|
1
|
Zhou Y, Ma W, Hu H, He Q, Yu C, Chen W, Yu G. Angiogenesis related gene signatures predict prognosis and guide therapeutic strategies in renal clear cell carcinoma. Sci Rep 2025; 15:17030. [PMID: 40379825 PMCID: PMC12084375 DOI: 10.1038/s41598-025-02134-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 05/12/2025] [Indexed: 05/19/2025] Open
Abstract
Kidney tumors are hypervascular tumors with crucial antiangiogenic effects in tumor therapy. This study aimed to develop a predictive model for kidney renal clear cell carcinoma (KIRC) by utilizing angiogenesis-related genes to formulate targeted therapy and immunotherapy strategies. Angiogenesis-related genes were screened via the GeneCard and Molecular Signatures Database (MSigDB). The KIRC data downloaded from The Cancer Genome Atlas (TCGA) were randomly divided into an experimental cohort and a validation cohort. In the experimental cohort, a risk score prediction model was constructed through successive analyses via univariate Cox regression, LASSO regression, and multivariate Cox regression. Receiver operating characteristic (ROC) curves were employed to assess the sensitivity of the model's predictions. The model's stability and generalizability were subsequently validated in both the validation cohort and the E-MTAB-1980 cohort. Subsequently, the TCGA-KIRC dataset was stratified into two distinct groups: a localized tumor cohort and a progression/metastasis cohort, based on tumor staging criteria. The efficacy of the prognostic prediction model was evaluated within each subgroup. A nomogram model was developed in conjunction with each independent prognostic factor to accurately predict patient outcomes. Additionally, single-cell and intercellular communication analyses were conducted via KIRC single-cell data obtained from the Gene Expression Omnibus (GEO) database. The effects of immunotherapy and targeted therapy on patients were predicted via prognostic modeling. A total of 260 angiogenesis-related genes were identified through screening in the GeneCards and Molecular Signatures Database(MSigDB). We subsequently developed a risk model comprising five genes: MEOX2, PLG, PROX1, TEK, and TIMP1. Survival analysis indicated that the prognosis for high-risk patients was significantly poorer than that for low-risk patients (P < 0.001), and the model demonstrated satisfactory accuracy in predicting 1-, 3-, and 5-year survival rates. This finding was further validated in both internal and external validation cohorts. The model demonstrated applicability for prognostic predictions in both the localized tumor cohort and the progression/metastasis cohort, with proficiency in forecasting the prognosis of patients diagnosed with metastatic renal cancer. The AUC values for 1, 3, and 5 years were recorded at 0.691, 0.709, and 0.773, respectively. We successfully constructed a nomogram model to facilitate accurate prognostic predictions for patients. Analysis of single-cell data revealed that PLG was expressed predominantly in tumor cell clusters, whereas TEK was highly expressed primarily in pericytes. TIMP1 was found to be highly expressed in vascular smooth muscle cells. In contrast, MEOX2 and PROX1 were highly expressed in specific cell clusters but presented low expression levels across the overall cell population. Cell communication analysis indicated that the modeling gene TEK was involved in the angiogenic pathway, with the interaction between the ligand ANGPT2 and the receptor ITGA5-ITGB1 being particularly prominent in this study. Furthermore, the immune dysfunction and rejection scores for high-risk patients within the non-localized renal cancer cohort were markedly elevated compared to those observed in the low-risk group. In terms of targeted pharmacological intervention, individuals classified in the low-risk group exhibited a heightened sensitivity to sorafenib. The KIRC prognostic prediction model, which is based on five angiogenesis-related genes, demonstrated reliable performance, indicating that high-risk patients have a significantly poorer prognosis than low-risk patients do. The developed nomogram model effectively visualizes and accurately predicts patient prognosis. It is essential to highlight that individuals diagnosed with low-risk metastatic KIRC may experience greater advantages from the administration of immunotherapy and sorafenib.
Collapse
Affiliation(s)
- Yuhe Zhou
- Department of Urology, Jinshan Branch of the Sixth People's Hospital of Shanghai, 147 Jiankang Road, Jinshan District, Shanghai, China
| | - Weixiong Ma
- Department of Urology, Jinshan Branch of the Sixth People's Hospital of Shanghai, 147 Jiankang Road, Jinshan District, Shanghai, China.
| | - Hengda Hu
- Department of Urology, Jinshan Branch of the Sixth People's Hospital of Shanghai, 147 Jiankang Road, Jinshan District, Shanghai, China
| | - Qirui He
- Department of Urology, Jinshan Branch of the Sixth People's Hospital of Shanghai, 147 Jiankang Road, Jinshan District, Shanghai, China
| | - Chengshuai Yu
- Department of Urology, Jinshan Branch of the Sixth People's Hospital of Shanghai, 147 Jiankang Road, Jinshan District, Shanghai, China
| | - Wenpu Chen
- Department of Urology, Jinshan Branch of the Sixth People's Hospital of Shanghai, 147 Jiankang Road, Jinshan District, Shanghai, China
| | - Guofeng Yu
- Department of Urology, Jinshan Branch of the Sixth People's Hospital of Shanghai, 147 Jiankang Road, Jinshan District, Shanghai, China
| |
Collapse
|
|
2
|
Tian Y, Liu X, Wang J, Zhang C, Yang W. Antitumor Effects and the Potential Mechanism of 10-HDA against SU-DHL-2 Cells. Pharmaceuticals (Basel) 2024; 17:1088. [PMID: 39204193 PMCID: PMC11357620 DOI: 10.3390/ph17081088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/13/2024] [Accepted: 08/16/2024] [Indexed: 09/03/2024] Open
Abstract
10-hydroxy-2-decenoic acid (10-HDA), which is a unique bioactive fatty acid of royal jelly synthesized by nurse bees for larvae and adult queen bees, is recognized for its dual utility in medicinal and nutritional applications. Previous research has indicated that 10-HDA exerts antitumor effects on numerous tumor cell lines, including colon cancer cells, A549 human lung cancer cells, and human hepatoma cells. The present study extends this inquiry to lymphoma, specifically evaluating the impact of 10-HDA on the SU-DHL-2 cell line. Our findings revealed dose-dependent suppression of SU-DHL-2 cell survival, with an IC50 of 496.8 μg/mL at a density of 3 × 106 cells/well after 24 h. For normal liver LO2 cells and human fibroblasts (HSFs), the IC50 values were approximately 1000 μg/mL and over 1000 μg/mL, respectively. The results of label-free proteomics revealed 147 upregulated and 347 downregulated differentially expressed proteins that were significantly enriched in the complement and coagulation cascades pathway (adjusted p-value = 0.012), including the differentially expressed proteins prothrombin, plasminogen, plasminogen, carboxypeptidase B2, fibrinogen beta chain, fibrinogen gamma chain, and coagulation factor V. The top three hub proteins, ribosomal protein L5, tumor protein p53, and ribosomal protein L24, were identified via protein-protein interaction (PPI) analysis. This result showed that the complement and coagulation cascade pathways might play a key role in the antitumor process of 10-HDA, suggesting a potential therapeutic avenue for lymphoma treatment. However, the specificity of the effect of 10-HDA on SU-DHL-2 cells warrants further investigation.
Collapse
Affiliation(s)
- Yuanyuan Tian
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (Y.T.); (X.L.); (J.W.); (C.Z.)
- College of JunCao Science and Ecology (College of Carbon Neutrality), Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Xiaoqing Liu
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (Y.T.); (X.L.); (J.W.); (C.Z.)
| | - Jie Wang
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (Y.T.); (X.L.); (J.W.); (C.Z.)
| | - Chuang Zhang
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (Y.T.); (X.L.); (J.W.); (C.Z.)
| | - Wenchao Yang
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (Y.T.); (X.L.); (J.W.); (C.Z.)
| |
Collapse
|
|
3
|
Wills CA, Liu X, Chen L, Zhao Y, Liu Z, Spiegelman VS, Sundstrom J, Wang HG. Chemotherapy-induced small extracellular vesicles prime the pre-metastatic niche to accelerate neuroblastoma metastasis. Genes Dis 2024; 11:101017. [PMID: 38495925 PMCID: PMC10940767 DOI: 10.1016/j.gendis.2023.05.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/11/2023] [Accepted: 05/12/2023] [Indexed: 03/19/2024] Open
Affiliation(s)
- Carson A. Wills
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, The Pennsylvania State University College of Medicine, PA 17033, USA
| | - Xiaoming Liu
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, The Pennsylvania State University College of Medicine, PA 17033, USA
| | - Longgui Chen
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, The Pennsylvania State University College of Medicine, PA 17033, USA
| | - Yuanjun Zhao
- Department of Ophthalmology, The Pennsylvania State University College of Medicine, PA 17033, USA
| | - Zhenqiu Liu
- Department of Public Health Sciences, The Pennsylvania State University College of Medicine, PA 17033, USA
| | - Vladimir S. Spiegelman
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, The Pennsylvania State University College of Medicine, PA 17033, USA
| | - Jeffrey Sundstrom
- Department of Ophthalmology, The Pennsylvania State University College of Medicine, PA 17033, USA
| | - Hong-Gang Wang
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, The Pennsylvania State University College of Medicine, PA 17033, USA
| |
Collapse
|
|
4
|
Desai TA, Hedman ÅK, Dimitriou M, Koprulu M, Figiel S, Yin W, Johansson M, Watts EL, Atkins JR, Sokolov AV, Schiöth HB, Gunter MJ, Tsilidis KK, Martin RM, Pietzner M, Langenberg C, Mills IG, Lamb AD, Mälarstig A, Key TJ, Travis RC, Smith-Byrne K. Identifying proteomic risk factors for overall, aggressive, and early onset prostate cancer using Mendelian Randomisation and tumour spatial transcriptomics. EBioMedicine 2024; 105:105168. [PMID: 38878676 PMCID: PMC11233900 DOI: 10.1016/j.ebiom.2024.105168] [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: 10/16/2023] [Revised: 05/09/2024] [Accepted: 05/10/2024] [Indexed: 06/25/2024] Open
Abstract
BACKGROUND Understanding the role of circulating proteins in prostate cancer risk can reveal key biological pathways and identify novel targets for cancer prevention. METHODS We investigated the association of 2002 genetically predicted circulating protein levels with risk of prostate cancer overall, and of aggressive and early onset disease, using cis-pQTL Mendelian randomisation (MR) and colocalisation. Findings for proteins with support from both MR, after correction for multiple-testing, and colocalisation were replicated using two independent cancer GWAS, one of European and one of African ancestry. Proteins with evidence of prostate-specific tissue expression were additionally investigated using spatial transcriptomic data in prostate tumour tissue to assess their role in tumour aggressiveness. Finally, we mapped risk proteins to drug and ongoing clinical trials targets. FINDINGS We identified 20 proteins genetically linked to prostate cancer risk (14 for overall [8 specific], 7 for aggressive [3 specific], and 8 for early onset disease [2 specific]), of which the majority replicated where data were available. Among these were proteins associated with aggressive disease, such as PPA2 [Odds Ratio (OR) per 1 SD increment = 2.13, 95% CI: 1.54-2.93], PYY [OR = 1.87, 95% CI: 1.43-2.44] and PRSS3 [OR = 0.80, 95% CI: 0.73-0.89], and those associated with early onset disease, including EHPB1 [OR = 2.89, 95% CI: 1.99-4.21], POGLUT3 [OR = 0.76, 95% CI: 0.67-0.86] and TPM3 [OR = 0.47, 95% CI: 0.34-0.64]. We confirmed an inverse association of MSMB with prostate cancer overall [OR = 0.81, 95% CI: 0.80-0.82], and also found an inverse association with both aggressive [OR = 0.84, 95% CI: 0.82-0.86] and early onset disease [OR = 0.71, 95% CI: 0.68-0.74]. Using spatial transcriptomics data, we identified MSMB as the genome-wide top-most predictive gene to distinguish benign regions from high grade cancer regions that comparatively had five-fold lower MSMB expression. Additionally, ten proteins that were associated with prostate cancer risk also mapped to existing therapeutic interventions. INTERPRETATION Our findings emphasise the importance of proteomics for improving our understanding of prostate cancer aetiology and of opportunities for novel therapeutic interventions. Additionally, we demonstrate the added benefit of in-depth functional analyses to triangulate the role of risk proteins in the clinical aggressiveness of prostate tumours. Using these integrated methods, we identify a subset of risk proteins associated with aggressive and early onset disease as priorities for investigation for the future prevention and treatment of prostate cancer. FUNDING This work was supported by Cancer Research UK (grant no. C8221/A29017).
Collapse
Affiliation(s)
- Trishna A Desai
- Cancer Epidemiology Unit, Oxford Population Health, University of Oxford, Oxford, United Kingdom.
| | - Åsa K Hedman
- External Science and Innovation, Pfizer Worldwide Research, Development and Medical, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Marios Dimitriou
- External Science and Innovation, Pfizer Worldwide Research, Development and Medical, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Mine Koprulu
- MRC Epidemiology Unit, University of Cambridge, United Kingdom
| | - Sandy Figiel
- University of Oxford, Nuffield Department of Surgical Sciences, Oxford, United Kingdom
| | - Wencheng Yin
- University of Oxford, Nuffield Department of Surgical Sciences, Oxford, United Kingdom
| | - Mattias Johansson
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Eleanor L Watts
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Joshua R Atkins
- Cancer Epidemiology Unit, Oxford Population Health, University of Oxford, Oxford, United Kingdom
| | - Aleksandr V Sokolov
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience Uppsala University, 75124, Uppsala, Sweden
| | - Helgi B Schiöth
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience Uppsala University, 75124, Uppsala, Sweden
| | - Marc J Gunter
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, United Kingdom
| | - Konstantinos K Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, United Kingdom; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Richard M Martin
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; NIHR Bristol Biomedical Research Centre, Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, United Kingdom
| | - Maik Pietzner
- MRC Epidemiology Unit, University of Cambridge, United Kingdom; Computational Medicine, Berlin Institute of HealthHealth (BIH) at Charité - Univeritätsmedizin- Universitätsmedizin Berlin, Berlin, Germany; Precision Healthcare University Research Institute, Queen Mary University of London, London, United Kingdom
| | - Claudia Langenberg
- MRC Epidemiology Unit, University of Cambridge, United Kingdom; Computational Medicine, Berlin Institute of HealthHealth (BIH) at Charité - Univeritätsmedizin- Universitätsmedizin Berlin, Berlin, Germany; Precision Healthcare University Research Institute, Queen Mary University of London, London, United Kingdom
| | - Ian G Mills
- University of Oxford, Nuffield Department of Surgical Sciences, Oxford, United Kingdom
| | - Alastair D Lamb
- University of Oxford, Nuffield Department of Surgical Sciences, Oxford, United Kingdom
| | - Anders Mälarstig
- External Science and Innovation, Pfizer Worldwide Research, Development and Medical, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Tim J Key
- Cancer Epidemiology Unit, Oxford Population Health, University of Oxford, Oxford, United Kingdom
| | - Ruth C Travis
- Cancer Epidemiology Unit, Oxford Population Health, University of Oxford, Oxford, United Kingdom
| | - Karl Smith-Byrne
- Cancer Epidemiology Unit, Oxford Population Health, University of Oxford, Oxford, United Kingdom
| |
Collapse
|
|
5
|
Hurtado MD, Tama E, D'Andre S, Shufelt CL. The relation between excess adiposity and breast cancer in women: Clinical implications and management. Crit Rev Oncol Hematol 2024; 193:104213. [PMID: 38008197 PMCID: PMC10843740 DOI: 10.1016/j.critrevonc.2023.104213] [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: 09/07/2023] [Accepted: 11/16/2023] [Indexed: 11/28/2023] Open
Abstract
BACKGROUND Breast cancer (BC) is the most common cancer in women. While the combination of improved screening, earlier detection, and advances in therapeutics has resulted in lower BC mortality, BC survivors are now increasingly dying of cardiovascular disease. Cardiovascular disease in the leading cause of non-cancer related mortality among BC survivors. This situation underscores the critical need to research the role of modifiable cardiometabolic risk factors, such as excess adiposity, that will affect BC remission, long-term survivorship, and overall health and quality of life. PURPOSE First, this review summarizes the evidence on the connection between adipose tissue and BC. Then we review the data on weight trends after BC diagnosis with a focus on the effect of weight gain on BC recurrence and BC- and non-BC-related death. Finally, we provide a guide for weight management in BC survivors, considering the available data on the effect of weight loss interventions on BC.
Collapse
Affiliation(s)
- Maria D Hurtado
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Jacksonville, FL, USA; Precision Medicine for Obesity Program, Mayo Clinic, Rochester, MN, USA.
| | - Elif Tama
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Jacksonville, FL, USA; Precision Medicine for Obesity Program, Mayo Clinic, Rochester, MN, USA
| | - Stacey D'Andre
- Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Chrisandra L Shufelt
- Center for Women's Health, Division of General Internal Medicine, Jacksonville, FL, USA
| |
Collapse
|
|
6
|
Bharadwaj AG, McLean ME, Dahn ML, Cahill HF, Wasson MD, Arun RP, Walker OL, Cruickshank BM, Fernando W, Venkatesh J, Barnes PJ, Bethune G, Knapp G, Helyer LK, Giacomantonio CA, Waisman DM, Marcato P. ALDH1A3 promotes invasion and metastasis in triple-negative breast cancer by regulating the plasminogen activation pathway. Mol Oncol 2024; 18:91-112. [PMID: 37753740 PMCID: PMC10766202 DOI: 10.1002/1878-0261.13528] [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: 04/20/2023] [Revised: 08/28/2023] [Accepted: 09/25/2023] [Indexed: 09/28/2023] Open
Abstract
Aldehyde dehydrogenase 1A3 (ALDH1A3) is a cancer stem cell marker that promotes metastasis. Triple-negative breast cancer (TNBC) progression has been linked to ALDH1A3-induced gene expression changes. To investigate the mechanism of ALDH1A3-mediated breast cancer metastasis, we assessed the effect of ALDH1A3 on the expression of proteases and the regulators of proteases that degrade the extracellular matrix, a process that is essential for invasion and metastasis. This revealed that ALDH1A3 regulates the plasminogen activation pathway; it increased the levels and activity of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA). This resulted in a corresponding increase in the activity of serine protease plasmin, the enzymatic product of tPA and uPA. The ALDH1A3 product all-trans-retinoic acid similarly increased tPA and plasmin activity. The increased invasion of TNBC cells by ALDH1A3 was plasminogen-dependent. In patient tumours, ALDH1A3 and tPA are co-expressed and their combined expression correlated with the TNBC subtype, high tumour grade and recurrent metastatic disease. Knockdown of tPA in TNBC cells inhibited plasmin generation and lymph node metastasis. These results identify the ALDH1A3-tPA-plasmin axis as a key contributor to breast cancer progression.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Gregory Knapp
- Department of SurgeryDalhousie UniversityHalifaxCanada
| | | | - Carman A. Giacomantonio
- Department of PathologyDalhousie UniversityHalifaxCanada
- Department of SurgeryDalhousie UniversityHalifaxCanada
| | - David M. Waisman
- Department of PathologyDalhousie UniversityHalifaxCanada
- Department of Biochemistry and Molecular BiologyDalhousie UniversityHalifaxCanada
| | - Paola Marcato
- Department of PathologyDalhousie UniversityHalifaxCanada
- Department of Microbiology and ImmunologyDalhousie UniversityHalifaxCanada
- Nova Scotia Health AuthorityHalifaxCanada
| |
Collapse
|
|
7
|
Rosenfeld MA, Yurina LV, Gavrilina ES, Vasilyeva AD. Post-Translational Oxidative Modifications of Hemostasis Proteins: Structure, Function, and Regulation. BIOCHEMISTRY. BIOKHIMIIA 2024; 89:S14-S33. [PMID: 38621742 DOI: 10.1134/s0006297924140025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 04/17/2024]
Abstract
Reactive oxygen species (ROS) are constantly generated in a living organism. An imbalance between the amount of generated reactive species in the body and their destruction leads to the development of oxidative stress. Proteins are extremely vulnerable targets for ROS molecules, which can cause oxidative modifications of amino acid residues, thus altering structure and function of intra- and extracellular proteins. The current review considers the effect of oxidation on the structural rearrangements and functional activity of hemostasis proteins: coagulation system proteins such as fibrinogen, prothrombin/thrombin, factor VII/VIIa; anticoagulant proteins - thrombomodulin and protein C; proteins of the fibrinolytic system such as plasminogen, tissue plasminogen activator and plasminogen activator inhibitor-1. Structure and function of the proteins, oxidative modifications, and their detrimental consequences resulting from the induced oxidation or oxidative stress in vivo are described. Possible effects of oxidative modifications of proteins in vitro and in vivo leading to disruption of the coagulation and fibrinolysis processes are summarized and systematized, and the possibility of a compensatory mechanism in maintaining hemostasis under oxidative stress is analyzed.
Collapse
Affiliation(s)
- Mark A Rosenfeld
- Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, 119334, Russia.
| | - Lyubov V Yurina
- Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, 119334, Russia
| | - Elizaveta S Gavrilina
- Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, 119334, Russia
| | - Alexandra D Vasilyeva
- Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, 119334, Russia
| |
Collapse
|
|
8
|
Jiang Y, Wang Y, Wang Z, Zhang Y, Hou Y, Wang X. Anoikis-related genes signature development for clear cell renal cell carcinoma prognosis and tumor microenvironment. Sci Rep 2023; 13:18909. [PMID: 37919386 PMCID: PMC10622575 DOI: 10.1038/s41598-023-46398-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 10/31/2023] [Indexed: 11/04/2023] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is one of the most common primary malignancies of the urinary tract, highly heterogeneous, and increasing in incidence worldwide. Anoikis is a specific type of programmed cell death in which solid tumor cells or normal epithelial cells that do not have metastatic properties lose adhesion to the extracellular matrix or undergo inappropriate cell adhesion-induced apoptosis. Anoikis is thought to play a critical role in tumorigenesis, maintenance, and treatment, according to an increasing amount of research. However, there is still some uncertainty regarding the general impact of anoikis-related genes (ARGs) on the prognostic importance, tumor microenvironment characteristics, and treatment reaction of ccRCC patients. For this study, we used The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus datasets to access the RNA sequencing results and clinical information from ccRCC patients. 29 ARGs related to survival were found using differential analysis and univariate Cox regression analysis. The samples were then divided into two clusters that had different immune traits via unsupervised cluster analysis using 29 prognosis-associated differently expressed ARGs. Then, to build an ARGs signature, 7 genes (PLAU, EDA2R, AFP, PLG, TUBB3, APOBEC3G, and MALAT1) were found using Least Absolute Shrinkage and Selection Operator regression analysis. The new ARGs signature demonstrated outstanding prognostic capability for ccRCC patients' overall survival. In conclusion, for ccRCC patients, we created an ARGs signature that strongly connects to immunological traits and therapy response. Clinicians may find this ARGs signature helpful in developing more individualized and detailed treatment strategies for ccRCC patients.
Collapse
Affiliation(s)
- Yinglei Jiang
- Dialysis Room, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, 120000, China
| | - Ying Wang
- Dialysis Room, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, 120000, China
| | - Zhengyan Wang
- Changchun University of Chinese Medicine, Changchun, 120000, China
| | - Yinzhen Zhang
- Changchun University of Chinese Medicine, Changchun, 120000, China
| | - Yulong Hou
- Changchun University of Chinese Medicine, Changchun, 120000, China
| | - Xukai Wang
- Dialysis Room, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, 120000, China.
| |
Collapse
|
|
9
|
Desai TA, Hedman ÅK, Dimitriou M, Koprulu M, Figiel S, Yin W, Johansson M, Watts EL, Atkins JR, Sokolov AV, Schiöth HB, Gunter MJ, Tsilidis KK, Martin RM, Pietzner M, Langenberg C, Mills IG, Lamb AD, Mälarstig A, Key TJ, Travis RC, Smith-Byrne K. Identifying proteomic risk factors for overall, aggressive and early onset prostate cancer using Mendelian randomization and tumor spatial transcriptomics. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.09.21.23295864. [PMID: 37790472 PMCID: PMC10543057 DOI: 10.1101/2023.09.21.23295864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/05/2023]
Abstract
Background Understanding the role of circulating proteins in prostate cancer risk can reveal key biological pathways and identify novel targets for cancer prevention. Methods We investigated the association of 2,002 genetically predicted circulating protein levels with risk of prostate cancer overall, and of aggressive and early onset disease, using cis-pQTL Mendelian randomization (MR) and colocalization. Findings for proteins with support from both MR, after correction for multiple-testing, and colocalization were replicated using two independent cancer GWAS, one of European and one of African ancestry. Proteins with evidence of prostate-specific tissue expression were additionally investigated using spatial transcriptomic data in prostate tumor tissue to assess their role in tumor aggressiveness. Finally, we mapped risk proteins to drug and ongoing clinical trials targets. Results We identified 20 proteins genetically linked to prostate cancer risk (14 for overall [8 specific], 7 for aggressive [3 specific], and 8 for early onset disease [2 specific]), of which a majority were novel and replicated. Among these were proteins associated with aggressive disease, such as PPA2 [Odds Ratio (OR) per 1 SD increment = 2.13, 95% CI: 1.54-2.93], PYY [OR = 1.87, 95% CI: 1.43-2.44] and PRSS3 [OR = 0.80, 95% CI: 0.73-0.89], and those associated with early onset disease, including EHPB1 [OR = 2.89, 95% CI: 1.99-4.21], POGLUT3 [OR = 0.76, 95% CI: 0.67-0.86] and TPM3 [OR = 0.47, 95% CI: 0.34-0.64]. We confirm an inverse association of MSMB with prostate cancer overall [OR = 0.81, 95% CI: 0.80-0.82], and also find an inverse association with both aggressive [OR = 0.84, 95% CI: 0.82-0.86] and early onset disease [OR = 0.71, 95% CI: 0.68-0.74]. Using spatial transcriptomics data, we identified MSMB as the genome-wide top-most predictive gene to distinguish benign regions from high grade cancer regions that had five-fold lower MSMB expression. Additionally, ten proteins that were associated with prostate cancer risk mapped to existing therapeutic interventions. Conclusion Our findings emphasize the importance of proteomics for improving our understanding of prostate cancer etiology and of opportunities for novel therapeutic interventions. Additionally, we demonstrate the added benefit of in-depth functional analyses to triangulate the role of risk proteins in the clinical aggressiveness of prostate tumors. Using these integrated methods, we identify a subset of risk proteins associated with aggressive and early onset disease as priorities for investigation for the future prevention and treatment of prostate cancer.
Collapse
Affiliation(s)
- Trishna A Desai
- Cancer Epidemiology Unit, Oxford Population Health, University of Oxford, Oxford, United Kingdom
| | - Åsa K Hedman
- External Science and Innovation, Pfizer Worldwide Research, Development and Medical, Stockholm, Sweden
- Department of Medicine, Department of Medicine, Stockholm, Sweden
| | - Marios Dimitriou
- External Science and Innovation, Pfizer Worldwide Research, Development and Medical, Stockholm, Sweden
- Department of Medicine, Department of Medicine, Stockholm, Sweden
| | - Mine Koprulu
- MRC Epidemiology Unit, University of Cambridge, United Kingdom
| | - Sandy Figiel
- University of Oxford, Nuffield Department of Surgical Sciences, Oxford, United Kingdom
| | - Wencheng Yin
- University of Oxford, Nuffield Department of Surgical Sciences, Oxford, United Kingdom
| | - Mattias Johansson
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Eleanor L Watts
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America
| | - Joshua R Atkins
- Cancer Epidemiology Unit, Oxford Population Health, University of Oxford, Oxford, United Kingdom
| | - Aleksandr V Sokolov
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience Uppsala University, 75124 Uppsala, Sweden
| | - Helgi B Schiöth
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience Uppsala University, 75124 Uppsala, Sweden
| | - Marc J Gunter
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, United Kingdom
| | - Konstantinos K Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, United Kingdom
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Richard M Martin
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
- NIHR Bristol Biomedical Research Centre, Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, United Kingdom
| | - Maik Pietzner
- MRC Epidemiology Unit, University of Cambridge, United Kingdom
- Computational Medicine, Berlin Institute of HealthHealth (BIH) at Charité - Univeritätsmedizin- Universitätsmedizin Berlin, Berlin, Germany
- Precision Healthcare University Research Institute, Queen Mary University of London, London, United Kingdom
| | - Claudia Langenberg
- MRC Epidemiology Unit, University of Cambridge, United Kingdom
- Computational Medicine, Berlin Institute of HealthHealth (BIH) at Charité - Univeritätsmedizin- Universitätsmedizin Berlin, Berlin, Germany
- Precision Healthcare University Research Institute, Queen Mary University of London, London, United Kingdom
| | - Ian G Mills
- University of Oxford, Nuffield Department of Surgical Sciences, Oxford, United Kingdom
| | - Alastair D Lamb
- University of Oxford, Nuffield Department of Surgical Sciences, Oxford, United Kingdom
| | - Anders Mälarstig
- External Science and Innovation, Pfizer Worldwide Research, Development and Medical, Stockholm, Sweden
- Department of Medicine, Department of Medicine, Stockholm, Sweden
| | - Tim J Key
- Cancer Epidemiology Unit, Oxford Population Health, University of Oxford, Oxford, United Kingdom
| | - Ruth C Travis
- Cancer Epidemiology Unit, Oxford Population Health, University of Oxford, Oxford, United Kingdom
| | - Karl Smith-Byrne
- Cancer Epidemiology Unit, Oxford Population Health, University of Oxford, Oxford, United Kingdom
| |
Collapse
|
|
10
|
Yunpeng P, Lingdi Y, Xiaole Z, Dongya H, Le H, Zipeng L, Kai Z, Chaoqun H, Yi M, Feng G, Qiang L. Establishment and validation of a nomogram based on coagulation parameters to predict the prognosis of pancreatic cancer. BMC Cancer 2023; 23:548. [PMID: 37322417 DOI: 10.1186/s12885-023-10908-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 05/02/2023] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND In recent years, multiple coagulation and fibrinolysis (CF) indexes have been reported to be significantly related to the progression and prognosis of some cancers. OBJECTIVE The purpose of this study was to comprehensively analyze the value of CF parameters in prognosis prediction of pancreatic cancer (PC). METHODS The preoperative coagulation related data, clinicopathological information, and survival data of patients with pancreatic tumor were collected retrospectively. Mann Whitney U test, Kaplan-Meier analysis, and Cox proportional hazards regression model were applied to analyze the differences of coagulation indexes between benign and malignant tumors, as well as the roles of these indexes in PC prognosis prediction. RESULTS Compared with benign tumors, the preoperative levels of some traditional coagulation and fibrinolysis (TCF) indexes (such as TT, Fibrinogen, APTT, and D-dimer) were abnormally increased or decreased in patients with pancreatic cancer, as well as Thromboelastography (TEG) parameters (such as R, K, α Angle, MA, and CI). Kaplan Meier survival analysis based on resectable PC patients showed that the overall survival (OS) of patients with elevated α angle, MA, CI, PT, D-dimer, or decreased PDW was markedly shorter than other patients; moreover, patients with lower CI or PT have longer disease-free survival. Further univariate and multivariate analysis revealed that PT, D-dimer, PDW, vascular invasion (VI), and tumor size (TS) were independent risk factors for poor prognosis of PC. According to the results of modeling group and validation group, the nomogram model based on independent risk factors could effectively predict the postoperative survival of PC patients. CONCLUSION Many abnormal CF parameters were remarkably correlated with PC prognosis, including α Angle, MA, CI, PT, D-dimer, and PDW. Furthermore, only PT, D-dimer, and PDW were independent prognostic indicators for poor prognosis of PC, and the prognosis prediction model based on these indicators was an effective tool to predict the postoperative survival of PC.
Collapse
Affiliation(s)
- Peng Yunpeng
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Yin Lingdi
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Zhu Xiaole
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Huang Dongya
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Hu Le
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Lu Zipeng
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Zhang Kai
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Hou Chaoqun
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Miao Yi
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Guo Feng
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China.
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People's Republic of China.
| | - Li Qiang
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China.
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People's Republic of China.
| |
Collapse
|
|
11
|
How to manage coagulopathies in critically ill patients. Intensive Care Med 2023; 49:273-290. [PMID: 36808215 DOI: 10.1007/s00134-023-06980-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 01/06/2023] [Indexed: 02/19/2023]
Abstract
Coagulopathy is a severe and frequent complication in critically ill patients, for which the pathogenesis and presentation may be variable depending on the underlying disease. Based on the dominant clinical phenotype, the current review differentiates between hemorrhagic coagulopathies, characterized by a hypocoagulable and hyperfibrinolysis state, and thrombotic coagulopathies with a systemic prothrombotic and antifibrinolytic phenotype. We discuss the differences in pathogenesis and treatment of the common coagulopathies.
Collapse
|
|
12
|
Naryzhny S, Ronzhina N, Zorina E, Kabachenko F, Klopov N, Zgoda V. Construction of 2DE Patterns of Plasma Proteins: Aspect of Potential Tumor Markers. Int J Mol Sci 2022; 23:ijms231911113. [PMID: 36232415 PMCID: PMC9569744 DOI: 10.3390/ijms231911113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/16/2022] [Accepted: 09/16/2022] [Indexed: 11/16/2022] Open
Abstract
The use of tumor markers aids in the early detection of cancer recurrence and prognosis. There is a hope that they might also be useful in screening tests for the early detection of cancer. Here, the question of finding ideal tumor markers, which should be sensitive, specific, and reliable, is an acute issue. Human plasma is one of the most popular samples as it is commonly collected in the clinic and provides noninvasive, rapid analysis for any type of disease including cancer. Many efforts have been applied in searching for “ideal” tumor markers, digging very deep into plasma proteomes. The situation in this area can be improved in two ways—by attempting to find an ideal single tumor marker or by generating panels of different markers. In both cases, proteomics certainly plays a major role. There is a line of evidence that the most abundant, so-called “classical plasma proteins”, may be used to generate a tumor biomarker profile. To be comprehensive these profiles should have information not only about protein levels but also proteoform distribution for each protein. Initially, the profile of these proteins in norm should be generated. In our work, we collected bibliographic information about the connection of cancers with levels of “classical plasma proteins”. Additionally, we presented the proteoform profiles (2DE patterns) of these proteins in norm generated by two-dimensional electrophoresis with mass spectrometry and immunodetection. As a next step, similar profiles representing protein perturbations in plasma produced in the case of different cancers will be generated. Additionally, based on this information, different test systems can be developed.
Collapse
Affiliation(s)
- Stanislav Naryzhny
- Institute of Biomedical Chemistry, Pogodinskaya, 10, 119121 Moscow, Russia
- Petersburg Institute of Nuclear Physics (PNPI) of National Research Center “Kurchatov Institute”, 188300 Gatchina, Russia
- Correspondence: ; Tel.: +7-911-176-4453
| | - Natalia Ronzhina
- Petersburg Institute of Nuclear Physics (PNPI) of National Research Center “Kurchatov Institute”, 188300 Gatchina, Russia
| | - Elena Zorina
- Institute of Biomedical Chemistry, Pogodinskaya, 10, 119121 Moscow, Russia
| | - Fedor Kabachenko
- Institute of Biomedical Systems and Biotechnology, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia
| | - Nikolay Klopov
- Petersburg Institute of Nuclear Physics (PNPI) of National Research Center “Kurchatov Institute”, 188300 Gatchina, Russia
| | - Victor Zgoda
- Institute of Biomedical Chemistry, Pogodinskaya, 10, 119121 Moscow, Russia
| |
Collapse
|
|
13
|
Cuypers A, Truong ACK, Becker LM, Saavedra-García P, Carmeliet P. Tumor vessel co-option: The past & the future. Front Oncol 2022; 12:965277. [PMID: 36119528 PMCID: PMC9472251 DOI: 10.3389/fonc.2022.965277] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 08/04/2022] [Indexed: 12/11/2022] Open
Abstract
Tumor vessel co-option (VCO) is a non-angiogenic vascularization mechanism that is a possible cause of resistance to anti-angiogenic therapy (AAT). Multiple tumors are hypothesized to primarily rely on growth factor signaling-induced sprouting angiogenesis, which is often inhibited during AAT. During VCO however, tumors invade healthy tissues by hijacking pre-existing blood vessels of the host organ to secure their blood and nutrient supply. Although VCO has been described in the context of AAT resistance, the molecular mechanisms underlying this process and the profile and characteristics of co-opted vascular cell types (endothelial cells (ECs) and pericytes) remain poorly understood, resulting in the lack of therapeutic strategies to inhibit VCO (and to overcome AAT resistance). In the past few years, novel next-generation technologies (such as single-cell RNA sequencing) have emerged and revolutionized the way of analyzing and understanding cancer biology. While most studies utilizing single-cell RNA sequencing with focus on cancer vascularization have centered around ECs during sprouting angiogenesis, we propose that this and other novel technologies can be used in future investigations to shed light on tumor EC biology during VCO. In this review, we summarize the molecular mechanisms driving VCO known to date and introduce the models used to study this phenomenon to date. We highlight VCO studies that recently emerged using sequencing approaches and propose how these and other novel state-of-the-art methods can be used in the future to further explore ECs and other cell types in the VCO process and to identify potential vulnerabilities in tumors relying on VCO. A better understanding of VCO by using novel approaches could provide new answers to the many open questions, and thus pave the way to develop new strategies to control and target tumor vascularization.
Collapse
Affiliation(s)
- Anne Cuypers
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), Vlaams Instituut voor Biotechnologie (VIB) and Department of Oncology, Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Anh-Co Khanh Truong
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), Vlaams Instituut voor Biotechnologie (VIB) and Department of Oncology, Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Lisa M. Becker
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), Vlaams Instituut voor Biotechnologie (VIB) and Department of Oncology, Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Paula Saavedra-García
- Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), Vlaams Instituut voor Biotechnologie (VIB) and Department of Oncology, Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| |
Collapse
|
|
14
|
Diosdado A, Simón F, Serrat J, González-Miguel J. Interaction of helminth parasites with the haemostatic system of their vertebrate hosts: a scoping review. Parasite 2022; 29:35. [PMID: 35833785 PMCID: PMC9281497 DOI: 10.1051/parasite/2022034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/14/2022] [Indexed: 12/23/2022] Open
Abstract
Helminth parasitoses are among the most prevalent health issues worldwide. Their control depends largely on unravelling host-parasite interactions, including parasitic exploitation of the host haemostatic system. The present study undertakes a scoping review of the research carried out in this field with the aim of unifying and updating concepts. Multiple keywords combined with Boolean operators were employed to design the literature search strategy. Two online databases were used to identify original peer-reviewed articles written in English and published before 1st January 2020 describing molecular interactions between helminth parasites and the host haemostatic system. Relevant data from the selected sources of evidence were extracted and analysed. Ninety-six publications reporting 259 interactions were selected. Fifty-three proteins belonging to 32 species of helminth parasites were involved in interactions with components of the host haemostatic system. Many of these proteins from both parasite and host were conserved among the different interactions identified. Most of these interactions were related to the inhibition of the coagulation system and the activation of fibrinolysis. This was associated mainly with a potential of parasites to reduce the formation of blood clots in the host and attributed to biological processes, such as parasite nutrition, survival, invasion, evasion and migration or the appearance of pathological mechanisms in the host. A wide range of helminth parasites have developed similar strategies to exploit the haemostatic system of their hosts, which could be regarded as an evolutionary conserved mechanism that could confer benefits to parasites in terms of survival and establishment in their vertebrate hosts.
Collapse
Affiliation(s)
- Alicia Diosdado
- Laboratory of Parasitology, Faculty of Pharmacy, University of Salamanca 37007 Salamanca Spain
| | - Fernando Simón
- Laboratory of Parasitology, Faculty of Pharmacy, University of Salamanca 37007 Salamanca Spain
| | - Judit Serrat
- Laboratory of Parasitology, Institute of Natural Resources and Agrobiology of Salamanca (IRNASA-CSIC) 37008 Salamanca Spain
| | - Javier González-Miguel
- Laboratory of Parasitology, Institute of Natural Resources and Agrobiology of Salamanca (IRNASA-CSIC) 37008 Salamanca Spain
- Molecular Parasitology Laboratory, Centre of One Health (COH), Ryan Institute, National University of Ireland H91 DK59 Galway Ireland
| |
Collapse
|
|
15
|
The effect of hypochlorite- and peroxide-induced oxidation of plasminogen on damage to the structure and biological activity. Int J Biol Macromol 2022; 206:64-73. [DOI: 10.1016/j.ijbiomac.2022.02.128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/20/2022] [Accepted: 02/21/2022] [Indexed: 11/18/2022]
|
|
16
|
Miles LA, Krajewski S, Baik N, Parmer RJ, Mueller BM. Plg-RKT Expression in Human Breast Cancer Tissues. Biomolecules 2022; 12:biom12040503. [PMID: 35454092 PMCID: PMC9028288 DOI: 10.3390/biom12040503] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 03/21/2022] [Accepted: 03/23/2022] [Indexed: 12/12/2022] Open
Abstract
The plasminogen activation system regulates the activity of the serine protease, plasmin. The role of plasminogen receptors in cancer progression is being increasingly appreciated as key players in modulation of the tumor microenvironment. The interaction of plasminogen with cells to promote plasminogen activation requires the presence of proteins exposing C-terminal lysines on the cell surface. Plg-RKT is a structurally unique plasminogen receptor because it is an integral membrane protein that is synthesized with and binds plasminogen via a C-terminal lysine exposed on the cell surface. Here, we have investigated the expression of Plg-RKT in human breast tumors and human breast cancer cell lines. Breast cancer progression tissue microarrays were probed with anti-Plg-RKT mAB and we found that Plg-RKT is widely expressed in human breast tumors, that its expression is increased in tumors that have spread to draining lymph nodes and distant organs, and that Plg-RKT expression is most pronounced in hormone receptor (HR)-positive tumors. Plg-RKT was detected by Western blotting in human breast cancer cell lines. By flow cytometry, Plg-RKT cell surface expression was highest on the most aggressive tumor cell line. Future studies are warranted to address the functions of Plg-RKT in breast cancer.
Collapse
Affiliation(s)
- Lindsey A. Miles
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037, USA; (L.A.M.); (N.B.)
| | | | - Nagyung Baik
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037, USA; (L.A.M.); (N.B.)
| | - Robert J. Parmer
- Department of Medicine, Veterans Administration San Diego Healthcare System, University of California San Diego, San Diego, CA 92161, USA;
| | - Barbara M. Mueller
- San Diego Biomedical Research Institute, San Diego, CA 92121, USA
- Correspondence:
| |
Collapse
|
|
17
|
Abstract
INTRODUCTION Calpain-1 and calpain-2 are prototypical classical isoforms of the calpain family of calcium-activated cysteine proteases. Their substrate proteins participate in a wide range of cellular processes, including transcription, survival, proliferation, apoptosis, migration, and invasion. Dysregulated calpain activity has been implicated in tumorigenesis, suggesting that calpains may be promising therapeutic targets. AREAS COVERED This review covers clinical and basic research studies implicating calpain-1 and calpain-2 expression and activity in tumorigenesis and metastasis. We highlight isoform specific functions and provide an overview of substrates and cancer-related signalling pathways affected by calpain-mediated proteolytic cleavage. We also discuss efforts to develop clinically relevant calpain specific inhibitors and spotlight the challenges facing inhibitor development. EXPERT OPINION Rationale for targeting calpain-1 and calpain-2 in cancer is supported by pre-clinical and clinical studies demonstrating that calpain inhibition has the potential to attenuate carcinogenesis and block metastasis of aggressive tumors. The wide range of substrates and cleavage products, paired with inconsistencies in model systems, underscores the need for more complete understanding of physiological substrates and how calpain cleavage alters their function in cellular processes. The development of isoform specific calpain inhibitors remains an important goal with therapeutic potential in cancer and other diseases.
Collapse
Affiliation(s)
- Ivan Shapovalov
- Department of Pathology and Molecular Medicine, Queen's University, Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, 10 Stuart Street, Botterell Hall, Room A309, Kingston, Ontario, K7L 3N6 Canada
| | - Danielle Harper
- Department of Pathology and Molecular Medicine, Queen's University, Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, 10 Stuart Street, Botterell Hall, Room A309, Kingston, Ontario, K7L 3N6 Canada
| | - Peter A Greer
- Department of Pathology and Molecular Medicine, Queen's University, Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, 10 Stuart Street, Botterell Hall, Room A309, Kingston, Ontario, K7L 3N6 Canada
| |
Collapse
|
|
18
|
Yu JE, Yeo IJ, Son DJ, Yun J, Han SB, Hong JT. Anti-Chi3L1 antibody suppresses lung tumor growth and metastasis through inhibition of M2 polarization. Mol Oncol 2021; 16:2214-2234. [PMID: 34861103 PMCID: PMC9168758 DOI: 10.1002/1878-0261.13152] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/29/2021] [Accepted: 12/01/2021] [Indexed: 11/08/2022] Open
Abstract
Chitinase 3-like 1 (Chi3L1) is associated with various biological processes, such as inflammation, tissue repair, proliferation, cell survival, invasion, and extracellular matrix remodeling. Recent studies indicated that Chi3L1 is critical for cancer development and metastasis. In this study, we demonstrate that Chi3L1 serum and tissue levels were significantly increased in lung cancer patients compared with controls. We previously developed an anti-Chi3L1-humanized antibody, and here, we investigate its antitumor and antimetastatic effect. The anti-Chi3L1 antibody attenuated tumor growth and metastasis both in vitro and in vivo in a lung cancer mouse model. These inhibitory effects are associated with signal transducer and activator of transcription 6 (STAT6)-dependent M2 polarization inhibition. Proteomics analysis revealed that plasminogen (PLG) interacts with Chi3L1 and affects M2 polarization. Chi3L1 plays a critical role in lung cancer progression, and the anti-Chi3L1 antibody could be a new anticancer therapy.
Collapse
Affiliation(s)
- Ji Eun Yu
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju-si, Korea
| | - In Jun Yeo
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju-si, Korea
| | - Dong Ju Son
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju-si, Korea
| | - Jaesuk Yun
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju-si, Korea
| | - Sang-Bae Han
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju-si, Korea
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju-si, Korea
| |
Collapse
|
|
19
|
Rango E, D'Antona L, Iovenitti G, Brai A, Mancini A, Zamperini C, Trivisani CI, Marianelli S, Fallacara AL, Molinari A, Cianciusi A, Schenone S, Perrotti N, Dreassi E, Botta M. Si113-prodrugs selectively activated by plasmin against hepatocellular and ovarian carcinoma. Eur J Med Chem 2021; 223:113653. [PMID: 34161866 DOI: 10.1016/j.ejmech.2021.113653] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/01/2021] [Accepted: 06/13/2021] [Indexed: 11/25/2022]
Abstract
Si113, a pyrazolo[3,4-d]pyrimidine derivative, gained more attention as an anticancer agent due to its potent anticancer activity on both in vitro and in vivo hepatocellular carcinomas (HCC) and ovarian carcinoma models. But the drawback is the low water solubility which prevents its further development. In this context, we successfully overcame this limitation by synthesizing two novel prodrugs introducing the amino acid sequence D-Ala-Leu-Lys (TP). Moreover, TP sequence has a high affinity with plasmin, a protease recognized as overexpressed in many solid cancers, including HCC and ovarian carcinoma. The prodrugs were synthesized and fully characterized in terms of in vitro ADME properties, plasma stability and plasmin-induced release of the parent drug. The inhibitory activity against Sgk1 was evaluated and in vitro growth inhibition was evaluated on ovarian carcinoma and HCC cell lines in the presence and absence of human plasmin. In vivo pharmacokinetic properties and preliminary tissue distribution confirmed a better profile highlighting the importance of the prodrug approach. Finally, the prodrug antitumor efficacy was evaluated in an HCC xenografted murine model, where a significant reduction (around 90%) in tumor growth was observed. Treatment with ProSi113-TP in combination with paclitaxel in a paclitaxel-resistant ovarian carcinoma xenografted murine model, resulted in an impressive reduction of tumor volume greater than 95%. Our results revealed a promising activity of Si113 prodrugs and pave the way for their further development against resistant cancer.
Collapse
Affiliation(s)
- Enrico Rango
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Lucia D'Antona
- Dipartimento di Scienze della Salute, Università"Magna Graecia" di Catanzaro, Viale Europa, 88100, Catanzaro, Italy
| | - Giulia Iovenitti
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Annalaura Brai
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Arianna Mancini
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Claudio Zamperini
- Lead Discovery Siena S.r.l., Via Vittorio Alfieri 31, 53019, Castelnuovo Berardenga, Siena, Italy
| | - Claudia Immacolata Trivisani
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Stefano Marianelli
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Anna Lucia Fallacara
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Alessio Molinari
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Annarita Cianciusi
- Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV 3, Genoa, 16132, Italy
| | - Silvia Schenone
- Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV 3, Genoa, 16132, Italy
| | - Nicola Perrotti
- Dipartimento di Scienze della Salute, Università"Magna Graecia" di Catanzaro, Viale Europa, 88100, Catanzaro, Italy.
| | - Elena Dreassi
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy.
| | - Maurizio Botta
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy; Lead Discovery Siena S.r.l., Via Vittorio Alfieri 31, 53019, Castelnuovo Berardenga, Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology Temple University, BioLife Science Building, Suite 333, 1900 North 12th Street, Philadelphia, PA, 19122, United States
| |
Collapse
|
|
20
|
Piperigkou Z, Kyriakopoulou K, Koutsakis C, Mastronikolis S, Karamanos NK. Key Matrix Remodeling Enzymes: Functions and Targeting in Cancer. Cancers (Basel) 2021; 13:1441. [PMID: 33809973 PMCID: PMC8005147 DOI: 10.3390/cancers13061441] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/05/2021] [Accepted: 03/17/2021] [Indexed: 12/13/2022] Open
Abstract
Tissue functionality and integrity demand continuous changes in distribution of major components in the extracellular matrices (ECMs) under normal conditions aiming tissue homeostasis. Major matrix degrading proteolytic enzymes are matrix metalloproteinases (MMPs), plasminogen activators, atypical proteases such as intracellular cathepsins and glycolytic enzymes including heparanase and hyaluronidases. Matrix proteases evoke epithelial-to-mesenchymal transition (EMT) and regulate ECM turnover under normal procedures as well as cancer cell phenotype, motility, invasion, autophagy, angiogenesis and exosome formation through vital signaling cascades. ECM remodeling is also achieved by glycolytic enzymes that are essential for cancer cell survival, proliferation and tumor progression. In this article, the types of major matrix remodeling enzymes, their effects in cancer initiation, propagation and progression as well as their pharmacological targeting and ongoing clinical trials are presented and critically discussed.
Collapse
Affiliation(s)
- Zoi Piperigkou
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 265 04 Patras, Greece; (K.K.); (C.K.)
- Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), 265 04 Patras, Greece
| | - Konstantina Kyriakopoulou
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 265 04 Patras, Greece; (K.K.); (C.K.)
| | - Christos Koutsakis
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 265 04 Patras, Greece; (K.K.); (C.K.)
| | | | - Nikos K. Karamanos
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 265 04 Patras, Greece; (K.K.); (C.K.)
- Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), 265 04 Patras, Greece
| |
Collapse
|
|
21
|
Fang L, Xu Q, Qian J, Zhou JY. Aberrant Factors of Fibrinolysis and Coagulation in Pancreatic Cancer. Onco Targets Ther 2021; 14:53-65. [PMID: 33442266 PMCID: PMC7797325 DOI: 10.2147/ott.s281251] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 12/11/2020] [Indexed: 12/13/2022] Open
Abstract
Aberrant factors associated with fibrinolysis and thrombosis are found in many cancer patients, which can promote metastasis and are associated with poor prognosis. The relationship between tumor-associated fibrinolysis and thrombosis is poorly understood in pancreatic cancer. This review provides a brief highlight of existing studies that the fibrinolysis and coagulation systems were activated in pancreatic cancer patients, along with aberrant high concentrations of tissue plasminogen activator (t-PA), urine plasminogen activator (u-PA), D-dimer, fibrinogen, or platelets. These factors cooperate with each other, propelling tumor cell shedding, localization, adhesion to distant metastasis. The relationship between thrombosis or fibrinolysis and cancer immune escape is also investigated. In addition, the potential prevention and therapy strategies of pancreatic cancer targeting factors in fibrinolysis and coagulation systems are also been discussed, in which we highlight two effective agents aspirin and low-molecular weight heparin (LMWH). Summarily, this review provides new directions for the research and treatment of pancreatic cancer.
Collapse
Affiliation(s)
- Lianghua Fang
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, People's Republic of China
| | - Qing Xu
- Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210029, People's Republic of China
| | - Jun Qian
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, People's Republic of China
| | - Jin-Yong Zhou
- Central Laboratory, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, People's Republic of China
| |
Collapse
|
|
22
|
Ma S, Dang Q, Yang Y, Liu Y, Sun Y, Sun M. Sintilimab, a PD-1 Inhibitor, Completely Reversed Rarely Refractory Hypofibrinogenemia in a Gastric Cancer Patient: A Case Report and Review of the Literature. Front Oncol 2020; 10:526096. [PMID: 33194584 PMCID: PMC7604326 DOI: 10.3389/fonc.2020.526096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 09/18/2020] [Indexed: 11/13/2022] Open
Abstract
While cancer is often related to hyperfibrinogenemia, it is rarely related to hypofibrinogenemia. Specifically, gastric cancer concomitant with unprovoked hypofibrinogenemia and the corresponding treatment approach have been rarely reported. We presented a case of gastric cancer in a 78-year-old Chinese woman in whom sudden, unprovoked refractory hypofibrinogenemia had been found during the whole brain radiotherapy despite stable clinical condition. Fibrinogen supplementation was not useful for controlling her level of fibrinogen. However, when she received sintilimab, an immunotherapy drug acting as programmed death receptor 1 inhibitor, to treat her gastric cancer, fibrinogen rose to the normal level. We also reviewed the literature to explore the causes of hypofibrinogenemia in tumor patients. This case suggests that we need to pay attention to tumor-related coagulation disorders, and monitoring coagulation indicators is essential. Treating primary disease by immunotherapy drugs may be an important method to improve the level of coagulation factors. This is the first report of sintilimab reversing a rare refractory hypofibrinogenemia in a patient with gastric cancer.
Collapse
Affiliation(s)
- Shuzhen Ma
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qi Dang
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yali Yang
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yongliang Liu
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yuping Sun
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Meili Sun
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
- *Correspondence: Meili Sun,
| |
Collapse
|
|
23
|
Kothari C, Diorio C, Durocher F. The Importance of Breast Adipose Tissue in Breast Cancer. Int J Mol Sci 2020; 21:ijms21165760. [PMID: 32796696 PMCID: PMC7460846 DOI: 10.3390/ijms21165760] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 07/31/2020] [Accepted: 08/06/2020] [Indexed: 02/07/2023] Open
Abstract
Adipose tissue is a complex endocrine organ, with a role in obesity and cancer. Adipose tissue is generally linked to excessive body fat, and it is well known that the female breast is rich in adipose tissue. Hence, one can wonder: what is the role of adipose tissue in the breast and why is it required? Adipose tissue as an organ consists of adipocytes, an extracellular matrix (ECM) and immune cells, with a significant role in the dynamics of breast changes throughout the life span of a female breast from puberty, pregnancy, lactation and involution. In this review, we will discuss the importance of breast adipose tissue in breast development and its involvement in breast changes happening during pregnancy, lactation and involution. We will focus on understanding the biology of breast adipose tissue, with an overview on its involvement in the various steps of breast cancer development and progression. The interaction between the breast adipose tissue surrounding cancer cells and vice-versa modifies the tumor microenvironment in favor of cancer. Understanding this mutual interaction and the role of breast adipose tissue in the tumor microenvironment could potentially raise the possibility of overcoming breast adipose tissue mediated resistance to therapies and finding novel candidates to target breast cancer.
Collapse
Affiliation(s)
- Charu Kothari
- Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec, QC G1T 1C2, Canada;
- Cancer Research Centre, CHU de Quebec Research Centre, Quebec, QC G1V 4G2, Canada;
| | - Caroline Diorio
- Cancer Research Centre, CHU de Quebec Research Centre, Quebec, QC G1V 4G2, Canada;
- Department of Preventive and Social Medicine, Faculty of Medicine, Laval University, Quebec, QC G1T 1C2, Canada
| | - Francine Durocher
- Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec, QC G1T 1C2, Canada;
- Cancer Research Centre, CHU de Quebec Research Centre, Quebec, QC G1V 4G2, Canada;
- Correspondence: ; Tel.: +1-(418)-525-4444 (ext. 48508)
| |
Collapse
|
|
24
|
Boon L, Ugarte-Berzal E, Vandooren J, Opdenakker G. Protease propeptide structures, mechanisms of activation, and functions. Crit Rev Biochem Mol Biol 2020; 55:111-165. [PMID: 32290726 DOI: 10.1080/10409238.2020.1742090] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Proteases are a diverse group of hydrolytic enzymes, ranging from single-domain catalytic molecules to sophisticated multi-functional macromolecules. Human proteases are divided into five mechanistic classes: aspartate, cysteine, metallo, serine and threonine proteases, based on the catalytic mechanism of hydrolysis. As a protective mechanism against uncontrolled proteolysis, proteases are often produced and secreted as inactive precursors, called zymogens, containing inhibitory N-terminal propeptides. Protease propeptide structures vary considerably in length, ranging from dipeptides and propeptides of about 10 amino acids to complex multifunctional prodomains with hundreds of residues. Interestingly, sequence analysis of the different protease domains has demonstrated that propeptide sequences present higher heterogeneity compared with their catalytic domains. Therefore, we suggest that protease inhibition targeting propeptides might be more specific and have less off-target effects than classical inhibitors. The roles of propeptides, besides keeping protease latency, include correct folding of proteases, compartmentalization, liganding, and functional modulation. Changes in the propeptide sequence, thus, have a tremendous impact on the cognate enzymes. Small modifications of the propeptide sequences modulate the activity of the enzymes, which may be useful as a therapeutic strategy. This review provides an overview of known human proteases, with a focus on the role of their propeptides. We review propeptide functions, activation mechanisms, and possible therapeutic applications.
Collapse
Affiliation(s)
- Lise Boon
- Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, Laboratory of Immunobiology, KU Leuven, Leuven, Belgium
| | - Estefania Ugarte-Berzal
- Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, Laboratory of Immunobiology, KU Leuven, Leuven, Belgium
| | - Jennifer Vandooren
- Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, Laboratory of Immunobiology, KU Leuven, Leuven, Belgium
| | - Ghislain Opdenakker
- Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, Laboratory of Immunobiology, KU Leuven, Leuven, Belgium
| |
Collapse
|
|
25
|
Märkl B, Kazik M, Harbeck N, Jakubowicz E, Hoffmann R, Jung T, Steinfeld D, Schenkirsch G, Schlimok G, Oruzio D. Impact of uPA/PAI-1 and disseminated cytokeratin-positive cells in breast cancer. BMC Cancer 2019; 19:692. [PMID: 31307406 PMCID: PMC6632216 DOI: 10.1186/s12885-019-5857-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 06/20/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The protease uPA and its inhibitor PAI-1 play major roles in hemostasis and are also involved in cancer progression. This is mainly caused by their ability to degrade extracellular matrix-facilitating tumor cell migration. This study aimed to investigate the impact of uPA/PAI-1 and disseminated cytokeratin-positive cells (dCK+) on the outcome and the existence of synergistic effects. METHODS We retrospectively analyzed a cohort of 480 breast cancer cases with known uPA/PAI-1 and dCK+ status. uPA/PAI-1 was tested on fresh tumor samples using a commercial ELISA test. Bone marrow aspirates were investigated immunocytochemically for CK18. RESULTS DCK+ cells were identified in 23% of cases. uPA positivity was significantly associated with the occurrence of dCK+ cells (P = 0.028). uPA and PAI-1 were significantly associated with outcome in the subgroup of early-stage cases without chemotherapy. DCK+ cells alone were not prognostic. However, we found synergistic effects. In the subgroup of node-negative cases with and without chemotherapy, the prognostic impact of uPA and PAI-1 was enhanced in cases with additional dCK-positivity (triple +). In cases without chemotherapy, triple-positive status was independently prognostic (HR: 9.3 CI: 1.1-75) next to T stage. CONCLUSIONS uPA and PAI-1 seem to influence the metastatic potential of dCK+ cells, which underlines its important role in tumor progression.
Collapse
Affiliation(s)
- Bruno Märkl
- Institute of Pathology, Universitätsklinikum, Stenglinstraße 2, 86156, Augsburg, Germany.
| | - Martin Kazik
- Institute of Pathology, Universitätsklinikum, Stenglinstraße 2, 86156, Augsburg, Germany.,Clinic for Anesthesiology and Intensive Care, Universitätsklinikum Augsburg, Augsburg, Germany
| | - Nadia Harbeck
- Brustzentrum, Frauenklinik, Universität München (LMU), Munich, Germany
| | - Elzbieta Jakubowicz
- Institute of Pathology, Universitätsklinikum, Stenglinstraße 2, 86156, Augsburg, Germany
| | - Reinhard Hoffmann
- Institute of Laboratory Medicine and Microbiology, Universitätsklinikum Augsburg, Augsburg, Germany
| | - Thomas Jung
- Clinic for Gynecology and Obstetrics, Universitätsklinikum Augsburg, Augsburg, Germany
| | - Dieter Steinfeld
- Gynecology, Gemeinschaftspraxis Gynäkologische Onkologie, Augsburg, Germany
| | - Gerhard Schenkirsch
- Clinical and Population-based Cancer Registry of Augsburg, Augsburg, Germany
| | - Günter Schlimok
- Hematology and Oncology, Diakonissenkrankenhaus, Augsburg, Germany
| | | |
Collapse
|
|
26
|
Hiroyasu S, Turner CT, Richardson KC, Granville DJ. Proteases in Pemphigoid Diseases. Front Immunol 2019; 10:1454. [PMID: 31297118 PMCID: PMC6607946 DOI: 10.3389/fimmu.2019.01454] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Accepted: 06/10/2019] [Indexed: 12/28/2022] Open
Abstract
Pemphigoid diseases are a subgroup of autoimmune skin diseases characterized by widespread tense blisters. Standard of care typically involves immunosuppressive treatments, which may be insufficient and are often associated with significant adverse events. As such, a deeper understanding of the pathomechanism(s) of pemphigoid diseases is necessary in order to identify improved therapeutic approaches. A major initiator of pemphigoid diseases is the accumulation of autoantibodies against proteins at the dermal-epidermal junction (DEJ), followed by protease activation at the lesion. The contribution of proteases to pemphigoid disease pathogenesis has been investigated using a combination of in vitro and in vivo models. These studies suggest proteolytic degradation of anchoring proteins proximal to the DEJ is crucial for dermal-epidermal separation and blister formation. In addition, proteases can also augment inflammation, expose autoantigenic cryptic epitopes, and/or provoke autoantigen spreading, which are all important in pemphigoid disease pathology. The present review summarizes and critically evaluates the current understanding with respect to the role of proteases in pemphigoid diseases.
Collapse
Affiliation(s)
- Sho Hiroyasu
- International Collaboration On Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, Canada
- BC Professional Firefighters' Burn and Wound Healing Group, Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, Canada
| | - Christopher T. Turner
- International Collaboration On Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, Canada
- BC Professional Firefighters' Burn and Wound Healing Group, Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, Canada
| | - Katlyn C. Richardson
- International Collaboration On Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, Canada
- BC Professional Firefighters' Burn and Wound Healing Group, Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, Canada
| | - David J. Granville
- International Collaboration On Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, Canada
- BC Professional Firefighters' Burn and Wound Healing Group, Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, Canada
| |
Collapse
|
|
27
|
Li X, Dong P, Wei W, Jiang L, Guo S, Huang C, Liu Z, Chen J, Zhou F, Xie D, Liu Z. Overexpression of CEP72 Promotes Bladder Urothelial Carcinoma Cell Aggressiveness via Epigenetic CREB-Mediated Induction of SERPINE1. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1284-1297. [DOI: 10.1016/j.ajpath.2019.02.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 02/16/2019] [Accepted: 02/21/2019] [Indexed: 01/20/2023]
|
|
28
|
HAI-2 as a novel inhibitor of plasmin represses lung cancer cell invasion and metastasis. Br J Cancer 2019; 120:499-511. [PMID: 30765871 PMCID: PMC6461989 DOI: 10.1038/s41416-019-0400-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 12/04/2018] [Accepted: 12/14/2018] [Indexed: 12/13/2022] Open
Abstract
Background Dysregulation of pericellular proteolysis usually accounts for cancer cell invasion and metastasis. Isolation of a cell-surface protease system for lung cancer metastasis is an important issue for mechanistic studies and therapeutic target identification. Methods Immunohistochemistry of a tissue array (n = 64) and TCGA database (n = 255) were employed to assess the correlation between serine protease inhibitors (SPIs) and lung adenocarcinoma progression. The role of SPI in cell motility was examined using transwell assays. Pulldown and LC/MS/MS were performed to identify the SPI-modulated novel protease(s). A xenografted mouse model was harnessed to demonstrate the role of the SPI in lung cancer metastasis. Results Hepatocyte growth factor activator inhibitor-2 (HAI-2) was identified to be downregulated following lung cancer progression, which was related to poor survival and tumour invasion. We further isolated a serum-derived serine protease, plasmin, to be a novel target of HAI-2. Downregulation of HAI-2 promotes cell surface plasmin activity, EMT, and cell motility. HAI-2 can suppress plasmin-mediated activations of HGF and TGF-β1, EMT and cell invasion. In addition, downregulated HAI-2 increased metastasis of lung adenocarcinoma via upregulating plasmin activity. Conclusion HAI-2 functions as a novel inhibitor of plasmin to suppress lung cancer cell motility, EMT and metastasis.
Collapse
|
|
29
|
Manou D, Caon I, Bouris P, Triantaphyllidou IE, Giaroni C, Passi A, Karamanos NK, Vigetti D, Theocharis AD. The Complex Interplay Between Extracellular Matrix and Cells in Tissues. Methods Mol Biol 2019; 1952:1-20. [PMID: 30825161 DOI: 10.1007/978-1-4939-9133-4_1] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Extracellular matrix (ECM) maintains the structural integrity of tissues and regulates cell and tissue functions. ECM is comprised of fibrillar proteins, proteoglycans (PGs), glycosaminoglycans, and glycoproteins, creating a heterogeneous but well-orchestrated network. This network communicates with resident cells via cell-surface receptors. In particular, integrins, CD44, discoidin domain receptors, and cell-surface PGs and additionally voltage-gated ion channels can interact with ECM components, regulating signaling cascades as well as cytoskeleton configuration. The interplay of ECM with recipient cells is enriched by the extracellular vesicles, as they accommodate ECM, signaling, and cytoskeleton molecules in their cargo. Along with the numerous biological properties that ECM can modify, autophagy and angiogenesis, which are critical for tissue homeostasis, are included. Throughout development and disease onset and progression, ECM endures rearrangement to fulfill cellular requirements. The main responsible molecules for tissue remodeling are ECM-degrading enzymes including matrix metalloproteinases, plasminogen activators, cathepsins, and hyaluronidases, which can modify the ECM structure and function in a dynamic mode. A brief summary of the complex interplay between ECM macromolecules and cells in tissues and the contribution of ECM in tissue homeostasis and diseases is given.
Collapse
Affiliation(s)
- Dimitra Manou
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - Ilaria Caon
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Panagiotis Bouris
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | | | - Cristina Giaroni
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Alberto Passi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Nikos K Karamanos
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - Davide Vigetti
- Department of Medicine and Surgery, University of Insubria, Varese, Italy.
| | | |
Collapse
|
|
30
|
Pusina S. Correlation of Serum Levels of Urokinase Activation Plasminogen (uPA) and Its Inhibitor (PAI-1) with Hormonal and HER-2 Status in the Early Invasive Breast Cancer. Med Arch 2018; 72:335-340. [PMID: 30524164 PMCID: PMC6282918 DOI: 10.5455/medarh.2018.72.335-340] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Introduction: Breast cancer is the most common malignant tumor in women. On the list of causes of death immediately after lung cancer. It is a heterogeneous disease, considering the differences in morphological, cytogenetic, molecular, clinical and therapeutic aspects, so that the prognosis in a patient with the same histological grade and pathological status may vary. Aim: In this paper we wanted to identify the correlation between the assay of the serum values of uPA-PAI-1 complexes and individual prognostic-predictive parameters, primarily with the status of estrogenic (Er), progesterogenic (PgR) and Her-2 receptors („human epidermal growth factor). Material and methods: The study was conducted at the Clinic for General and Abdominal Surgery, University Clinical Center of Sarajevo (CCUS), from September 2016 to April 2017. The study included 66 patients, ages 18 to 75, in whom by the needle biopsy preoperatively was pathohistologically verified primary invasive breast cancer. Results: Two thirds of the sample were classified as invasive ductal carcinoma, similar to the percentage (68.2%) of pT2 size, and almost half in the grade G3. Lymph node status was negative in 54.5% of respondents, and positive in 31.8% of respondents. Most patients had positive estrogenic (83.3%) and progesterone receptors (62.1%). Almost 80% was Her-2 negative. The blood vessel invasion was present in 56.1%, while the neural invasion was present in less than a third of the sample (30.3%). Median values of uPA-PAI-1 complexes were 1.4 (interquartile range 0.9); almost 70% of the sample was negative for the status analysis of uPA-PAI-1 complex (<1). Discussion: A statistically significant difference was determined in the mean values of uPA-PAI-1 complexes in subgroups according to menopausal status, tumor size, histological grade, histological type (invasive ductal carcinoma vs. invasive lobular cancer versus invasive ductal carcinoma vs. invasive lobular cancer), status axillary lymph nodes, Ki67 status (as binary variables), invasion of the blood vessels and neural invasion, as well as subgroups according to the status of expression of hormonal (estrogen and progesterone) receptors. Conclusion: There is a statistically significant difference in the mean values of the uPA-PAI-1 complex and Her-2 receptor expression. Generally, in perspective, this would be the role played by the uPA/PAI-1 complex in breast cancer, which is that the elevated complex values have a negative prognosis and effect on survival, similar to the negative Her-2 receptor status. Complex uPA/PAI-1 is not a specific serum protein in breast cancer patients and cannot be taken as an individual prognostic-predictive marker for mass pre- or post treatment screening and prediction. Unfortunately, none of the biomarkers are able to independently and fully identify patients of the unknown stage of the disease with better or worse prognosis or to identify cases of more aggressive tumor behavior of the same stage for timely inclusion of adjuvant therapy and reduction of the risk of metastatic disease. The decision on treatment and prognosis should be the result of a combination of all diagnostic, therapeutic, pathohistological and molecular-genetic variables.
Collapse
Affiliation(s)
- Sadat Pusina
- Clinic for General and Abdominal Surgery, Clinical Center University of Sarajevo, Bosnia and Herzegovina
| |
Collapse
|
|
31
|
Plasminogen-binding proteins as an evasion mechanism of the host's innate immunity in infectious diseases. Biosci Rep 2018; 38:BSR20180705. [PMID: 30166455 PMCID: PMC6167496 DOI: 10.1042/bsr20180705] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 07/27/2018] [Accepted: 08/14/2018] [Indexed: 02/07/2023] Open
Abstract
Pathogens have developed particular strategies to infect and invade their hosts. Amongst these strategies’ figures the modulation of several components of the innate immune system participating in early host defenses, such as the coagulation and complement cascades, as well as the fibrinolytic system. The components of the coagulation cascade and the fibrinolytic system have been proposed to be interfered during host invasion and tissue migration of bacteria, fungi, protozoa, and more recently, helminths. One of the components that has been proposed to facilitate pathogen migration is plasminogen (Plg), a protein found in the host’s plasma, which is activated into plasmin (Plm), a serine protease that degrades fibrin networks and promotes degradation of extracellular matrix (ECM), aiding maintenance of homeostasis. However, pathogens possess Plg-binding proteins that can activate it, therefore taking advantage of the fibrin degradation to facilitate establishment in their hosts. Emergence of Plg-binding proteins appears to have occurred in diverse infectious agents along evolutionary history of host–pathogen relationships. The goal of the present review is to list, summarize, and analyze different examples of Plg-binding proteins used by infectious agents to invade and establish in their hosts. Emphasis was placed on mechanisms used by helminth parasites, particularly taeniid cestodes, where enolase has been identified as a major Plg-binding and activating protein. A new picture is starting to arise about how this glycolytic enzyme could acquire an entirely new role as modulator of the innate immune system in the context of the host–parasite relationship.
Collapse
|
|
32
|
Bydoun M, Sterea A, Weaver ICG, Bharadwaj AG, Waisman DM. A novel mechanism of plasminogen activation in epithelial and mesenchymal cells. Sci Rep 2018; 8:14091. [PMID: 30237490 PMCID: PMC6148250 DOI: 10.1038/s41598-018-32433-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 09/03/2018] [Indexed: 12/22/2022] Open
Abstract
Cancer dissemination is initiated by the movement of cells into the vasculature which has been reported to be triggered by EMT (epithelial to mesenchymal transition). Cellular dissemination also requires proteases that remodel the extracellular matrix. The protease, plasmin is a prominent player in matrix remodeling and invasion. Despite the contribution of both EMT and the plasminogen activation (PA) system to cell dissemination, these processes have never been functionally linked. We reveal that canonical Smad-dependent TGFβ1 signaling and FOXC2-mediated PI3K signaling in cells undergoing EMT reciprocally modulate plasminogen activation partly by regulating the plasminogen receptor, S100A10 and the plasminogen activation inhibitor, PAI-1. Plasminogen activation and plasminogen-dependent invasion were more prominent in epithelial-like cells and were partly dictated by the expression of S100A10 and PAI-1.
Collapse
Affiliation(s)
- Moamen Bydoun
- Department of Pathology, Halifax, Nova Scotia, Canada
| | - Andra Sterea
- Department of Physiology and Biophysics, Halifax, Nova Scotia, Canada
| | - Ian C G Weaver
- Department of Pathology, Halifax, Nova Scotia, Canada
- Department of Psychology and Neuroscience, Halifax, Nova Scotia, Canada
- Department of Psychiatry, Halifax, Nova Scotia, Canada
- Brain Repair Centre, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Alamelu G Bharadwaj
- Department of Biochemistry and Molecular Biology, Halifax, Nova Scotia, Canada
| | - David M Waisman
- Department of Pathology, Halifax, Nova Scotia, Canada.
- Department of Biochemistry and Molecular Biology, Halifax, Nova Scotia, Canada.
| |
Collapse
|
|
33
|
S100P enhances the motility and invasion of human trophoblast cell lines. Sci Rep 2018; 8:11488. [PMID: 30065265 PMCID: PMC6068119 DOI: 10.1038/s41598-018-29852-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 06/26/2018] [Indexed: 01/11/2023] Open
Abstract
S100P has been shown to be a marker for carcinogenesis where its expression in solid tumours correlates with metastasis and a poor patient prognosis. This protein's role in any physiological process is, however, unknown. Here we first show that S100P is expressed both in trophoblasts in vivo as well as in some corresponding cell lines in culture. We demonstrate that S100P is predominantly expressed during the early stage of placental formation with its highest expression levels occurring during the first trimester of gestation, particularly in the invading columns and anchoring villi. Using gain or loss of function studies through overexpression or knockdown of S100P expression respectively, our work shows that S100P stimulates both cell motility and cellular invasion in different trophoblastic and first trimester EVT cell lines. Interestingly, cell invasion was seen to be more dramatically affected than cell migration. Our results suggest that S100P may be acting as an important regulator of trophoblast invasion during placentation. This finding sheds new light on a hitherto uncharacterized molecular mechanism which may, in turn, lead to the identification of novel targets that may explain why significant numbers of confirmed human pregnancies suffer complications through poor placental implantation.
Collapse
|
|
34
|
Calandro P, Iovenitti G, Zamperini C, Candita F, Dreassi E, Chiariello M, Angelucci A, Schenone S, Botta M, Mancini A. Plasmin-Binding Tripeptide-Decorated Liposomes Loading Pyrazolo[3,4- d]pyrimidines for Targeting Hepatocellular Carcinoma. ACS Med Chem Lett 2018; 9:646-651. [PMID: 30034594 DOI: 10.1021/acsmedchemlett.8b00062] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 05/07/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most fatal cancer types worldwide. HCC cells were proved to overexpress c-Src and Sgk1, a tyrosine and a serine-threonine kinase, respectively, whose role is crucial for the development and progression of the tumor. Pyrazolo[3,4-d]pyrimidine derivatives are a class of tyrosine kinase inhibitors that have shown good activity against HepG2. HCC cells were also proved to overexpress plasmin, which is localized on the cell surface bound to its receptors. In this study, a tripeptide with sequence d-Ala-Phe-Lys, which binds a specific reactive site of plasmin, was synthesized and characterized. This tripeptide was used to decorate liposomes encapsulating three selected pyrazolo[3,4-d]pyrimidines. Liposomes bearing tripeptide have been characterized, not showing remarkable differences with respect to the corresponding tripeptide-free liposomes. In vitro HepG2 cell uptake profiles and cytotoxicities showed that the presence of the tripeptide on the liposomal membrane surface improves the cell-penetrating ability of liposomes and increases the activity of two of the three tested compounds.
Collapse
Affiliation(s)
- Pierpaolo Calandro
- Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100 Siena, Italy
- Consiglio Nazionale delle Ricerche, Istituto di Fisiologia Clinica and Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Core Research Laboratory, Via Fiorentina 1, 53100 Siena, Italy
| | - Giulia Iovenitti
- Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100 Siena, Italy
| | - Claudio Zamperini
- Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100 Siena, Italy
- Lead Discovery Siena S.r.l., Via Vittorio Alfieri 31, 53019 Castelnuovo Berardenga, Siena, Italy
| | - Francesca Candita
- Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100 Siena, Italy
| | - Elena Dreassi
- Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100 Siena, Italy
| | - Mario Chiariello
- Consiglio Nazionale delle Ricerche, Istituto di Fisiologia Clinica and Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Core Research Laboratory, Via Fiorentina 1, 53100 Siena, Italy
| | - Adriano Angelucci
- Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università degli Studi dell’Aquila, Via Vetoio, 67100, Coppito, L’Aquila, Italy
| | - Silvia Schenone
- Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy
| | - Maurizio Botta
- Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100 Siena, Italy
- Lead Discovery Siena S.r.l., Via Vittorio Alfieri 31, 53019 Castelnuovo Berardenga, Siena, Italy
- Biotechnology College of Science and Technology, Temple University, Biolife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, Pennsylvania 19122, United States
| | - Arianna Mancini
- Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100 Siena, Italy
- Dipartimento di Farmacia, Università di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy
| |
Collapse
|
|
35
|
Luo T, Chen X, Zeng S, Guan B, Hu B, Meng Y, Liu F, Wong T, Lu Y, Yun C, Hocher B, Yin L. Bioinformatic identification of key genes and analysis of prognostic values in clear cell renal cell carcinoma. Oncol Lett 2018; 16:1747-1757. [PMID: 30008862 PMCID: PMC6036467 DOI: 10.3892/ol.2018.8842] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 05/22/2018] [Indexed: 12/29/2022] Open
Abstract
The present study aimed to identify new key genes as potential biomarkers for the diagnosis, prognosis or targeted therapy of clear cell renal cell carcinoma (ccRCC). Three expression profiles (GSE36895, GSE46699 and GSE71963) were collected from Gene Expression Omnibus. GEO2R was used to identify differentially expressed genes (DEGs) in ccRCC tissues and normal samples. The Database for Annotation, Visualization and Integrated Discovery was utilized for functional and pathway enrichment analysis. STRING v10.5 and Molecular Complex Detection were used for protein-protein interaction (PPI) network construction and module analysis, respectively. Regulation network analyses were performed with the WebGestal tool. UALCAN web-portal was used for expression validation and survival analysis of hub genes in ccRCC patients from The Cancer Genome Atlas (TCGA). A total of 65 up- and 164 downregulated genes were identified as DEGs. DEGs were enriched with functional terms and pathways compactly related to ccRCC pathogenesis. Seventeen hub genes and one significant module were filtered out and selected from the PPI network. The differential expression of hub genes was verified in TCGA patients. Kaplan-Meier plot showed that high mRNA expression of enolase 2 (ENO2) was associated with short overall survival in ccRCC patients (P=0.023). High mRNA expression of cyclin D1 (CCND1) (P<0.001), fms related tyrosine kinase 1 (FLT1) (P=0.004), plasminogen (PLG) (P<0.001) and von Willebrand factor (VWF) (P=0.008) appeared to serve as favorable factors in survival. These findings indicate that the DEGs may be key genes in ccRCC pathogenesis and five genes, including ENO2, CCND1, PLT1, PLG and VWF, may serve as potential prognostic biomarkers in ccRCC.
Collapse
Affiliation(s)
- Ting Luo
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Xiaoyi Chen
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Shufei Zeng
- Department of Nephrology, Charité-Universitätsmedizin Berlin, Campus Mitte, D-10117 Berlin, Germany
| | - Baozhang Guan
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Bo Hu
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Yu Meng
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Fanna Liu
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Taksui Wong
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Yongpin Lu
- Department of Nephrology, Charité-Universitätsmedizin Berlin, Campus Mitte, D-10117 Berlin, Germany
| | - Chen Yun
- Department of Nephrology, Charité-Universitätsmedizin Berlin, Campus Mitte, D-10117 Berlin, Germany
| | - Berthold Hocher
- Institute of Nutritional Sciences, University of Potsdam, D-14558 Potsdam, Germany
| | - Lianghong Yin
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| |
Collapse
|
|
36
|
Cao H, Huang Y, Wang L, Wang H, Pang X, Li K, Dang W, Tang H, Wei L, Su M, Tang C, Chen T. Leptin promotes migration and invasion of breast cancer cells by stimulating IL-8 production in M2 macrophages. Oncotarget 2018; 7:65441-65453. [PMID: 27588409 PMCID: PMC5323167 DOI: 10.18632/oncotarget.11761] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Accepted: 08/13/2016] [Indexed: 02/02/2023] Open
Abstract
This study aims to investigate the mechanisms underlying leptin-mediated crosstalk between tumor-associated macrophages (M2 macrophages) and breast cancer cells. THP1 human leukemic monocytes were induced to differentiate into M2 macrophages by PMA (100 nM) and IL-4 (20 ng/mL). Quantitative RT-PCR and Western blot revealed that leptin (100 nM) significantly increased the expression of leptin receptor (ObR) in the M2 macrophages (P < 0.01) and stimulated interleukin (IL)-8 expression in the M2 macrophages, mouse macrophage cells RAW264.7, and primary mouse peritoneal macrophages in a dose- and time-dependent manner. Leptin-induced IL-8 production was sensitive to the ERK inhibitor PD980590 (10 μmol/L), p38 MAPK inhibitor SB203580 (20 μmol/L), and anti-ObR neutralizing antibody (4 μg/mL). Leptin (100 ng/mL) substantially increased the phosphorylation of p38 and ERK1/2. Thus, leptin may induce IL-8 production in M2 macrophages by interacting with ObR to activate the p38 and ERK signaling pathways. Scratch and transwell chamber assay showed that both recombinant IL-8 and leptin-induced M2 macrophage-derived IL-8 promoted the migration and invasion of human breast cancer cells MCF7 and MDA-MB-231 (All P < 0.01). In a nude mice xenograft model of breast cancer (n = 5 per group), injection of leptin (0.1 μg/g) dramatically increased tumor volume and mass, reduced survival, exacerbated pulmonary metastasis, and elevated IL-8 and Ki67 expression in the tumor tissue (All P < 0.05) compared with PBS injection. Depletion of mouse macrophage by Clophosome®-clodronate liposome and injection of anti-mouse IL-8 neutralizing antibodies in the xenograft tumor significantly attenuated those leptin-mediated stimulations (All P < 0.05). These findings indicate that leptin may promote tumor growth and metastasis by stimulating IL-8 production in tumor-associated macrophage.
Collapse
Affiliation(s)
- Hong Cao
- Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China
| | - Yunxiu Huang
- Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China
| | - Lin Wang
- Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China
| | - Hong Wang
- Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China
| | - Xueli Pang
- Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China
| | - Kuangfa Li
- Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China
| | - Weiqi Dang
- Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China
| | - Hao Tang
- Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China
| | - Lan Wei
- Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China
| | - Min Su
- Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China
| | - Cuiping Tang
- Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China
| | - Tingmei Chen
- Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
37
|
Afaloniati H, Karagiannis GS, Hardas A, Poutahidis T, Angelopoulou K. Inflammation-driven colon neoplasmatogenesis in uPA-deficient mice is associated with an increased expression of Runx transcriptional regulators. Exp Cell Res 2017; 361:257-264. [DOI: 10.1016/j.yexcr.2017.10.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 10/23/2017] [Accepted: 10/24/2017] [Indexed: 02/06/2023]
|
|
38
|
Karagüzel E, Menteşe A, Kazaz İO, Demir S, Örem A, Okatan AE, Altay DU, Yaman SÖ. SCUBE1: a promising biomarker in renal cell cancer. Int Braz J Urol 2017; 43:638-643. [PMID: 28379666 PMCID: PMC5557438 DOI: 10.1590/s1677-5538.ibju.2016.0316] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Accepted: 01/04/2017] [Indexed: 12/29/2022] Open
Abstract
PURPOSE To investigate the efficacy of signal peptide-CUB-EGF domain-containing protein 1 (SCUBE-1) as a novel biomarker of renal tumors. MATERIALS AND METHODS 48 individuals were included in the study. The patient group (Group-1) consisted of 23 subjects diagnosed with renal tumor, and the control group (Group-2) of 25 healthy individuals. Patients diagnosed with renal tumor received surgical treatment consisting of radical or partial nephrectomy. Blood specimens were collected following overnight fasting. Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE-1), soluble urokinase plasminogen activator receptor (suPAR) and carbonic anhydrase IX (CA IX) levels were measured from plasma samples. Patients in groups 1 and 2 were compared in terms of these biochemical parameters. RESULTS The 23-member renal tumor group was made up of 17 (73.91%) male and 6 (26.08%) female patients with a mean age of 58.5±15.7 years (range 25 to 80). The 24-member healthy control group was made up of 16 (64%) male and 9 (36%) female subjects with a mean age of 52.4±9.12 years (range 40 to 67). Analysis revealed significant elevation in SCUBE-1 levels in the renal tumor group (p=0.005). No significant differences were detected between the groups with regard to CA IX or suPAR measurements (p=0.062 vs. p=0.176). CONCLUSIONS SCUBE-1 appears to represent a promising biomarker in the diagnosis and follow-up of patients with renal tumor.
Collapse
Affiliation(s)
- Ersagun Karagüzel
- Department of Urology, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey
| | - Ahmet Menteşe
- Program of Medical Laboratory Techniques, Karadeniz Technical University, Vocational School of Health Sciences, Trabzon, Turkey
| | - İlke O Kazaz
- Department of Urology, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey
| | - Selim Demir
- Department of Nutrition and Dietetics, Karadeniz Technical University, School of Medicine, Trabzon, Turkey
| | - Asım Örem
- Department of Medical Biochemistry, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey
| | - Ali Ertan Okatan
- Department of Urology, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey
| | - Diler Us Altay
- Department of Chemistry and Chemical Processing Technology, Ordu University, Ulubey Vocational School, Ordu, Turkey
| | - Serap Özer Yaman
- Department of Medical Biochemistry, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey
| |
Collapse
|
|
39
|
Stallings-Mann ML, Heinzen EP, Vierkant RA, Winham SJ, Hoskin TL, Denison LA, Nassar A, Hartmann LC, Visscher DW, Frost MH, Sherman ME, Degnim AC, Radisky DC. Postlactational involution biomarkers plasminogen and phospho-STAT3 are linked with active age-related lobular involution. Breast Cancer Res Treat 2017; 166:133-143. [PMID: 28752190 PMCID: PMC5645446 DOI: 10.1007/s10549-017-4413-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 07/22/2017] [Indexed: 11/30/2022]
Abstract
Purpose Breast terminal duct lobular units undergo two distinctive physiological processes of involution: age-related lobular involution (LI), which is gradual and associated with decreased breast cancer risk, and postlactational involution, which is relatively precipitous, occurs with weaning, and has been associated with potentiation of tumor aggressiveness in animal models. Here we assessed whether markers of postlactational involution are associated with ongoing LI in a retrospective tissue cohort. Methods We selected 57 women from the Mayo Clinic Benign Breast Disease Cohort who underwent multiple biopsies and who were average age 48 at initial biopsy. Women were classified as having progressive or non-progressive LI between initial and subsequent biopsy. Serial tissue sections were immunostained for plasminogen, matrix metalloproteinase 9 (MMP-9), phospho-STAT3 (pSTAT3), tenascin C, Ki67, CD44, cytokeratin 14 (CK14), cytokeratin 19 (CK19), and c-myc. All but Ki67 were digitally quantified. Associations between maximal marker expression per sample and progressive versus non-progressive LI were assessed using logistic regression and adjusted for potential confounders. Results While no biomarker showed statistically significant association with LI progression when evaluated individually, lower expression of pSTAT3 (OR 0.35, 95% CI 0.13–0.82, p = 0.01) and higher expression of plasminogen (OR 2.89, 95% CI 1.14–8.81, p = 0.02) were associated with progressive LI in models simultaneously adjusted for all biomarkers. Sensitivity analyses indicated that the strengthening in association for pSTAT3 and plasminogen with progressive LI was due to collinearity between these two markers. Conclusions This is the first study to identify biomarkers of active LI. Our findings that plasminogen and pSTAT3 are significantly associated with LI suggest that they may represent signaling nodes or biomarkers of pathways common to the processes of postlactational involution and LI. Electronic supplementary material The online version of this article (doi:10.1007/s10549-017-4413-3) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
| | - Ethan P Heinzen
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA
| | - Robert A Vierkant
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA
| | - Stacey J Winham
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA
| | - Tanya L Hoskin
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA
| | - Lori A Denison
- Department of Information Technology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Aziza Nassar
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Lynn C Hartmann
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Daniel W Visscher
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Marlene H Frost
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Mark E Sherman
- Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Amy C Degnim
- Department of Surgery, Mayo Clinic, Rochester, MN, 55905, USA
| | - Derek C Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA.
| |
Collapse
|
|
40
|
Paquet-Fifield S, Roufail S, Zhang YF, Sofian T, Byrne DJ, Coughlin PB, Fox SB, Stacker SA, Achen MG. The fibrinolysis inhibitor α 2-antiplasmin restricts lymphatic remodelling and metastasis in a mouse model of cancer. Growth Factors 2017; 35:61-75. [PMID: 28697634 DOI: 10.1080/08977194.2017.1349765] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Remodelling of lymphatic vessels in tumours facilitates metastasis to lymph nodes. The growth factors VEGF-C and VEGF-D are well known inducers of lymphatic remodelling and metastasis in cancer. They are initially produced as full-length proteins requiring proteolytic processing in order to bind VEGF receptors with high affinity and thereby promote lymphatic remodelling. The fibrinolytic protease plasmin promotes processing of VEGF-C and VEGF-D in vitro, but its role in processing them in cancer was unknown. Here we explore plasmin's role in proteolytically activating VEGF-D in vivo, and promoting lymphatic remodelling and metastasis in cancer, by co-expressing the plasmin inhibitor α2-antiplasmin with VEGF-D in a mouse tumour model. We show that α2-antiplasmin restricts activation of VEGF-D, enlargement of intra-tumoural lymphatics and occurrence of lymph node metastasis. Our findings indicate that the fibrinolytic system influences lymphatic remodelling in tumours which is consistent with previous clinicopathological observations correlating fibrinolytic components with cancer metastasis.
Collapse
Affiliation(s)
- Sophie Paquet-Fifield
- a Tumour Angiogenesis and Microenvironment Program , Peter MacCallum Cancer Centre , Melbourne , Australia
| | - Sally Roufail
- a Tumour Angiogenesis and Microenvironment Program , Peter MacCallum Cancer Centre , Melbourne , Australia
| | - You-Fang Zhang
- a Tumour Angiogenesis and Microenvironment Program , Peter MacCallum Cancer Centre , Melbourne , Australia
| | - Trifina Sofian
- b Australian Centre for Blood Diseases , Monash University , Prahran, Melbourne , Australia
| | - David J Byrne
- a Tumour Angiogenesis and Microenvironment Program , Peter MacCallum Cancer Centre , Melbourne , Australia
- c Department of Pathology , Peter MacCallum Cancer Centre , Melbourne , Australia
| | - Paul B Coughlin
- b Australian Centre for Blood Diseases , Monash University , Prahran, Melbourne , Australia
- d Eastern Health , Box Hill , Australia
| | - Stephen B Fox
- a Tumour Angiogenesis and Microenvironment Program , Peter MacCallum Cancer Centre , Melbourne , Australia
- c Department of Pathology , Peter MacCallum Cancer Centre , Melbourne , Australia
- e Sir Peter MacCallum Department of Oncology , University of Melbourne , Parkville , Australia
| | - Steven A Stacker
- a Tumour Angiogenesis and Microenvironment Program , Peter MacCallum Cancer Centre , Melbourne , Australia
- e Sir Peter MacCallum Department of Oncology , University of Melbourne , Parkville , Australia
| | - Marc G Achen
- a Tumour Angiogenesis and Microenvironment Program , Peter MacCallum Cancer Centre , Melbourne , Australia
- e Sir Peter MacCallum Department of Oncology , University of Melbourne , Parkville , Australia
| |
Collapse
|
|
41
|
Overexpression of MMP-3 and uPA with Diminished PAI-1 Related to Metastasis in Ductal Breast Cancer Patients Attending a Public Hospital in Mexico City. J Immunol Res 2016; 2016:8519648. [PMID: 27975070 PMCID: PMC5126427 DOI: 10.1155/2016/8519648] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Accepted: 08/28/2016] [Indexed: 02/07/2023] Open
Abstract
Extracellular matrix metalloproteases and the fibrinolytic system are important protease systems interacting with each other in charge of remodeling and recycling of tissues. Their role in tumor invasion and metastasis is often discussed. In this study several metalloproteases such as MMP-1, MMP-3, MMP-9, and TIMP-1 together with molecules from the fibrinolytic system like uPA, its receptor uPAR, and its inhibitor, PAI-1, were studied by immune-histochemistry to establish a comparison with and without metastasis. From the (118) primary tumors of Mexican patients with ductal breast cancer studied, 56% were grade II and 69% were size T2; the group with metastatic ganglia included 64 samples (54.3%). In patients with metastasis the estimated expression of MMP-3 and uPA (resp., 28% and 45%) was higher than that from no metastatic tumors; it means there is higher expression of both markers in metastatic tumors (p < 0.05). At the same time, metastatic tumors showed statistically significant lower signal of PAI-1 (24%) than tumors without metastasis (p < 0.05). We concluded that overexpression of MMP-3 and uPA, altogether with diminished expression of PAI-1 from metastatic tumors, might be a crucial step towards metastasis in ductal breast cancer. Nevertheless, additional studies in different populations are necessary to establish a pattern.
Collapse
|
|
42
|
Ricciardelli C, Lokman NA, Ween MP, Oehler MK. WOMEN IN CANCER THEMATIC REVIEW: Ovarian cancer-peritoneal cell interactions promote extracellular matrix processing. Endocr Relat Cancer 2016; 23:T155-T168. [PMID: 27578826 DOI: 10.1530/erc-16-0320] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 08/30/2016] [Indexed: 12/13/2022]
Abstract
Ovarian cancer has a distinct tendency for metastasising via shedding of cancerous cells into the peritoneal cavity and implanting onto the peritoneum that lines the pelvic organs. Once ovarian cancer cells adhere to the peritoneal cells, they migrate through the peritoneal layer and invade the local organs. Alterations in the extracellular environment are critical for tumour initiation, progression and intra-peritoneal dissemination. To increase our understanding of the molecular mechanisms involved in ovarian cancer metastasis and to identify novel therapeutic targets, we recently studied the interaction of ovarian cancer and peritoneal cells using a proteomic approach. We identified several extracellular matrix (ECM) proteins including, fibronectin, TGFBI, periostin, annexin A2 and PAI-1 that were processed as a result of the ovarian cancer-peritoneal cell interaction. This review focuses on the functional role of these proteins in ovarian cancer metastasis. Our findings together with published literature support the notion that ECM processing via the plasminogen-plasmin pathway promotes the colonisation and attachment of ovarian cancer cells to the peritoneum and actively contributes to the early steps of ovarian cancer metastasis.
Collapse
Affiliation(s)
- C Ricciardelli
- Discipline of Obstetrics and GynaecologyAdelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia
| | - N A Lokman
- Discipline of Obstetrics and GynaecologyAdelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia
| | - M P Ween
- Lung Research LaboratoryHanson Institute, Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - M K Oehler
- Discipline of Obstetrics and GynaecologyAdelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia
- Department of Gynaecological OncologyRoyal Adelaide Hospital, Adelaide, South Australia, Australia
| |
Collapse
|
|
43
|
El Edel RH, Essa ES, Essa AS, Hegazy SA, El Rowedy DI. Serum PAI-1 andPAI-14G/5G Polymorphism in Hepatitis C Virus-Induced Cirrhosis and Hepatitis C Virus-Induced Hepatocellular Carcinoma Patients. Viral Immunol 2016; 29:510-515. [DOI: 10.1089/vim.2016.0027] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Rawhia H. El Edel
- Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebein ElKom, Egypt
| | - Enas Said Essa
- Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebein ElKom, Egypt
| | - Abdallah S. Essa
- Department of Tropical Medicine, Faculty of Medicine, Menoufia University, Shebein ElKom, Egypt
| | - Sara A. Hegazy
- Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebein ElKom, Egypt
| | - Dalia I. El Rowedy
- Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebein ElKom, Egypt
| |
Collapse
|
|
44
|
mTORC2 activation is regulated by the urokinase receptor (uPAR) in bladder cancer. Cell Signal 2016; 29:96-106. [PMID: 27777073 DOI: 10.1016/j.cellsig.2016.10.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 10/18/2016] [Accepted: 10/18/2016] [Indexed: 01/03/2023]
Abstract
Mammalian target of rapamycin complex 2 (mTORC2) has been identified as a major regulator of bladder cancer cell migration and invasion. Upstream pathways that mediate mTORC2 activation remain poorly defined. Urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored membrane protein and known activator of cell-signaling. We identified increased uPAR expression in 94% of invasive human bladder cancers and in 54-71% of non-invasive bladder cancers, depending on grade. Normal urothelium was uPAR-immunonegative. Analysis of publicly available datasets identified uPAR gene amplification or mRNA upregulation in a subset of bladder cancer patients with reduced overall survival. Using biochemical approaches, we showed that uPAR activates mTORC2 in bladder cancer cells. Highly invasive bladder cancer cell lines, including T24, J82 and UM-UC-3 cells, showed increased uPAR mRNA expression and protein levels compared with the less aggressive cell lines, UROtsa and RT4. uPAR gene-silencing significantly reduced phosphorylation of Serine-473 in Akt, an mTORC2 target. uPAR gene-silencing also reduced bladder cancer cell migration and Matrigel invasion. S473 phosphorylation was observed by immunohistochemistry in human bladder cancers only when the tumors expressed high levels of uPAR. S473 phosphorylation was not controlled by uPAR in bladder cancer cell lines that are PTEN-negative; however, this result probably did not reflect altered mTORC2 regulation. Instead, PTEN deficiency de-repressed alternative kinases that phosphorylate S473. Our results suggest that uPAR and mTORC2 are components of a single cell-signaling pathway. Targeting uPAR or mTORC2 may be beneficial in patients with bladder cancer.
Collapse
|
|
45
|
Fortenberry YM, Brandal SM, Carpentier G, Hemani M, Pathak AP. Intracellular Expression of PAI-1 Specific Aptamers Alters Breast Cancer Cell Migration, Invasion and Angiogenesis. PLoS One 2016; 11:e0164288. [PMID: 27755560 PMCID: PMC5068744 DOI: 10.1371/journal.pone.0164288] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 09/22/2016] [Indexed: 02/07/2023] Open
Abstract
Plasminogen activator inhibitor-1 (PAI-1) is elevated in various cancers, where it has been shown to effect cell migration and invasion and angiogenesis. While, PAI-1 is a secreted protein, its intercellular levels are increased in cancer cells. Consequently, intracellular PAI-1 could contribute to cancer progression. While various small molecule inhibitors of PAI-1 are currently being investigated, none specifically target intracellular PAI-1. A class of inhibitors, termed aptamers, has been used effectively in several clinical applications. We previously generated RNA aptamers that target PAI-1 and demonstrated their ability to inhibit extracellular PAI-1. In the current study we explored the effect of these aptamers on intracellular PAI-1. We transiently transfected the PAI-1 specific aptamers into both MDA-MB-231 human breast cancer cells, and human umbilical vein endothelial cells (HUVECs) and studied their effects on cell migration, invasion and angiogenesis. Aptamer expressing MDA-MB-231 cells exhibited a decrease in cell migration and invasion. Additionally, intracellular PAI-1 and urokinase plasminogen activator (uPA) protein levels decreased, while the PAI-1/uPA complex increased. Moreover, a significant decrease in endothelial tube formation in HUVECs transfected with the aptamers was observed. In contrast, conditioned media from aptamer transfected MDA-MB-231 cells displayed a slight pro-angiogenic effect. Collectively, our study shows that expressing functional aptamers inside breast and endothelial cells is feasible and may exhibit therapeutic potential.
Collapse
Affiliation(s)
- Yolanda M Fortenberry
- Department of Pediatric Hematology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.,Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Stephanie M Brandal
- Department of Pediatric Hematology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Gilles Carpentier
- Laboratoire CRRET, Faculté des Sciences et Technologie, Université Paris-Est Créteil, 61 avenue du général De Gaulle, 94010 Créteil, France
| | - Malvi Hemani
- Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Arvind P Pathak
- Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| |
Collapse
|
|
46
|
Pakrashi T, Taylor JE, Nelson A, Archer DF, Jacot T. The Effect of Levonorgestrel on Fibrinolytic Factors in Human Endometrial Endothelial Cells. Reprod Sci 2016; 23:1536-1541. [DOI: 10.1177/1933719116645193] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Tarita Pakrashi
- Department of Obstetrics and Gynecology, Jones Institute for Reproductive Medicine/Eastern Virginia Medical School, Norfolk, VA, USA
| | | | - Ashley Nelson
- Department of Obstetrics and Gynecology, Jones Institute for Reproductive Medicine/Eastern Virginia Medical School, Norfolk, VA, USA
| | - David F. Archer
- Department of Obstetrics and Gynecology, Jones Institute for Reproductive Medicine/Eastern Virginia Medical School, Norfolk, VA, USA
| | - Terry Jacot
- Department of Obstetrics and Gynecology, Jones Institute for Reproductive Medicine/Eastern Virginia Medical School, Norfolk, VA, USA
| |
Collapse
|
|
47
|
Purwin M, Markowska A, Bruzgo I, Rusak T, Surażyński A, Jaworowska U, Midura-Nowaczek K. Peptides with 6-Aminohexanoic Acid: Synthesis and Evaluation as Plasmin Inhibitors. Int J Pept Res Ther 2016; 23:235-245. [PMID: 28491013 PMCID: PMC5401710 DOI: 10.1007/s10989-016-9555-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2016] [Indexed: 12/04/2022]
Abstract
Fifteen new peptide derivatives of ɛ-aminocaproic acid (EACA) containing the known fragment –Ala–Phe–Lys– with an affinity for plasmin were synthesised in the present study. The synthesis was carried out a solid phase. The following compounds were synthesised: H–Phe–Lys–EACA–X, H–d-Ala–Phe–Lys–EACA–X, H–Ala–Phe–Lys–EACA–X, H–d-Ala–Phe–EACA–X and H–Ala–Phe–EACA–X, where X = OH, NH2 and NH–(CH2)5–NH2. All peptides, except for those containing the sequence H–Ala–Phe–EACA–X, displayed higher inhibitory activity against plasmin than EACA. The most active and selective inhibitor of plasmin was the compound H–d-Ala–Phe–Lys–EACA–NH2 which inhibited the amidolytic activity of plasmin (IC50 = 0.02 mM), with the antifibrinolytic activity weaker than EACA. The resulting peptides did not affect the viability of fibroblast cells, colon cancer cell line DLD-1, breast MCF-7 and MDA-MB-231 cell lines.
Collapse
Affiliation(s)
- Maciej Purwin
- Department of Organic Chemistry, Medical University of Bialystok, Mickiewicza 2A Str, 15-222 Białystok, Poland
| | - Agnieszka Markowska
- Department of Organic Chemistry, Medical University of Bialystok, Mickiewicza 2A Str, 15-222 Białystok, Poland
| | - Irena Bruzgo
- Department of Organic Chemistry, Medical University of Bialystok, Mickiewicza 2A Str, 15-222 Białystok, Poland
| | - Tomasz Rusak
- Department of Physical Chemistry, Medical University of Bialystok, Mickiewicza 2A Str, 15-222 Białystok, Poland
| | - Arkadiusz Surażyński
- Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2A Str, 15-222 Białystok, Poland
| | - Urszula Jaworowska
- Department of Organic Chemistry, Medical University of Bialystok, Mickiewicza 2A Str, 15-222 Białystok, Poland
| | - Krystyna Midura-Nowaczek
- Department of Organic Chemistry, Medical University of Bialystok, Mickiewicza 2A Str, 15-222 Białystok, Poland
| |
Collapse
|
|
48
|
Pavón MA, Arroyo-Solera I, Téllez-Gabriel M, León X, Virós D, López M, Gallardo A, Céspedes MV, Casanova I, López-Pousa A, Mangues MA, Quer M, Barnadas A, Mangues R. Enhanced cell migration and apoptosis resistance may underlie the association between high SERPINE1 expression and poor outcome in head and neck carcinoma patients. Oncotarget 2016; 6:29016-33. [PMID: 26359694 DOI: 10.18632/oncotarget.5032] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 08/14/2015] [Indexed: 12/24/2022] Open
Abstract
High SERPINE1 expression is a common event in head and neck squamous cell carcinoma (HNSCC); however, whether it plays a role in determining clinical outcome remains still unknown. We studied SERPINE1 as a prognostic marker in two HNSCC patient cohorts. In a retrospective study (n = 80), high expression of SERPINE1 was associated with poor progression-free (p = 0.022) and cancer-specific (p = 0.040) survival. In a prospective study (n = 190), high SERPINE1 expression was associated with poor local recurrence-free (p = 0.022), progression-free (p = 0.002) and cancer-specific (p = 0.006) survival. SERPINE1 expression was identified as an independent risk factor for progression-free survival in patients treated with chemo-radiotherapy or radiotherapy (p = 0.043). In both patient cohorts, high SERPINE1 expression increased the risk of metastasis spread (p = 0.045; p = 0.029). The association between SERPINE1 expression and survival was confirmed using the HNSCC cohort included in The Cancer Genome Atlas project (n = 507). Once again, patients showing high expression had a poorer survival (p < 0.001). SERPINE1 over-expression in HNSCC cells reduced cell proliferation and enhanced migration. It also protected cells from cisplatin-induced apoptosis, which was accompanied by PI3K/AKT pathway activation. Downregulation of SERPINE1 expression had the opposite effect. We propose SERPINE1 expression as a prognostic marker that could be used to stratify HNSCC patients according to their risk of recurrence.
Collapse
Affiliation(s)
- Miguel Angel Pavón
- Grup d'Oncogènesi i Antitumorals, lnstitut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain.,Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomecidicina (CIBER-BBN), Barcelona, Spain
| | - Irene Arroyo-Solera
- Grup d'Oncogènesi i Antitumorals, lnstitut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain.,Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomecidicina (CIBER-BBN), Barcelona, Spain
| | - Marta Téllez-Gabriel
- Grup d'Oncogènesi i Antitumorals, lnstitut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain.,Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomecidicina (CIBER-BBN), Barcelona, Spain
| | - Xavier León
- Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomecidicina (CIBER-BBN), Barcelona, Spain.,Department of Otorrinolaryngology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - David Virós
- Department of Otorrinolaryngology, Hospital Moises Broggi, Sant Joan Despí, Spain
| | - Montserrat López
- Department of Otorrinolaryngology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | | | - Maria Virtudes Céspedes
- Grup d'Oncogènesi i Antitumorals, lnstitut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain.,Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomecidicina (CIBER-BBN), Barcelona, Spain
| | - Isolda Casanova
- Grup d'Oncogènesi i Antitumorals, lnstitut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain.,Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomecidicina (CIBER-BBN), Barcelona, Spain
| | - Antonio López-Pousa
- Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomecidicina (CIBER-BBN), Barcelona, Spain.,Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | | | - Miquel Quer
- Department of Otorrinolaryngology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Agustí Barnadas
- Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Ramón Mangues
- Grup d'Oncogènesi i Antitumorals, lnstitut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain.,Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomecidicina (CIBER-BBN), Barcelona, Spain
| |
Collapse
|
|
49
|
Filtjens J, Keirsse J, Van Ammel E, Taveirne S, Van Acker A, Kerre T, Taghon T, Vandekerckhove B, Plum J, Van Ginderachter JA, Leclercq G. Expression of the inhibitory Ly49E receptor is not critically involved in the immune response against cutaneous, pulmonary or liver tumours. Sci Rep 2016; 6:30564. [PMID: 27469529 PMCID: PMC4965774 DOI: 10.1038/srep30564] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 07/06/2016] [Indexed: 02/08/2023] Open
Abstract
Natural killer (NK) lymphocytes are part of the innate immune system and are important in immune protection against tumourigenesis. NK cells display a broad repertoire of activating and inhibitory cell surface receptors that regulate NK cell activity. The Ly49 family of NK receptors is composed of several members that recognize major histocompatibility complex class I (MHC-I) or MHC-I-related molecules. Ly49E is a unique inhibitory member, being triggered by the non-MHC-I-related protein urokinase plasminogen activator (uPA) in contrast to the known MHC-I-triggering of the other inhibitory Ly49 receptors. Ly49E also has an uncommon expression pattern on NK cells, including high expression on liver DX5− NK cells. Furthermore, Ly49E is the only Ly49 member expressed by epidermal γδ T cells. As γδ T cells and/or NK cells have been shown to be involved in the regulation of cutaneous, pulmonary and liver malignancies, and as uPA is involved in tumourigenesis, we investigated the role of the inhibitory Ly49E receptor in the anti-tumour immune response. We demonstrate that, although Ly49E is highly expressed on epidermal γδ T cells and liver NK cells, this receptor does not play a major role in the control of skin tumour formation or in lung and liver tumour development.
Collapse
Affiliation(s)
- Jessica Filtjens
- Laboratory of Experimental Immunology, Ghent University, Ghent, Belgium
| | - Jiri Keirsse
- Myeloid Cell Immunology Lab, VIB Inflammation Research Center, Ghent, Belgium.,Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Els Van Ammel
- Laboratory of Experimental Immunology, Ghent University, Ghent, Belgium
| | - Sylvie Taveirne
- Laboratory of Experimental Immunology, Ghent University, Ghent, Belgium
| | - Aline Van Acker
- Laboratory of Experimental Immunology, Ghent University, Ghent, Belgium
| | - Tessa Kerre
- Laboratory of Experimental Immunology, Ghent University, Ghent, Belgium
| | - Tom Taghon
- Laboratory of Experimental Immunology, Ghent University, Ghent, Belgium
| | | | - Jean Plum
- Laboratory of Experimental Immunology, Ghent University, Ghent, Belgium
| | - Jo A Van Ginderachter
- Myeloid Cell Immunology Lab, VIB Inflammation Research Center, Ghent, Belgium.,Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Georges Leclercq
- Laboratory of Experimental Immunology, Ghent University, Ghent, Belgium
| |
Collapse
|
|
50
|
Botla SK, Savant S, Jandaghi P, Bauer AS, Mücke O, Moskalev EA, Neoptolemos JP, Costello E, Greenhalf W, Scarpa A, Gaida MM, Büchler MW, Strobel O, Hackert T, Giese NA, Augustin HG, Hoheisel JD. Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression. Cancer Res 2016; 76:4149-59. [PMID: 27216198 DOI: 10.1158/0008-5472.can-15-0390] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Accepted: 04/22/2016] [Indexed: 12/27/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial-mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149-59. ©2016 AACR.
Collapse
Affiliation(s)
- Sandeep K Botla
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Soniya Savant
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faulty Mannheim, Heidelberg University, Mannheim, Germany
| | - Pouria Jandaghi
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andrea S Bauer
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Oliver Mücke
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Evgeny A Moskalev
- Diagnostic Molecular Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - John P Neoptolemos
- National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK
| | - Eithne Costello
- National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK
| | - William Greenhalf
- National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK
| | - Aldo Scarpa
- Department of Pathology and Diagnostics, Università di Verona, Verona, Italy
| | - Matthias M Gaida
- Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Markus W Büchler
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Oliver Strobel
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Thilo Hackert
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Nathalia A Giese
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Hellmut G Augustin
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faulty Mannheim, Heidelberg University, Mannheim, Germany. German Cancer Consortium, Heidelberg, Germany
| | - Jörg D Hoheisel
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| |
Collapse
|