prognosis. A better understanding of the tumor microenvironment within the pancreas and of the factors affecting its composition is of utmost importance for developing new diagnostic and treatment tools. In this context, the complement system plays a prominent role. Not only has it been shown to shape a T cell-mediated immune response, but it also directly affects proliferation and apoptosis of the tumor cells, influencing angiogenesis, metastatic spread and therapeutic resistance. This makes complement proteins appealing not only as early biomarkers of PDAC development, but also as therapeutic targets. Fungal dysbiosis is currently the new kid on the block in tumorigenesis with cancer-associated mycobiomes extracted from several cancer types. For PDAC, colonization with the yeast Malassezia seems to promote cancer progression, already in precursor lesions. One responsible mechanism appears to be complement activation via the lectin pathway. In the present article, we review the role of the complement system in tumorigenesis, presenting observations that propose it as the missing link between fungal dysbiosis and PDAC development. We also present the results of a small pilot study supporting the crucial interplay between the complement system and Malassezia colonization in PDAC pathogenesis.
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11
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He Y, Chen J, Ma Y, Chen H. Apolipoproteins: New players in cancers. Front Pharmacol 2022; 13:1051280. [PMID: 36506554 PMCID: PMC9732396 DOI: 10.3389/fphar.2022.1051280] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 11/15/2022] [Indexed: 11/26/2022] Open
Abstract
Apolipoproteins (APOs), the primary protein moiety of lipoproteins, are known for their crucial role in lipid traffic and metabolism. Despite extensive exploration of APOs in cardiovascular diseases, their roles in cancers did not attract enough attention. Recently, research focusing on the roles of APOs in cancers has flourished. Multiple studies demonstrate the interaction of APOs with classical pathways of tumorigenesis. Besides, the dysregulation of APOs may indicate cancer occurrence and progression, thus serving as potential biomarkers for cancer patients. Herein, we summarize the mechanisms of APOs involved in the development of various cancers, their applications as cancer biomarkers and their genetic polymorphism associated with cancer risk. Additionally, we also discuss the potential anti-cancer therapies by virtue of APOs. The comprehensive review of APOs in cancers may advance the understanding of the roles of APOs in cancers and their potential mechanisms. We hope that it will provide novel clues and new therapeutic strategies for cancers.
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Affiliation(s)
- Yingcheng He
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi, China,Medical Department, Queen Mary School, Nanchang University, Nanchang, Jiangxi, China
| | - Jianrui Chen
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi, China,Medical Department, Queen Mary School, Nanchang University, Nanchang, Jiangxi, China
| | - Yanbing Ma
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi, China,Medical Department, Queen Mary School, Nanchang University, Nanchang, Jiangxi, China
| | - Hongping Chen
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi, China,Jiangxi Key Laboratory of Experimental Animals, Nanchang University, Nanchang, Jiangxi, China,*Correspondence: Hongping Chen,
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12
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Ashok G, Miryala SK, Saju MT, Anbarasu A, Ramaiah S. FN1 encoding fibronectin as a pivotal signaling gene for therapeutic intervention against pancreatic cancer. Mol Genet Genomics 2022; 297:1565-1580. [PMID: 35982245 DOI: 10.1007/s00438-022-01943-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 08/08/2022] [Indexed: 10/15/2022]
Abstract
The delayed diagnosis of pancreatic cancer has resulted in rising mortality rate and low survival rate that can be circumvented using potent theranostics biomarkers. The treatment gets complicated with delayed detection resulting in lowered 5-year relative survival rate. In our present study, we employed systems biology approach to identify central genes that play crucial roles in tumor progression. Pancreatic cancer genes collected from various databases were used to construct a statistically significant interactome with 812 genes that was further analysed thoroughly using topological parameters and functional enrichment analysis. The significant genes in the network were then identified based on the maximum degree parameter. The overall survival analysis indicated through hazard ratio [HR] and gene expression [log Fold Change] across pancreatic adenocarcinoma revealed the critical role of FN1 [HR 1.4; log2(FC) 5.748], FGA [HR 0.78; log2(FC) 1.639] FGG [HR 0.9; log2(FC) 1.597], C3 [HR 1.1; log2(FC) 2.637], and QSOX1 [HR 1.4; log2(FC) 2.371]. The functional significance of the identified hub genes signified the enrichment of integrin cell surface interactions and proteoglycan syndecan-mediated cell signaling. The differential expression, low overall survival and functional significance of FN1 gene implied its possible role in controlling metastasis in pancreatic cancer. Furthermore, alternate splice variants of FN1 gene showed 10 protein coding transcripts with conserved cell attachment site and functional domains indicating the variants' potential role in pancreatic cancer. The strong association of the identified hub-genes can be better directed to design potential theranostics biomarkers for metastasized pancreatic tumor.
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Affiliation(s)
- Gayathri Ashok
- Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.,Department of Bio-Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Sravan Kumar Miryala
- Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.,Department of Bio-Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Megha Treesa Saju
- Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.,Department of Bio-Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Anand Anbarasu
- Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.,Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Sudha Ramaiah
- Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India. .,Department of Bio-Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
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13
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Trilla-Fuertes L, Gámez-Pozo A, Lumbreras-Herrera MI, López-Vacas R, Heredia-Soto V, Ghanem I, López-Camacho E, Zapater-Moros A, Miguel M, Peña-Burgos EM, Palacios E, de Uribe M, Guerra L, Dittmann A, Mendiola M, Fresno Vara JÁ, Feliu J. Identification of Carcinogenesis and Tumor Progression Processes in Pancreatic Ductal Adenocarcinoma Using High-Throughput Proteomics. Cancers (Basel) 2022; 14:cancers14102414. [PMID: 35626021 PMCID: PMC9139847 DOI: 10.3390/cancers14102414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/05/2022] [Accepted: 05/11/2022] [Indexed: 11/16/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with an overall 5-year survival rate of just 5%. A better understanding of the carcinogenesis processes and the mechanisms of the progression of PDAC is mandatory. Fifty-two PDAC patients treated with surgery and adjuvant therapy, with available primary tumors, normal tissue, preneoplastic lesions (PanIN), and/or lymph node metastases, were selected for the study. Proteins were extracted from small punches and analyzed by LC-MS/MS using data-independent acquisition. Proteomics data were analyzed using probabilistic graphical models, allowing functional characterization. Comparisons between groups were made using linear mixed models. Three proteomic tumor subtypes were defined. T1 (32% of patients) was related to adhesion, T2 (34%) had metabolic features, and T3 (34%) presented high splicing and nucleoplasm activity. These proteomics subtypes were validated in the PDAC TCGA cohort. Relevant biological processes related to carcinogenesis and tumor progression were studied in each subtype. Carcinogenesis in the T1 subtype seems to be related to an increase of adhesion and complement activation node activity, whereas tumor progression seems to be related to nucleoplasm and translation nodes. Regarding the T2 subtype, it seems that metabolism and, especially, mitochondria act as the motor of cancer development. T3 analyses point out that nucleoplasm, mitochondria and metabolism, and extracellular matrix nodes could be involved in T3 tumor carcinogenesis. The identified processes were different among proteomics subtypes, suggesting that the molecular motor of the disease is different in each subtype. These differences can have implications for the development of future tailored therapeutic approaches for each PDAC proteomics subtype.
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Affiliation(s)
- Lucía Trilla-Fuertes
- Molecular Oncology & Pathology Laboratory, Instituto de Genética Médica y Molecular-INGEMM, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (L.T.-F.); (A.G.-P.); (M.I.L.-H.); (R.L.-V.); (J.Á.F.V.)
| | - Angelo Gámez-Pozo
- Molecular Oncology & Pathology Laboratory, Instituto de Genética Médica y Molecular-INGEMM, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (L.T.-F.); (A.G.-P.); (M.I.L.-H.); (R.L.-V.); (J.Á.F.V.)
| | - María Isabel Lumbreras-Herrera
- Molecular Oncology & Pathology Laboratory, Instituto de Genética Médica y Molecular-INGEMM, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (L.T.-F.); (A.G.-P.); (M.I.L.-H.); (R.L.-V.); (J.Á.F.V.)
| | - Rocío López-Vacas
- Molecular Oncology & Pathology Laboratory, Instituto de Genética Médica y Molecular-INGEMM, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (L.T.-F.); (A.G.-P.); (M.I.L.-H.); (R.L.-V.); (J.Á.F.V.)
| | - Victoria Heredia-Soto
- Molecular Pathology and Therapeutic Targets Group, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (V.H.-S.); (M.M.); (M.M.)
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, 28029 Madrid, Spain
| | - Ismael Ghanem
- Medical Oncology Service, Hospital Universitario La Paz, 28046 Madrid, Spain;
| | | | | | - María Miguel
- Molecular Pathology and Therapeutic Targets Group, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (V.H.-S.); (M.M.); (M.M.)
| | - Eva M. Peña-Burgos
- Pathology Department, Hospital Universitario La Paz, 28046 Madrid, Spain; (E.M.P.-B.); (E.P.); (M.d.U.); (L.G.)
| | - Elena Palacios
- Pathology Department, Hospital Universitario La Paz, 28046 Madrid, Spain; (E.M.P.-B.); (E.P.); (M.d.U.); (L.G.)
| | - Marta de Uribe
- Pathology Department, Hospital Universitario La Paz, 28046 Madrid, Spain; (E.M.P.-B.); (E.P.); (M.d.U.); (L.G.)
| | - Laura Guerra
- Pathology Department, Hospital Universitario La Paz, 28046 Madrid, Spain; (E.M.P.-B.); (E.P.); (M.d.U.); (L.G.)
| | - Antje Dittmann
- Functional Genomics Center Zurich, University of Zurich/ETH Zurich, 8057 Zurich, Switzerland;
| | - Marta Mendiola
- Molecular Pathology and Therapeutic Targets Group, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (V.H.-S.); (M.M.); (M.M.)
| | - Juan Ángel Fresno Vara
- Molecular Oncology & Pathology Laboratory, Instituto de Genética Médica y Molecular-INGEMM, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (L.T.-F.); (A.G.-P.); (M.I.L.-H.); (R.L.-V.); (J.Á.F.V.)
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, 28029 Madrid, Spain
| | - Jaime Feliu
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, 28029 Madrid, Spain
- Medical Oncology Service, Hospital Universitario La Paz, 28046 Madrid, Spain;
- Cátedra UAM-ANGEM, Faculty of Medicine, Universidad Autónoma de Madrid, 28046 Madrid, Spain
- Correspondence:
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14
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Kandikattu HK, Venkateshaiah SU, Mishra A. Chronic Pancreatitis and the Development of Pancreatic Cancer. Endocr Metab Immune Disord Drug Targets 2021; 20:1182-1210. [PMID: 32324526 DOI: 10.2174/1871530320666200423095700] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 12/31/2019] [Accepted: 01/20/2020] [Indexed: 02/07/2023]
Abstract
Pancreatitis is a fibro-inflammatory disorder of the pancreas that can occur acutely or chronically as a result of the activation of digestive enzymes that damage pancreatic cells, which promotes inflammation. Chronic pancreatitis with persistent fibro-inflammation of the pancreas progresses to pancreatic cancer, which is the fourth leading cause of cancer deaths across the globe. Pancreatic cancer involves cross-talk of inflammatory, proliferative, migratory, and fibrotic mechanisms. In this review, we discuss the role of cytokines in the inflammatory cell storm in pancreatitis and pancreatic cancer and their role in the activation of SDF1α/CXCR4, SOCS3, inflammasome, and NF-κB signaling. The aberrant immune reactions contribute to pathological damage of acinar and ductal cells, and the activation of pancreatic stellate cells to a myofibroblast-like phenotype. We summarize several aspects involved in the promotion of pancreatic cancer by inflammation and include a number of regulatory molecules that inhibit that process.
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Affiliation(s)
- Hemanth K Kandikattu
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Sathisha U Venkateshaiah
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Anil Mishra
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, United States
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15
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Popeda M, Markiewicz A, Stokowy T, Szade J, Niemira M, Kretowski A, Bednarz-Knoll N, Zaczek AJ. Reduced expression of innate immunity-related genes in lymph node metastases of luminal breast cancer patients. Sci Rep 2021; 11:5097. [PMID: 33658651 PMCID: PMC7930267 DOI: 10.1038/s41598-021-84568-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 02/18/2021] [Indexed: 01/31/2023] Open
Abstract
Immune system plays a dual role in cancer by either targeting or supporting neoplastic cells at various stages of disease, including metastasis. Yet, the exact immune-related transcriptome profiles of primary tumours (PT) and lymph node metastases (LNM) and their evolution during luminal breast cancer (BCa) dissemination remain undiscovered. In order to identify the immune-related transcriptome changes that accompany lymphatic spread, we analysed PT-LNM pairs of luminal BCa using NanoString technology. Decrease in complement C3-one of the top-downregulated genes, in LNM was validated at the protein level using immunohistochemistry. Thirty-three of 360 analysed genes were downregulated (9%), whereas only 3 (0.8%) upregulated in LNM when compared to the corresponding PT. In LNM, reduced expression was observed in genes related to innate immunity, particularly to the complement system (C1QB, C1S, C1R, C4B, CFB, C3, SERPING1 and C3AR1). In validation cohort, complement C3 protein was less frequently expressed in LNM than in PT and it was associated with worse prognosis. To conclude, local expression of the complement system components declines during lymphatic spread of non-metastatic luminal BCa, whilst further reduction of tumoral complement C3 in LNM is indicative for poor survival. This points to context-dependent role of complement C3 in BCa dissemination.
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Affiliation(s)
- Marta Popeda
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdansk, 80-211, Gdansk, Poland
| | - Aleksandra Markiewicz
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdansk, 80-211, Gdansk, Poland
| | - Tomasz Stokowy
- Department of Clinical Science, University of Bergen, 5021, Bergen, Norway
| | - Jolanta Szade
- Department of Pathomorphology, Medical University of Gdansk, 80-211, Gdansk, Poland
| | - Magdalena Niemira
- Clinical Research Centre, Medical University of Bialystok, 15-276, Bialystok, Poland
| | - Adam Kretowski
- Clinical Research Centre, Medical University of Bialystok, 15-276, Bialystok, Poland
| | - Natalia Bednarz-Knoll
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdansk, 80-211, Gdansk, Poland
| | - Anna J Zaczek
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdansk, 80-211, Gdansk, Poland.
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16
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Rasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Plasma levels of apolipoprotein E, APOE genotype, and all-cause and cause-specific mortality in 105 949 individuals from a white general population cohort. Eur Heart J 2020; 40:2813-2824. [PMID: 31236578 PMCID: PMC6735871 DOI: 10.1093/eurheartj/ehz402] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 02/01/2019] [Accepted: 05/24/2019] [Indexed: 11/25/2022] Open
Abstract
Aims To determine whether plasma apoE levels and APOE genotype are associated with all-cause and cause-specific mortality. Methods and results Using a prospective cohort design with 105 949 white individuals from the general population, we tested the association between plasma apoE at study enrolment and death during follow-up, and whether this was independent of APOE genotype. We confirmed the well-known association between APOE genotypes and mortality. For all-cause, cardiovascular, and cancer mortality, high levels of apoE were associated with increased risk, while for dementia-associated mortality low levels were associated with increased risk. For the highest vs. the fifth septile of plasma apoE, hazard ratios (HRs) were 1.20 (95% confidence interval 1.12–1.28) for all-cause mortality, 1.28 (1.13–1.44) for cardiovascular mortality, and 1.18 (1.05–1.32) for cancer mortality. Conversely, for the lowest vs. the fifth septile the HR was 1.44 (1.01–2.05) for dementia-associated mortality. Results were similar in analyses restricted to APOE ɛ33 carriers. Examining genetically determined plasma apoE, a 1 mg/dL increase conferred risk ratios of 0.97 (0.92–1.03) for cardiovascular mortality and 1.01 (0.95–1.06) for cancer mortality, while a 1 mg/dL decrease conferred a risk ratio of 1.70 (1.36–2.12) for dementia-associated mortality. Conclusion High plasma levels of apoE were associated with increased all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low levels were causally associated with increased dementia-associated mortality. ![]()
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Affiliation(s)
- Katrine L Rasmussen
- Department of Clinical Biochemistry, Rigshospitalet, Blegdamsvej 9, DK Copenhagen, Denmark.,The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK Herlev, Denmark.,Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK Herlev, Denmark
| | - Anne Tybjærg-Hansen
- Department of Clinical Biochemistry, Rigshospitalet, Blegdamsvej 9, DK Copenhagen, Denmark.,The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK Herlev, Denmark.,The Copenhagen City Heart Study, Frederiksberg Hospital, Nordre Fasanvej 57, DK Frederiksberg, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK Copenhagen, Denmark
| | - Børge G Nordestgaard
- The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK Herlev, Denmark.,Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK Herlev, Denmark.,The Copenhagen City Heart Study, Frederiksberg Hospital, Nordre Fasanvej 57, DK Frederiksberg, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK Copenhagen, Denmark
| | - Ruth Frikke-Schmidt
- Department of Clinical Biochemistry, Rigshospitalet, Blegdamsvej 9, DK Copenhagen, Denmark.,The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK Herlev, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK Copenhagen, Denmark
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17
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Complement System: Promoter or Suppressor of Cancer Progression? Antibodies (Basel) 2020; 9:antib9040057. [PMID: 33113844 PMCID: PMC7709131 DOI: 10.3390/antib9040057] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/10/2020] [Accepted: 10/20/2020] [Indexed: 12/13/2022] Open
Abstract
Constituent of innate immunity, complement is present in the tumor microenvironment. The functions of complement include clearance of pathogens and maintenance of homeostasis, and as such could contribute to an anti-tumoral role in the context of certain cancers. However, multiple lines of evidence show that in many cancers, complement has pro-tumoral actions. The large number of complement molecules (over 30), the diversity of their functions (related or not to the complement cascade), and the variety of cancer types make the complement-cancer topic a very complex matter that has just started to be unraveled. With this review we highlight the context-dependent role of complement in cancer. Recent studies revealed that depending of the cancer type, complement can be pro or anti-tumoral and, even for the same type of cancer, different models presented opposite effects. We aim to clarify the current knowledge of the role of complement in human cancers and the insights from mouse models. Using our classification of human cancers based on the prognostic impact of the overexpression of complement genes, we emphasize the strong potential for therapeutic targeting the complement system in selected subgroups of cancer patients.
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Zhang Y, Zheng L. Apolipoprotein: prospective biomarkers in digestive tract cancer. Transl Cancer Res 2020; 9:3712-3720. [PMID: 35117733 PMCID: PMC8799137 DOI: 10.21037/tcr-19-2106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 03/27/2020] [Indexed: 01/17/2023]
Abstract
Digestive tract cancer, which is characterized by high morbidity and mortality, seriously affects the quality of life of patients worldwide. The digestive tract has abundant blood supply and nutriment, providing a suitable environment for tumor cells. Under chemical, physical, and biological stimuli, the activated cancer-related genes promote tumorigenesis. The synthesis of apolipoprotein occurs in the liver, intestine, and other digestive organs. However, the functions of apolipoproteins are not limited to lipid metabolism. An increasing number of studies have revealed that apolipoproteins take part in the regulation of tumor behavior. Apolipoprotein A (apoA) has recently been acknowledged as a beneficial indicator of several cancers, including colon, hepatocellular, and pancreatic cancer. Apolipoprotein E (apoE) can affect tumor susceptibility on account of genetic polymorphism. Levels of apolipoprotein C (apoC), B (apoB), and D (apoD) also impact tumor progression and the prognosis of patients. However, because of individual, racial, and genetic differences, a consensus has not yet been reached. Based on clinical data and analysis, apolipoproteins could be a novel target and marker in tumor therapy and prevention.
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Affiliation(s)
- Yibo Zhang
- Comprehensive Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Lu Zheng
- Comprehensive Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China
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19
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Lin L, Zheng J, Zheng F, Cai Z, Yu Q. Advancing serum peptidomic profiling by data-independent acquisition for clear-cell renal cell carcinoma detection and biomarker discovery. J Proteomics 2020; 215:103671. [DOI: 10.1016/j.jprot.2020.103671] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 12/28/2019] [Accepted: 01/26/2020] [Indexed: 12/20/2022]
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20
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Roumenina LT, Daugan MV, Petitprez F, Sautès-Fridman C, Fridman WH. Context-dependent roles of complement in cancer. Nat Rev Cancer 2019; 19:698-715. [PMID: 31666715 DOI: 10.1038/s41568-019-0210-0] [Citation(s) in RCA: 243] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/14/2019] [Indexed: 12/16/2022]
Abstract
The tumour microenvironment (TME) highly influences the growth and spread of tumours, thus impacting the patient's clinical outcome. In this context, the complement system plays a major and complex role. It may either act to kill antibody-coated tumour cells, support local chronic inflammation or hamper antitumour T cell responses favouring tumour progression. Recent studies demonstrate that these opposing effects are dependent upon the sites of complement activation, the composition of the TME and the tumour cell sensitivity to complement attack. In this Review, we present the evidence that has so far accrued showing a role for complement activation and its effects on cancer control and clinical outcome under different TME contexts. We also include a new analysis of the publicly available transcriptomic data to provide an overview of the prognostic value of complement gene expression in 30 cancer types. We argue that the interplay of complement components within each cancer type is unique, governed by the properties of the tumour cells and the TME. This concept is of critical importance for the design of efficient therapeutic strategies aimed at targeting complement components and their signalling.
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Affiliation(s)
- Lubka T Roumenina
- INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Sorbonne Universités, Université de Paris, Paris, France.
| | - Marie V Daugan
- INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Sorbonne Universités, Université de Paris, Paris, France
| | - Florent Petitprez
- INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Sorbonne Universités, Université de Paris, Paris, France
- Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France
| | - Catherine Sautès-Fridman
- INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Sorbonne Universités, Université de Paris, Paris, France
| | - Wolf Herman Fridman
- INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Sorbonne Universités, Université de Paris, Paris, France.
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21
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Tang P, Tao L, Yuan C, Zhang L, Xiu D. Serum Derived Exosomes From Pancreatic Cancer Patients Promoted Metastasis: An iTRAQ-Based Proteomic Analysis. Onco Targets Ther 2019; 12:9329-9339. [PMID: 31807013 PMCID: PMC6844101 DOI: 10.2147/ott.s229494] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 10/17/2019] [Indexed: 01/18/2023] Open
Abstract
Background Pancreatic cancer (PC) is one of the most aggressive malignancies and has a poor prognosis despite being extensively researched. The role of serum-derived exosomes in tumorigenesis and the development of PC is still unclear. Method The present study employed iTRAQ-based proteomic analysis to search for differences between the serum exosomes of PC patients and those from control patients. Then, bioinformatics methods were used to analyze the functions of the identified proteins, and the possible functions were verified through cell culture experiments. Results A total of 611 proteins were identified from exosomes, and 141 proteins were differentially expressed, with 91 up- and 50 down regulated proteins in PC cancer compared to healthy controls. Further analysis indicated that APOE serves as an important hub in the network. In addition, CRP, VWF, APOA2, NIN, and GSK3B potentially interact with many other proteins. We then tested the effect of patient serum-derived exosomes on pancreatic cancer cells and found that patient serum-derived exosomes, but not those from healthy controls, induced cell proliferation, migration, and EMT, supporting the role of exosomes in metastasis. Conclusion Our data suggest that exosomes derived from PC patients may promote PC metastasis.
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Affiliation(s)
- Puxian Tang
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, People's Republic of China.,Department of Intensive Care Unit, Beijing Hospital, Beijing 100730, People's Republic of China
| | - Lianyuan Tao
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, People's Republic of China.,Department of Hepatobiliary Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, People's Republic of China
| | - Chunhui Yuan
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, People's Republic of China
| | - Lingfu Zhang
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, People's Republic of China
| | - Dianrong Xiu
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, People's Republic of China
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22
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Osther K, Förnvik K, Liljedahl E, Salford LG, Redebrandt HN. Upregulation of C1-inhibitor in pancreatic cancer. Oncotarget 2019; 10:5703-5712. [PMID: 31620245 PMCID: PMC6779287 DOI: 10.18632/oncotarget.27191] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 08/16/2019] [Indexed: 12/17/2022] Open
Abstract
Purpose The complement system has recently sparked more interest in cancer research. The classical pathway is initiated by activation of the C1 complex, which irreversibly can be bound to and inhibited by C1-INH. We have previously shown that C1-INH is upregulated in human glioblastoma (astrocytoma grade IV) on both gene and protein level. We here examine whether the complement system seems to play a role also in pancreatic cancer. Technique and results We performed an expression analysis of complement associated genes in 36 pancreatic ductal adenocarcinoma tumors and matching normal pancreatic tissue samples from pancreatic cancer patients (data from the publicly available database GSE15471). C1-INH was significantly upregulated in the pancreatic cancer tissue. None of the downstream components of the cascade were significantly upregulated in the cancer samples as compared to the control samples, which is the same pattern as we found in glioblastoma. GO analysis showed that membrane attack complex came up as the second most significantly associated cellular component. Analyzing gene expression of C1-INH in the pancreatic cancer cell lines from primary tumors versus metastatic tumor revealed no difference for the two mRNA transcripts (GSE59357). Interpretation Analysis of gene expression of complement related genes shows an upregulation of C1-INH and a downregulation of downstream components. This could suggest that C1-INH plays a role also in pancreatic cancer.
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Affiliation(s)
- Kurt Osther
- The Rausing Laboratory, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Karolina Förnvik
- The Rausing Laboratory, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden.,Department of Clinical Chemistry, Skåne University Hospital, Scania, Sweden
| | - Emma Liljedahl
- The Rausing Laboratory, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden.,Department of Neurosurgery, Skåne University Hospital, Scania, Sweden
| | - Leif G Salford
- The Rausing Laboratory, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden.,Department of Neurosurgery, Skåne University Hospital, Scania, Sweden
| | - Henrietta Nittby Redebrandt
- The Rausing Laboratory, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden.,Department of Neurosurgery, Skåne University Hospital, Scania, Sweden
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23
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Lee YS, Yeo IJ, Kim KC, Han SB, Hong JT. Inhibition of Lung Tumor Development in ApoE Knockout Mice via Enhancement of TREM-1 Dependent NK Cell Cytotoxicity. Front Immunol 2019; 10:1379. [PMID: 31275318 PMCID: PMC6592261 DOI: 10.3389/fimmu.2019.01379] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Accepted: 05/31/2019] [Indexed: 01/06/2023] Open
Abstract
Apolipoprotein E (ApoE) is known to regulate lipid homeostasis and associated with atherosclerogenesis. Eventhough atherosclerogenesis is associated with tumor development, the role of ApoE in lung tumorigenesis and metastasis is not clear. Thus, the tumor growth and metastasis were compared in WT and ApoE knockout (KO) mice. Urethane-induced lung tumor incidence and B16F10 lung metastasis in ApoE knockout (KO) mice were significantly reduced in comparison to that in WT mice. Knockdown of ApoE expression in lung cancer cells and B16F10 cells also decreased cancer cell growth and metastasis. The inhibitory effect of ApoE KO on tumor development and metastasis was associated with increase of infiltration of NK cells. NK cells derived from ApoE KO mice showed much greater cytotoxicity than those from WT mice. These cytotoxic effect of NK cells derived from ApoE KO mice was associated with higher expression of Granzyme B, Fas Ligand, IFN-γ, TNF-α, NKG2D, NKp46, and DNAM-1 expression. Triggering receptor expressed on myeloid cell (TREM)-1 is a proinflammatory mediator expressed on NK cells, and is known to be associated with NK cell cytotoxicity. Thus, we investigated the role of TREM-1 on ApoE KO mice originated NK cell mediated cytotoxicity for cancer cells. Blockade of TREM-1 expression with a TREM-1 antagonist prevented NK cell-mediated cytotoxicity. TREM-1 antibody recovered cytotoxic effect of NK cells derived from KO mice of T-bet, which upregulating gene for TREM-1. These data indicate that ApoE KO suppressed lung tumor development and metastasis via increase of TREM-1-dependent anti-tumor activity of NK cells.
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Affiliation(s)
- Yong Sun Lee
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, South Korea
| | - In Jun Yeo
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, South Korea
| | - Ki Cheon Kim
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, South Korea
| | - Sang-Bae Han
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, South Korea
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, South Korea
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24
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马 燕, 贺 龙, 武 倩, 马 运, 王 晓. [Detection of chitinase 3-like 1 combined with other biomarkers for diagnosis of pancreatic cancer]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2018; 38:450-454. [PMID: 29735446 PMCID: PMC6765668 DOI: 10.3969/j.issn.1673-4254.2018.04.13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Indexed: 06/08/2023]
Abstract
OBJECTIVE To assess the value of chitinase 3-like 1 (CHI3L1) alone or in combination with other biomarkers in the diagnosis of pancreatic cancer. METHODS Serum samples were collected from 70 patients with pancreatic cancer and 31 healthy subjects and the levels of CHI3L1, CA199, C3, C4, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) in serum were detected. RESULTS The serum samples from pancreatic cancer patients showed significantly higher CHI3L1, CA199, C3, C4, HDL-C, and LDL-C levels than those from healthy subjects (P<0.05). In patients with pancreatic cancer, serum CHI3L1 level was significantly correlated with the administration of anti-cancer therapy (P<0.05), but not with gender, age, metastasis or other clinicopathological parameters (P<0.05). ROC curve analysis showed that serum CHI3L1, CA199, C3, C4, HDL-C, and LDL-C all had diagnostic value for pancreatic cancer. Multivariate analysis suggested that the combined detection model of CHI3L1, CA199, C3, and HDL-C (AUC=0.964) had a greater diagnostic value than CA199 (AUC=0.896) alone and the combined detection model consisting of CA199, C3, and HDL-C (AUC=0.923; P<0.05). CONCLUSION Serum levels of CHI3L1, CA199, C3, C4, HDL-C, and LDL-C all have diagnostic value for pancreatic cancer, and the combined model consisting of CHI3L1, CA199, C3, and HDL-C have greater diagnostic efficacy than the other biomarkers either alone or in combination.
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Affiliation(s)
- 燕粉 马
- 西安交通大学 第一附属医院检验科，陕西 西安 710061Clinical Laboratory of First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - 龙梅 贺
- 西安交通大学 第一附属医院检验科，陕西 西安 710061Clinical Laboratory of First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
- 陕西省中医医院检验科，陕西 西安 710003Clinical Laboratory of Shanxi Traditional Chinese Medicine Hospital, Xi'an 710003, China
| | - 倩 武
- 西安交通大学 第一附属医院检验科，陕西 西安 710061Clinical Laboratory of First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - 运峰 马
- 西安交通大学 基础医学院，陕西 西安 710061School of Basic Medical Science, Xi'an Jiaotong University, Xi'an 710061, China
| | - 晓琴 王
- 西安交通大学 第一附属医院检验科，陕西 西安 710061Clinical Laboratory of First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
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25
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Song Y, Wang Q, Wang D, Junqiang Li, Yang J, Li H, Wang X, Jin X, Jing R, Yang JH, Su H. Label-Free Quantitative Proteomics Unravels Carboxypeptidases as the Novel Biomarker in Pancreatic Ductal Adenocarcinoma. Transl Oncol 2018; 11:691-699. [PMID: 29631213 PMCID: PMC6154863 DOI: 10.1016/j.tranon.2018.03.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 03/13/2018] [Accepted: 03/13/2018] [Indexed: 01/26/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a high mortality rate and poor prognosis. However, little is known concerning the molecular mechanism of PDAC at the proteomics level. Here we report a proteomics analysis of PDAC tumor and adjacent tissues by shotgun proteomics followed by label-free quantification, and in total, 3031 and 3306 proteins were identified in three pairs of PDAC tumor and adjacent tissues, respectively; 40 of them were differentially expressed for at least three-fold in PDAC tumor tissues. Ontological and interaction network analysis highlighted the dysregulation of a set of four proteins in the carboxypeptidase family: carboxypeptidase A1 (CPA1), A2 (CPA2), B1 (CPB1), and chymotrypsin C (CTRC). Western blotting confirmed the downregulation of the carboxypeptidase network in PDAC. Immunohistochemistry of tissue microarray from 90 PDAC patients demonstrated that CPB1 was downregulated 7.07-fold (P < .0001, n = 81) in tumor comparing with the peritumor tissue. Further 208 pancreatic tissues from PDAC tumor, peritumor, and pancreatis confirmed the downregulation of CPB1 in the PDAC patients. In summary, our results displayed that the expression of carboxypeptidase is significantly downregulated in PDAC tumor tissues and may be novel biomarker in the patient with PDAC.
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Affiliation(s)
- Yang Song
- Department of Oncology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Qing Wang
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Desheng Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Junqiang Li
- Department of Oncology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Jing Yang
- Department of Oncology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Hong Li
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Xiang Wang
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Xuerong Jin
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Ruirui Jing
- Cancer Research Center, Shandong University School of Medicine, Jinan, 250012, China
| | - Jing-Hua Yang
- Cancer Research Center, Shandong University School of Medicine, Jinan, 250012, China; Departments of Surgery and Urology, VA Boston Healthcare System, Boston University School of Medicine, Boston, 510660, MA, USA.
| | - Haichuan Su
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi, China.
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Bettac L, Denk S, Seufferlein T, Huber-Lang M. Complement in Pancreatic Disease-Perpetrator or Savior? Front Immunol 2017; 8:15. [PMID: 28144242 PMCID: PMC5239781 DOI: 10.3389/fimmu.2017.00015] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 01/05/2017] [Indexed: 12/13/2022] Open
Abstract
The complement system is a major pillar of the humoral innate immune system. As a first line of defense against pathogens, it mediates early inflammatory response and links different branches of humoral and cellular immunity. Disorders affecting the exocrine pancreas, such as acute pancreatitis, potentially lead to a life-threatening systemic inflammatory response with aberrant activation of complement and coagulation cascades. Pancreatic proteases can activate key effectors of the complement system, which in turn drive local and systemic inflammation. Beyond that, the extent of pancreas–complement interaction covers complex pro- and anti-inflammatory mechanisms, which to this day remain to be fully elucidated. This review provides a comprehensive overview of the pathophysiological role of complement in diseases of the exocrine pancreas, based on existing experimental and clinical data. Participation of complement in acute and chronic pancreatitis is addressed, as well as its role in tumor immunology. Therapeutic strategies targeting complement in these diseases have long been proposed but have not yet arrived in the clinical setting.
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Affiliation(s)
- Lucas Bettac
- Department of Internal Medicine I, University Hospital of Ulm , Ulm , Germany
| | - Stephanie Denk
- Department of Orthopedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm , Ulm , Germany
| | - Thomas Seufferlein
- Department of Internal Medicine I, University Hospital of Ulm , Ulm , Germany
| | - Markus Huber-Lang
- Department of Orthopedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm , Ulm , Germany
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27
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Gerdtsson AS, Wingren C, Persson H, Delfani P, Nordström M, Ren H, Wen X, Ringdahl U, Borrebaeck CAK, Hao J. Plasma protein profiling in a stage defined pancreatic cancer cohort - Implications for early diagnosis. Mol Oncol 2016; 10:1305-16. [PMID: 27522951 DOI: 10.1016/j.molonc.2016.07.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 07/01/2016] [Accepted: 07/04/2016] [Indexed: 12/30/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a disease where detection preceding clinical symptoms significantly increases the life expectancy of patients. In this study, a recombinant antibody microarray platform was used to analyze 213 Chinese plasma samples from PDAC patients and normal control (NC) individuals. The cohort was stratified according to disease stage, i.e. resectable disease (stage I/II), locally advanced (stage III) and metastatic disease (stage IV). Support vector machine analysis showed that all PDAC stages could be discriminated from controls and that the accuracy increased with disease progression, from stage I to IV. Patients with stage I/II PDAC could be discriminated from NC with high accuracy based on a plasma protein signature, indicating a possibility for early diagnosis and increased detection rate of surgically resectable tumors.
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Affiliation(s)
- Anna Sandström Gerdtsson
- Department of Immunotechnology, CREATE Health Translational Cancer Center, Medicon Village bldg. 406, Lund University, SE 223 81 Lund, Sweden.
| | - Christer Wingren
- Department of Immunotechnology, CREATE Health Translational Cancer Center, Medicon Village bldg. 406, Lund University, SE 223 81 Lund, Sweden.
| | - Helena Persson
- Department of Immunotechnology, CREATE Health Translational Cancer Center, Medicon Village bldg. 406, Lund University, SE 223 81 Lund, Sweden.
| | - Payam Delfani
- Department of Immunotechnology, CREATE Health Translational Cancer Center, Medicon Village bldg. 406, Lund University, SE 223 81 Lund, Sweden.
| | | | - He Ren
- Tianjin Medical University Cancer Institute & Hospital, Huan-Hu-Xi Road, Ti-Huan-Bei, He Xi District, Tianjin 300060, PR China.
| | - Xin Wen
- Tianjin Medical University Cancer Institute & Hospital, Huan-Hu-Xi Road, Ti-Huan-Bei, He Xi District, Tianjin 300060, PR China.
| | - Ulrika Ringdahl
- Department of Immunotechnology, CREATE Health Translational Cancer Center, Medicon Village bldg. 406, Lund University, SE 223 81 Lund, Sweden.
| | - Carl A K Borrebaeck
- Department of Immunotechnology, CREATE Health Translational Cancer Center, Medicon Village bldg. 406, Lund University, SE 223 81 Lund, Sweden.
| | - Jihui Hao
- Tianjin Medical University Cancer Institute & Hospital, Huan-Hu-Xi Road, Ti-Huan-Bei, He Xi District, Tianjin 300060, PR China.
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Luo J, Song J, Feng P, Wang Y, Long W, Liu M, Li L. Elevated serum apolipoprotein E is associated with metastasis and poor prognosis of non-small cell lung cancer. Tumour Biol 2016; 37:10715-21. [PMID: 26873483 DOI: 10.1007/s13277-016-4975-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 02/03/2016] [Indexed: 12/28/2022] Open
Abstract
Apolipoprotein E (ApoE) is a factor involved in Alzheimer's disease, which recently attracted great attention as an important protein related to tumorigenesis and metastasis. However, serum ApoE levels and its diagnosis and prognosis value in non-small cell lung cancer (NSCLC) patients are still unknown. In 196 NSCLC patients and 203 healthy controls, serum ApoE was measured by turbidimetric immunoassay. The associations of serum ApoE levels with the clinicopathological characteristics and clinical outcomes of NSCLC patients were analyzed. Serum ApoE levels were obviously elevated in NSCLC patients compared with healthy controls (41.6 ± 11.63 vs. 33.8 ± 6.24 mg/L) and were associated with TNM stage, lymph node metastasis status, and distant metastasis status (all P < 0.0001). For NSCLC diagnosis, the area under the receiver operating characteristic (ROC) curve was 0.71 at a specificity of 0.90 and sensitivity of 0.47. For lymph node metastasis predicting, the area under the ROC curve was 0.68 at a specificity of 0.56 and sensitivity of 0.73. From ROC/area under curve (AUC) analysis, we used 41.25 mg/L as the serum ApoE cut-off value, to divide NSCLC patients into two groups, the median survival was 11.0 weeks (95 % CI = 8.7 to 13.3) for patients in high serum ApoE group and 20.0 weeks (95 % CI = 15.0 to 25.0) in low serum ApoE group. Serum ApoE levels elevated in NSCLC patients, which also associated with TNM stages, lymph node metastasis, distant metastasis, and poor prognosis, suggest that serum ApoE may act as a useful clinical serological biomarkers for evaluating the progress of NSCLC.
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Affiliation(s)
- Jinmei Luo
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road, Guangzhou, 510080, People's Republic of China.,Department of Medical Intensive Care Unit, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, People's Republic of China
| | - Junli Song
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road, Guangzhou, 510080, People's Republic of China.,Reproductive Medicine Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Pinning Feng
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road, Guangzhou, 510080, People's Republic of China
| | - Yanhong Wang
- Department of Medical Intensive Care Unit, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, People's Republic of China
| | - Weiqing Long
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road, Guangzhou, 510080, People's Republic of China
| | - Min Liu
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road, Guangzhou, 510080, People's Republic of China.
| | - Laisheng Li
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road, Guangzhou, 510080, People's Republic of China.
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Bagante F, Tran TB, Postlewait LM, Maithel SK, Wang TS, Evans DB, Hatzaras I, Shenoy R, Phay JE, Keplinger K, Fields RC, Jin LX, Weber SM, Salem A, Sicklick JK, Gad S, Yopp AC, Mansour JC, Duh QY, Seiser N, Solorzano CC, Kiernan CM, Votanopoulos KI, Levine EA, Poultsides GA, Pawlik TM. Neutrophil-lymphocyte and platelet-lymphocyte ratio as predictors of disease specific survival after resection of adrenocortical carcinoma. J Surg Oncol 2015; 112:164-72. [PMID: 26234285 DOI: 10.1002/jso.23982] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 07/01/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND The systemic inflammatory response may be associated with tumor progression. We sought to analyze the impact of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) on recurrence-free survival (RFS) and disease-specific survival (DSS) among patients who underwent surgery for adrenocortical carcinoma (ACC). METHODS Patients undergoing surgery for ACC were identified from a multi-center database. Cut-off values of 5 and 190 were defined as elevated NLR and PLR, respectively, and long-term outcome was assessed. RESULTS Among 84 patients with ACC, 29 (34.%) had NLR > 5 while 32 (40.5%) had PLR > 190. NLR and PLR were associated with larger tumors (NLR > 5: ≤ 5 cm, 0% vs. >5 cm, 39.7%; PLR > 190: ≤ 5cm, 0% vs. >5 cm, 45.7%), as well as need to resect of other organs (NLR > 5: other organ resected 48.8% vs. not resected 20.9%; PLR > 190: other organ resected 25.0% vs. not resected 56.4%)(all P < 0.05). Five-year RFS was associated with an elevated NLR (NLR ≤ 5, 14.2% vs. NLR> 5, 10.5%) and PLR (PLR ≤ 190: 19.4% vs. PLR > 190: 5.2%) (both P < 0.05). On multivariate survival analyses, PLR remained a predictor of RFS (HR 1.72), while NLR was associated with both DSS (HR 2.21) and RFS (HR 1.99) (both P < 0.05). CONCLUSIONS Immune markers such as NLR and PLR may be useful to stratify patients with regards to prognosis following surgery for ACC.
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Affiliation(s)
- Fabio Bagante
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Thuy B Tran
- Department of Surgery, Stanford University School of Medicine, Stanford, California
| | | | | | - Tracy S Wang
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Douglas B Evans
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ioannis Hatzaras
- Department of Surgery, New York University School of Medicine, New York, New York
| | - Rivfka Shenoy
- Department of Surgery, New York University School of Medicine, New York, New York
| | - John E Phay
- Department of Surgery, The Ohio State University, Columbus, Ohio
| | - Kara Keplinger
- Department of Surgery, The Ohio State University, Columbus, Ohio
| | - Ryan C Fields
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Linda X Jin
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Sharon M Weber
- Department of General Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Ahmed Salem
- Department of General Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Jason K Sicklick
- Department of Surgery, University of California San Diego, San Diego, California
| | - Shady Gad
- Department of Surgery, University of California San Diego, San Diego, California
| | - Adam C Yopp
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - John C Mansour
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Quan-Yang Duh
- Department of Surgery, University of California San Francisco, San Francisco, California
| | - Natalie Seiser
- Department of Surgery, University of California San Francisco, San Francisco, California
| | | | | | | | - Edward A Levine
- Department of Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - George A Poultsides
- Department of Surgery, Stanford University School of Medicine, Stanford, California
| | - Timothy M Pawlik
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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30
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Evasion and interactions of the humoral innate immune response in pathogen invasion, autoimmune disease, and cancer. Clin Immunol 2015; 160:244-54. [PMID: 26145788 DOI: 10.1016/j.clim.2015.06.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 06/22/2015] [Accepted: 06/26/2015] [Indexed: 02/07/2023]
Abstract
The humoral innate immune system is composed of three major branches, complement, coagulation, and natural antibodies. To persist in the host, pathogens, such as bacteria, viruses, and cancers must evade parts of the innate humoral immune system. Disruptions in the humoral innate immune system also play a role in the development of autoimmune diseases. This review will examine how Gram positive bacteria, viruses, cancer, and the autoimmune conditions systemic lupus erythematosus and anti-phospholipid syndrome, interact with these immune system components. Through examining evasion techniques it becomes clear that an interplay between these three systems exists. By exploring the interplay and the evasion/disruption of the humoral innate immune system, we can develop a better understanding of pathogenic infections, cancer, and autoimmune disease development.
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Jenkinson C, Earl J, Ghaneh P, Halloran C, Carrato A, Greenhalf W, Neoptolemos J, Costello E. Biomarkers for early diagnosis of pancreatic cancer. Expert Rev Gastroenterol Hepatol 2015; 9:305-15. [PMID: 25373768 DOI: 10.1586/17474124.2015.965145] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma is an aggressive malignancy with a 5-year survival rate of approximately 5%. The lack of established strategies for early detection contributes to this poor prognosis. Although several novel candidate biomarkers have been proposed for earlier diagnosis, none have been adopted into routine clinical use. In this review, the authors examine the challenges associated with finding new pancreatic cancer diagnostic biomarkers and explore why translation of biomarker research for patient benefit has thus far failed. The authors also review recent progress and highlight advances in the understanding of the biology of pancreatic cancer that may lead to improvements in biomarker detection and implementation.
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Affiliation(s)
- Claire Jenkinson
- Department of Molecular and Clinical Cancer Medicine, National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK
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32
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Liu Z, Gao Y, Hao F, Lou X, Zhang X, Li Y, Wu D, Xiao T, Yang L, Li Q, Qiu X, Wang E. Secretomes are a potential source of molecular targets for cancer therapies and indicate that APOE is a candidate biomarker for lung adenocarcinoma metastasis. Mol Biol Rep 2014; 41:7507-23. [PMID: 25098600 DOI: 10.1007/s11033-014-3641-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Accepted: 07/23/2014] [Indexed: 12/20/2022]
Abstract
Identifying patients at high risk of metastasis is a major challenge in lung adenocarcinoma (ADC) therapy, therefore discovery of noninvasive biomarkers and therapeutic targets is urgent. We found significant differences between the secretomes of differentially expressed proteins in lung ADC cell lines, clinical tissue samples and serum plasma samples with high and low metastatic potential. In particular, Apolipoprotein E (APOE) levels were three-times greater in cells with lymph node metastases (LNM) than those without. Our study indicates that APOE is a potential indicator of metastatic lung ADC and that secretomes may offer a valuable resource for biomarkers of lung ADC with LNM.
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Affiliation(s)
- Zan Liu
- Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, 110001, China
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33
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Nolen BM, Brand RE, Prosser D, Velikokhatnaya L, Allen PJ, Zeh HJ, Grizzle WE, Lomakin A, Lokshin AE. Prediagnostic serum biomarkers as early detection tools for pancreatic cancer in a large prospective cohort study. PLoS One 2014; 9:e94928. [PMID: 24747429 PMCID: PMC3991628 DOI: 10.1371/journal.pone.0094928] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 03/21/2014] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The clinical management of pancreatic cancer is severely hampered by the absence of effective screening tools. METHODS Sixty-seven biomarkers were evaluated in prediagnostic sera obtained from cases of pancreatic cancer enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). RESULTS The panel of CA 19-9, OPN, and OPG, identified in a prior retrospective study, was not effective. CA 19-9, CEA, NSE, bHCG, CEACAM1 and PRL were significantly altered in sera obtained from cases greater than 1 year prior to diagnosis. Levels of CA 19-9, CA 125, CEA, PRL, and IL-8 were negatively associated with time to diagnosis. A training/validation study using alternate halves of the PLCO set failed to identify a biomarker panel with significantly improved performance over CA 19-9 alone. When the entire PLCO set was used for training at a specificity (SP) of 95%, a panel of CA 19-9, CEA, and Cyfra 21-1 provided significantly elevated sensitivity (SN) levels of 32.4% and 29.7% in samples collected <1 and >1 year prior to diagnosis, respectively, compared to SN levels of 25.7% and 17.2% for CA 19-9 alone. CONCLUSIONS Most biomarkers identified in previously conducted case/control studies are ineffective in prediagnostic samples, however several biomarkers were identified as significantly altered up to 35 months prior to diagnosis. Two newly derived biomarker combinations offered advantage over CA 19-9 alone in terms of SN, particularly in samples collected >1 year prior to diagnosis. However, the efficacy of biomarker-based tools remains limited at present. Several biomarkers demonstrated significant velocity related to time to diagnosis, an observation which may offer considerable potential for enhancements in early detection.
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Affiliation(s)
- Brian M. Nolen
- University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America
| | - Randall E. Brand
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America
| | - Denise Prosser
- University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America
| | - Liudmila Velikokhatnaya
- University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America
| | - Peter J. Allen
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Herbert J. Zeh
- University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - William E. Grizzle
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Aleksey Lomakin
- Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
| | - Anna E. Lokshin
- University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America
- Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Department of Ob/Gyn, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
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Ansari D, Aronsson L, Sasor A, Welinder C, Rezeli M, Marko-Varga G, Andersson R. The role of quantitative mass spectrometry in the discovery of pancreatic cancer biomarkers for translational science. J Transl Med 2014; 12:87. [PMID: 24708694 PMCID: PMC3998064 DOI: 10.1186/1479-5876-12-87] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 03/13/2014] [Indexed: 02/06/2023] Open
Abstract
In the post-genomic era, it has become evident that genetic changes alone are not sufficient to understand most disease processes including pancreatic cancer. Genome sequencing has revealed a complex set of genetic alterations in pancreatic cancer such as point mutations, chromosomal losses, gene amplifications and telomere shortening that drive cancerous growth through specific signaling pathways. Proteome-based approaches are important complements to genomic data and provide crucial information of the target driver molecules and their post-translational modifications. By applying quantitative mass spectrometry, this is an alternative way to identify biomarkers for early diagnosis and personalized medicine. We review the current quantitative mass spectrometric technologies and analyses that have been developed and applied in the last decade in the context of pancreatic cancer. Examples of candidate biomarkers that have been identified from these pancreas studies include among others, asporin, CD9, CXC chemokine ligand 7, fibronectin 1, galectin-1, gelsolin, intercellular adhesion molecule 1, insulin-like growth factor binding protein 2, metalloproteinase inhibitor 1, stromal cell derived factor 4, and transforming growth factor beta-induced protein. Many of these proteins are involved in various steps in pancreatic tumor progression including cell proliferation, adhesion, migration, invasion, metastasis, immune response and angiogenesis. These new protein candidates may provide essential information for the development of protein diagnostics and targeted therapies. We further argue that new strategies must be advanced and established for the integration of proteomic, transcriptomic and genomic data, in order to enhance biomarker translation. Large scale studies with meta data processing will pave the way for novel and unexpected correlations within pancreatic cancer, that will benefit the patient, with targeted treatment.
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Affiliation(s)
- Daniel Ansari
- Department of Surgery, Clinical Sciences Lund, Lund University, and Skåne University Hospital, SE-221 85 Lund, Sweden
| | - Linus Aronsson
- Department of Surgery, Clinical Sciences Lund, Lund University, and Skåne University Hospital, SE-221 85 Lund, Sweden
| | - Agata Sasor
- Department of Pathology, Clinical Sciences Lund, Lund University, and Skåne University Hospital, Lund, Sweden
| | - Charlotte Welinder
- Department of Oncology, Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Melinda Rezeli
- Clinical Protein Science & Imaging, Biomedical Center, Department of Measurement Technology and Industrial Electrical Engineering, Lund University, Lund, Sweden
| | - György Marko-Varga
- Clinical Protein Science & Imaging, Biomedical Center, Department of Measurement Technology and Industrial Electrical Engineering, Lund University, Lund, Sweden
| | - Roland Andersson
- Department of Surgery, Clinical Sciences Lund, Lund University, and Skåne University Hospital, SE-221 85 Lund, Sweden
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