|
1
|
Ibrahim AA, Fujimura T, Uno T, Terada T, Hirano KI, Hosokawa H, Ohta A, Miyata T, Ando K, Yahata T. Plasminogen activator inhibitor-1 promotes immune evasion in tumors by facilitating the expression of programmed cell death-ligand 1. Front Immunol 2024; 15:1365894. [PMID: 38779680 PMCID: PMC11109370 DOI: 10.3389/fimmu.2024.1365894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 04/23/2024] [Indexed: 05/25/2024] Open
Abstract
Background Increased levels of plasminogen activator inhibitor-1 (PAI-1) in tumors have been found to correlate with poor clinical outcomes in patients with cancer. Although abundant data support the involvement of PAI-1 in cancer progression, whether PAI-1 contributes to tumor immune surveillance remains unclear. The purposes of this study are to determine whether PAI-1 regulates the expression of immune checkpoint molecules to suppresses the immune response to cancer and demonstrate the potential of PAI-1 inhibition for cancer therapy. Methods The effects of PAI-1 on the expression of the immune checkpoint molecule programmed cell death ligand 1 (PD-L1) were investigated in several human and murine tumor cell lines. In addition, we generated tumor-bearing mice and evaluated the effects of a PAI-1 inhibitor on tumor progression or on the tumor infiltration of cells involved in tumor immunity either alone or in combination with immune checkpoint inhibitors. Results PAI-1 induces PD-L1 expression through the JAK/STAT signaling pathway in several types of tumor cells and surrounding cells. Blockade of PAI-1 impedes PD-L1 induction in tumor cells, significantly reducing the abundance of immunosuppressive cells at the tumor site and increasing cytotoxic T-cell infiltration, ultimately leading to tumor regression. The anti-tumor effect elicited by the PAI-1 inhibitor is abolished in immunodeficient mice, suggesting that PAI-1 blockade induces tumor regression by stimulating the immune system. Moreover, combining a PAI-1 inhibitor with an immune checkpoint inhibitor significantly increases tumor regression. Conclusions PAI-1 protects tumors from immune surveillance by increasing PD-L1 expression; hence, therapeutic PAI-1 blockade may prove valuable in treating malignant tumors.
Collapse
Affiliation(s)
- Abd Aziz Ibrahim
- Translational Molecular Therapeutics Laboratory, Division of Host Defense Mechanism, Tokai University School of Medicine, Kanagawa, Japan
| | - Taku Fujimura
- Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomoko Uno
- Department of Hematology and Oncology, Tokai University School of Medicine, Kanagawa, Japan
| | - Tomoya Terada
- Translational Molecular Therapeutics Laboratory, Division of Host Defense Mechanism, Tokai University School of Medicine, Kanagawa, Japan
| | - Ken-ichi Hirano
- Department of Immunology, Tokai University School of Medicine, Kanagawa, Japan
| | - Hiroyuki Hosokawa
- Department of Immunology, Tokai University School of Medicine, Kanagawa, Japan
| | - Akio Ohta
- Department of Immunology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan
| | - Toshio Miyata
- Department of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Kiyoshi Ando
- Department of Hematology and Oncology, Tokai University School of Medicine, Kanagawa, Japan
| | - Takashi Yahata
- Translational Molecular Therapeutics Laboratory, Division of Host Defense Mechanism, Tokai University School of Medicine, Kanagawa, Japan
| |
Collapse
|
|
2
|
Kumar AA, Vine KL, Ranson M. Recent Advances in Targeting the Urokinase Plasminogen Activator with Nanotherapeutics. Mol Pharm 2023. [PMID: 37119285 DOI: 10.1021/acs.molpharmaceut.3c00055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2023]
Abstract
The aberrant proteolytic landscape of the tumor microenvironment is a key contributor of cancer progression. Overexpression of urokinase plasminogen activator (uPA) and/or its associated cell-surface receptor (uPAR) in tumor versus normal tissue is significantly associated with worse clinicopathological features and poorer patient survival across multiple cancer types. This is linked to mechanisms that facilitate tumor cell invasion and migration, via direct and downstream activation of various proteolytic processes that degrade the extracellular matrix─ultimately leading to metastasis. Targeting uPA has thus long been considered an attractive anticancer strategy. However, poor bioavailability of several uPA-selective small-molecule inhibitors has limited early clinical progress. Nanodelivery systems have emerged as an exciting method to enhance the pharmacokinetic (PK) profile of existing chemotherapeutics, allowing increased circulation time, improved bioavailability, and targeted delivery to tumor tissue. Combining uPA inhibitors with nanoparticle-based delivery systems thus offers a remarkable opportunity to overcome existing PK challenges associated with conventional uPA inhibitors, while leveraging potent candidates into novel targeted nanotherapeutics for an improved anticancer response in uPA positive tumors.
Collapse
Affiliation(s)
- Ashna A Kumar
- School of Chemistry and Molecular Biosciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Kara L Vine
- School of Chemistry and Molecular Biosciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Marie Ranson
- School of Chemistry and Molecular Biosciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia
| |
Collapse
|
|
3
|
Li R, Dong F, Zhang L, Ni X, Lin G. Role of adipocytokines in endometrial cancer progression. Front Pharmacol 2022; 13:1090227. [PMID: 36578551 PMCID: PMC9791063 DOI: 10.3389/fphar.2022.1090227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
Endometrial cancer is considered a significant barrier to increasing life expectancy and remains one of the most common malignant cancers among women in many countries worldwide. The increasing mortality rates are potentially proportional to the increasing obesity incidence. Adipose tissue secretes numerous adipocytokines, which may play important roles in endometrial cancer progression. In this scenario, we describe the role of adipocytokines in cell proliferation, cell invasion, cell adhesion, inflammation, angiogenesis, and anti-apoptotic action. A better understanding of the mechanisms of these adipocytokines may open up new therapeutic avenues for women with endometrial cancer. In the future, larger prospective studies focusing on adipocytokines and specific inhibitors should be directed at preventing the rapidly increasing prevalence of gynecological malignancies.
Collapse
Affiliation(s)
- Ran Li
- School of Health Sciences, Jiangsu Food and Pharmaceutical Science College, Huaian, China
| | - Fang Dong
- School of Health Sciences, Jiangsu Food and Pharmaceutical Science College, Huaian, China
| | - Ling Zhang
- School of Health Sciences, Jiangsu Food and Pharmaceutical Science College, Huaian, China
| | - Xiuqin Ni
- School of Health Sciences, Jiangsu Food and Pharmaceutical Science College, Huaian, China
| | - Guozhi Lin
- Department of Obstetrics and Gynecology, Second Affiliated Hospital to Shandong First Medical University, Taian, China,*Correspondence: Guozhi Lin,
| |
Collapse
|
|
4
|
O’Connell C, VandenHeuvel S, Kamat A, Raghavan S, Godin B. The Proteolytic Landscape of Ovarian Cancer: Applications in Nanomedicine. Int J Mol Sci 2022; 23:9981. [PMID: 36077371 PMCID: PMC9456334 DOI: 10.3390/ijms23179981] [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: 08/07/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 11/17/2022] Open
Abstract
Ovarian cancer (OvCa) is one of the leading causes of mortality globally with an overall 5-year survival of 47%. The predominant subtype of OvCa is epithelial carcinoma, which can be highly aggressive. This review launches with a summary of the clinical features of OvCa, including staging and current techniques for diagnosis and therapy. Further, the important role of proteases in OvCa progression and dissemination is described. Proteases contribute to tumor angiogenesis, remodeling of extracellular matrix, migration and invasion, major processes in OvCa pathology. Multiple proteases, such as metalloproteinases, trypsin, cathepsin and others, are overexpressed in the tumor tissue. Presence of these catabolic enzymes in OvCa tissue can be exploited for improving early diagnosis and therapeutic options in advanced cases. Nanomedicine, being on the interface of molecular and cellular scales, can be designed to be activated by proteases in the OvCa microenvironment. Various types of protease-enabled nanomedicines are described and the studies that focus on their diagnostic, therapeutic and theranostic potential are reviewed.
Collapse
Affiliation(s)
- Cailin O’Connell
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
- School of Engineering Medicine, Texas A&M University, Houston, TX 77030, USA
| | - Sabrina VandenHeuvel
- Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Aparna Kamat
- Division of Gynecologic Oncology, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Shreya Raghavan
- Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Biana Godin
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Obstetrics and Gynecology, Houston Methodist Hospital, Houston, TX 77030, USA
- Houston Methodist Neal Cancer Center, Houston, TX 77030, USA
- Department of Obstetrics, Gynecology, and Reproductive Sciences at McGovern Medical School-UTHealth, Houston, TX 77030, USA
| |
Collapse
|
|
5
|
Polymeric biocompatible iron oxide nanoparticles labeled with peptides for imaging in ovarian cancer. Biosci Rep 2022; 42:230723. [PMID: 35103283 PMCID: PMC8837818 DOI: 10.1042/bsr20212622] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/11/2022] [Accepted: 01/26/2022] [Indexed: 11/17/2022] Open
Abstract
Compared with other nanomaterials, surface-modified iron oxide nanoparticles (IONPs) have gained attraction for cancer therapy applications due to its low toxicity, and long retention time. An innocuous targeting strategy was developed by generation of fluorescein isothiocyanate (FITC)-labeled peptide (growth factor domain (GFD) and somatomedin B domain (SMB)) functionalized, chitosan-coated IONPs (IONPs/C). It can be used to target urokinase plasminogen activator receptor (uPAR), which is a surface biomarker, in ovarian cancer. Binding affinity between uPAR and peptides (GFD and SMB) were revealed by in-silico docking studies. The biophysical characterizations of IONPs, IONPs/C, and IONPs/C/GFD-FITC or SMB-FITC nanoprobes were assessed via Vibrating Sample Magnetometer (VSM), Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), and Fourier Transform Infrared Spectroscopy (FT-IR). Prussian Blue staining, fluorescence spectroscopy, and fluorescence imaging were performed to confirm the targeting of nanoprobes with the surface receptor uPAR. The combination of IONPs/C/GFD+SMB showed efficient targeting of uPAR in the tumor microenvironment, and thus can be implemented as a molecular magnetic nanoprobe for cancer cell imaging and targeting.
Collapse
|
|
6
|
Li X, Buckley B, Stoletov K, Jing Y, Ranson M, Lewis JD, Kelso M, Fliegel L. Roles of the Na +/H + Exchanger Isoform 1 and Urokinase in Prostate Cancer Cell Migration and Invasion. Int J Mol Sci 2021; 22:ijms222413263. [PMID: 34948058 PMCID: PMC8705693 DOI: 10.3390/ijms222413263] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/02/2021] [Accepted: 12/06/2021] [Indexed: 01/06/2023] Open
Abstract
Prostate cancer is a leading cause of cancer-associated deaths in men over 60 years of age. Most patients are killed by tumor metastasis. Recent evidence has implicated a role of the tumor microenvironment and urokinase plasminogen activator (uPA) in cancer cell migration, invasion, and metastasis. Here, we examine the role of the Na+/H+ exchanger isoform 1 (NHE1) and uPA in DU 145 prostate cancer cell migration and colony formation. Knockout of NHE1 reduced cell migration. The effects of a series of novel NHE1/uPA hexamethylene-amiloride-based inhibitors with varying efficacy towards NHE1 and uPA were examined on prostate cancer cells. Inhibition of NHE1-alone, or with inhibitors combining NHE1 or uPA inhibition-generally did not prevent prostate cancer cell migration. However, uPA inhibition-but not NHE1 inhibition-prevented anchorage-dependent colony formation. Application of inhibitors at concentrations that only saturate uPA inhibition decreased tumor invasion in vivo. The results suggest that while knockout of NHE1 affects cell migration, these effects are not due to NHE1-dependent proton translocation. Additionally, while neither NHE1 nor uPA activity was critical in cell migration, only uPA activity appeared to be critical in anchorage-dependent colony formation of DU 145 prostate cancer cells and invasion in vivo.
Collapse
Affiliation(s)
- Xiuju Li
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada; (X.L.); (Y.J.)
| | - Benjamin Buckley
- Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia; (B.B.); (M.R.); (M.K.)
- School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
- Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Konstantin Stoletov
- Department of Oncology, University of Alberta, Edmonton, AB T6G 2H7, Canada; (K.S.); (J.D.L.)
| | - Yang Jing
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada; (X.L.); (Y.J.)
| | - Marie Ranson
- Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia; (B.B.); (M.R.); (M.K.)
- School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
- Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia
| | - John D. Lewis
- Department of Oncology, University of Alberta, Edmonton, AB T6G 2H7, Canada; (K.S.); (J.D.L.)
| | - Mike Kelso
- Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia; (B.B.); (M.R.); (M.K.)
- School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
- Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Larry Fliegel
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada; (X.L.); (Y.J.)
- Correspondence: ; Tel.: +1-780-492-1848
| |
Collapse
|
|
7
|
Chou CH, Lu KH, Yang JS, Hsieh YH, Lin CW, Yang SF. Dihydromyricetin suppresses cell metastasis in human osteosarcoma through SP-1- and NF-κB-modulated urokinase plasminogen activator inhibition. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 90:153642. [PMID: 34265701 DOI: 10.1016/j.phymed.2021.153642] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/18/2021] [Accepted: 06/22/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Metastasis caused a decline in the 5-years survival rate of osteosarcoma. Therefore, developing new targeted therapeutics for osteosarcoma treatment is imperative. Dihydromyricetin (DHM) has several physiological functions: it counteracts inflammation, oxidation, and antitumor properties. However, the effects of DHM on osteosarcoma and its underlying mechanisms are still not well understood. PURPOSE In this study, we investigated the antimetastatic properties of DHM in human osteosarcoma U-2 OS and HOS cells. METHODS The effects of DHM (0, 25, 50, 75, and 100 μM) on cell viability, migration, and invasion were examined. Western blotting, RT-PCR, and quantitative real-time PCR (QPCR) were determined urokinase plasminogen activator (uPA) expression. The expression of transcriptional factor SP-1 and NF-κB was determined by using immunofluorescence assay, chromatin immunoprecipitation assay, and site-directed mutagenesis luciferase reporter. RESULTS We observed that DHM suppresses cell migration and invasion in osteosarcoma cell lines. In addition, DHM inhibits metastasis by downregulating urokinase plasminogen activator (uPA) expression. Moreover, real-time polymerase chain reaction and promoter activity assays revealed that DHM decreased uPA expression at transcription levels. Furthermore, the inhibition of uPA expression was associated with the suppression of SP-1 and NF-κB, which bind to the uPA promoter. Regardless of blocking or inducing the extracellular signal-regulated kinase (ERK) pathway, we verified that the DHM-related suppression of uPA and cell metastasis occurred through the p-ERK pathway. CONCLUSION We are the first study to propose that DHM suppresses osteosarcoma metastasis through the ERK pathway and through the suppression of SP-1 and NF-κB to inhibit downstream uPA expression. DHM is a potential therapeutic agent for antimetastatic therapy against osteosarcoma.
Collapse
Affiliation(s)
- Chia-Hsuan Chou
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Ko-Hsiu Lu
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Orthopedics, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Jia-Sin Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yi-Hsien Hsieh
- Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan
| | - Chiao-Wen Lin
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
| |
Collapse
|
|
8
|
Shahdeo D, Chandra AB, Gandhi S. Urokinase Plasminogen Activator Receptor-Mediated Targeting of a Stable Nanocomplex Coupled with Specific Peptides for Imaging of Cancer. Anal Chem 2021; 93:11868-11877. [PMID: 34410104 DOI: 10.1021/acs.analchem.1c02697] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Targeting peptides are a promising tool for early diagnosis and therapy of cancer. Overexpression of urokinase plasminogen activator receptor (uPAR) leads to the progression of tumors including prostate, colorectal, ovarian, and breast cancers. To improve the diagnosis and imaging efficiency, herein we report a stable nanocomplex comprising methoxy-PEG-hydrazide (mPEG-H-M)-modified gold nanoparticles (AuNPs) conjugated to uPAR (urokinase plasminogen activator receptor)-targeting peptides GFD (growth factor domain-G) and SMB (somatomedian B-S) for efficient imaging of uPAR-overexpressing cancer cells. Fluorescently labeled targeting peptides were covalently linked to mPEG-H coated AuNPs, characterized, and analyzed by UV-vis spectroscopy, diffraction light scattering (DLS), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), and fluorescence spectroscopy. In vitro evaluation was assessed with a fluorescence-activated cell sorter (FACS), cell adhesion, and fluorescence microscopy. The peptide-functionalized nanocomplex showed a higher uptake of AuNPs@MGS in comparison with AuNPs@G or AuNPs@S alone in uPAR-overexpressing cells and exhibits no toxicity when analyzed with MTT assay. Our results demonstrated that the developed nanocomplex can be used as a platform for imaging and diagnosis of metastatic tumors.
Collapse
Affiliation(s)
- Deepshikha Shahdeo
- DBT-National Institute of Animal Biotechnology, Hyderabad-500032, Telangana, India
| | - Akshay B Chandra
- DBT-National Institute of Animal Biotechnology, Hyderabad-500032, Telangana, India
| | - Sonu Gandhi
- DBT-National Institute of Animal Biotechnology, Hyderabad-500032, Telangana, India.,Amity Institute of Biotechnology, Amity University, Noida-201301, Uttar Pradesh, India
| |
Collapse
|
|
9
|
Rickard BP, Conrad C, Sorrin AJ, Ruhi MK, Reader JC, Huang SA, Franco W, Scarcelli G, Polacheck WJ, Roque DM, del Carmen MG, Huang HC, Demirci U, Rizvi I. Malignant Ascites in Ovarian Cancer: Cellular, Acellular, and Biophysical Determinants of Molecular Characteristics and Therapy Response. Cancers (Basel) 2021; 13:4318. [PMID: 34503128 PMCID: PMC8430600 DOI: 10.3390/cancers13174318] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/17/2021] [Accepted: 08/22/2021] [Indexed: 12/27/2022] Open
Abstract
Ascites refers to the abnormal accumulation of fluid in the peritoneum resulting from an underlying pathology, such as metastatic cancer. Among all cancers, advanced-stage epithelial ovarian cancer is most frequently associated with the production of malignant ascites and is the leading cause of death from gynecologic malignancies. Despite decades of evidence showing that the accumulation of peritoneal fluid portends the poorest outcomes for cancer patients, the role of malignant ascites in promoting metastasis and therapy resistance remains poorly understood. This review summarizes the current understanding of malignant ascites, with a focus on ovarian cancer. The first section provides an overview of heterogeneity in ovarian cancer and the pathophysiology of malignant ascites. Next, analytical methods used to characterize the cellular and acellular components of malignant ascites, as well the role of these components in modulating cell biology, are discussed. The review then provides a perspective on the pressures and forces that tumors are subjected to in the presence of malignant ascites and the impact of physical stress on therapy resistance. Treatment options for malignant ascites, including surgical, pharmacological and photochemical interventions are then discussed to highlight challenges and opportunities at the interface of drug discovery, device development and physical sciences in oncology.
Collapse
Affiliation(s)
- Brittany P. Rickard
- Curriculum in Toxicology & Environmental Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, and North Carolina State University, Raleigh, NC 27599, USA; (M.K.R.); (S.A.H.); (W.J.P.)
| | - Christina Conrad
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (C.C.); (A.J.S.); (G.S.); (H.-C.H.)
| | - Aaron J. Sorrin
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (C.C.); (A.J.S.); (G.S.); (H.-C.H.)
| | - Mustafa Kemal Ruhi
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, and North Carolina State University, Raleigh, NC 27599, USA; (M.K.R.); (S.A.H.); (W.J.P.)
| | - Jocelyn C. Reader
- Department of Obstetrics, Gynecology and Reproductive Medicine, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (J.C.R.); (D.M.R.)
- Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
| | - Stephanie A. Huang
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, and North Carolina State University, Raleigh, NC 27599, USA; (M.K.R.); (S.A.H.); (W.J.P.)
| | - Walfre Franco
- Department of Biomedical Engineering, University of Massachusetts Lowell, Lowell, MA 01854, USA;
| | - Giuliano Scarcelli
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (C.C.); (A.J.S.); (G.S.); (H.-C.H.)
| | - William J. Polacheck
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, and North Carolina State University, Raleigh, NC 27599, USA; (M.K.R.); (S.A.H.); (W.J.P.)
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Dana M. Roque
- Department of Obstetrics, Gynecology and Reproductive Medicine, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (J.C.R.); (D.M.R.)
- Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
| | - Marcela G. del Carmen
- Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA;
| | - Huang-Chiao Huang
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (C.C.); (A.J.S.); (G.S.); (H.-C.H.)
- Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
| | - Utkan Demirci
- Bio-Acoustic MEMS in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology, School of Medicine, Stanford University, Palo Alto, CA 94304, USA;
| | - Imran Rizvi
- Curriculum in Toxicology & Environmental Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, and North Carolina State University, Raleigh, NC 27599, USA; (M.K.R.); (S.A.H.); (W.J.P.)
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| |
Collapse
|
|
10
|
Assessment of breast cancer surgical margins with multimodal optical microscopy: A feasibility clinical study. PLoS One 2021; 16:e0245334. [PMID: 33571221 PMCID: PMC7877783 DOI: 10.1371/journal.pone.0245334] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 12/28/2020] [Indexed: 11/18/2022] Open
Abstract
Providing surgical margin information during breast cancer surgery is crucial for the success of the procedure. The margin is defined as the distance from the tumor to the cut surface of the resection specimen. The consensus among surgeons and radiation oncologists is that there should be no tumor left within 1 to maximum 2 mm from the surface of the surgical specimen. If a positive margin remains, there is substantial risk for tumor recurrence, which may also result in potentially reduced cosmesis and eventual need for mastectomy. In this paper we report a novel multimodal optical imaging instrument based on combined high-resolution confocal microscopy-optical coherence tomography imaging for assessing the presence of potential positive margins on surgical specimens. Since rapid specimen analysis is critical during surgery, this instrument also includes a fluorescence imaging channel to enable rapid identification of the areas of the specimen that have potential positive margins. This is possible by specimen incubation with a cancer specific agent prior to imaging. In this study we used a quenched contrast agent, which is activated by cancer specific enzymes, such as urokinase plasminogen activators (uPA). Using this agent or a similar one, one may limit the use of high-resolution optical imaging to only fluorescence-highlighted areas for visualizing tissue morphology at the sub-cellular scale and confirming or ruling out cancer presence. Preliminary evaluation of this technology was performed on 20 surgical specimens and testing of the optical imaging findings was performed against histopathology. The combination of the three imaging modes allowed for high correlation between optical image analysis and histological ground-truth. The initial results are encouraging, showing instrument capability to assess margins on clinical specimens with a positive predictive value of 1.0 and a negative predictive value of 0.83.
Collapse
|
|
11
|
Tsai MC, Yen YH, Chang KC, Hung CH, Chen CH, Lin MT, Hu TH. Elevated levels of serum urokinase plasminogen activator predict poor prognosis in hepatocellular carcinoma after resection. BMC Cancer 2019; 19:1169. [PMID: 31791275 PMCID: PMC6889356 DOI: 10.1186/s12885-019-6397-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 11/22/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Urokinase plasminogen activator (uPA) is an extracellular matrix-degrading protease that is involved in the invasiveness and progression of cancer. There is good evidence that uPA expression is a clinically relevant biomarker in some solid tumors, but its role in hepatocellulcar carcinoma (HCC) is uncertain. We evaluated the prognostic value of serum uPA before surgery in HCC patients receiving curative resection. METHODS Serum uPA levels were determined by enzyme-linked immunosorbent assay in 282 HCC patients who received complete liver resections at Kaohsiung Chang Gung Memorial Hospital. Overall survival (OS) curves were constructed using the Kaplan-Meier method and compared using the log-rank test. A Cox proportional -hazards regression model was used to identify independent prognostic factors. The median follow-up time was 52 months. RESULTS Patients with higher pretreatment serum uPA (≥1 ng/ml) had significantly shorter OS (p = 0.002). Patients with liver cirrhosis, hypoalbuminemia, and thrombocytopenia were significantly more likely to present with elevated uPA levels. Multivariate Cox regression analyses indicated that high pretreatment serum uPA [hazard ratio (HR), 1.848, p = 0.006], vascular invasion (HR, 2.940, p < 0.001), and pathology stage III/IV (HR, 3.517, p < 0.001) were independent prognostic factors for OS. In further stratified analyses, the combination of serum uPA and AFP had more capacity to predict OS. CONCLUSIONS We conclude that uPA is a clinically relevant biomarker in HCC patients receiving curative resection, with higher expression of uPA being associated with higher mortality. This also highlights the potential utility of uPA as a therapeutic target for improved treatment strategies.
Collapse
Affiliation(s)
- Ming-Chao Tsai
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist., Kaohsiung City, 83301, Taiwan.,Institute of Clinical Medical Sciences, Chang Gung University, Kaohsiung, 83301, Taiwan
| | - Yi-Hao Yen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist., Kaohsiung City, 83301, Taiwan
| | - Kuo-Chin Chang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist., Kaohsiung City, 83301, Taiwan
| | - Chao-Hung Hung
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist., Kaohsiung City, 83301, Taiwan.,Division of Hepato-Gastroenterology, Department of Internal Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, 61363, Taiwan
| | - Chien-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist., Kaohsiung City, 83301, Taiwan
| | - Ming-Tsung Lin
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist., Kaohsiung City, 83301, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist., Kaohsiung City, 83301, Taiwan.
| |
Collapse
|
|
12
|
Siu MKY, Jiang YX, Wang JJ, Leung THY, Han CY, Tsang BK, Cheung ANY, Ngan HYS, Chan KKL. Hexokinase 2 Regulates Ovarian Cancer Cell Migration, Invasion and Stemness via FAK/ERK1/2/MMP9/NANOG/SOX9 Signaling Cascades. Cancers (Basel) 2019; 11:813. [PMID: 31212816 PMCID: PMC6627345 DOI: 10.3390/cancers11060813] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 05/31/2019] [Accepted: 06/04/2019] [Indexed: 01/10/2023] Open
Abstract
Metabolic reprogramming is a common phenomenon in cancers. Thus, glycolytic enzymes could be exploited to selectively target cancer cells in cancer therapy. Hexokinase 2 (HK2) converts glucose to glucose-6-phosphate, the first committed step in glucose metabolism. Here, we demonstrated that HK2 was overexpressed in ovarian cancer and displayed significantly higher expression in ascites and metastatic foci. HK2 expression was significantly associated with advanced stage and high-grade cancers, and was an independent prognostic factor. Functionally, knockdown of HK2 in ovarian cancer cell lines and ascites-derived tumor cells hindered lactate production, cell migration and invasion, and cell stemness properties, along with reduced FAK/ERK1/2 activation and metastasis- and stemness-related genes. 2-DG, a glycolysis inhibitor, retarded cell migration and invasion and reduced stemness properties. Inversely, overexpression of HK2 promoted cell migration and invasion through the FAK/ERK1/2/MMP9 pathway, and enhanced stemness properties via the FAK/ERK1/2/NANOG/SOX9 cascade. HK2 abrogation impeded in vivo tumor growth and dissemination. Notably, ovarian cancer-associated fibroblast-derived IL-6 contributed to its up-regulation. In conclusion, HK2, which is regulated by the tumor microenvironment, controls lactate production and contributes to ovarian cancer metastasis and stemness regulation via FAK/ERK1/2 signaling pathway-mediated MMP9/NANOG/SOX9 expression. HK2 could be a potential prognostic marker and therapeutic target for ovarian cancer.
Collapse
Affiliation(s)
- Michelle K Y Siu
- Department of Obstetrics and Gynecology, University of Hong Kong, Hong Kong, China.
| | - Yu-Xin Jiang
- Department of Obstetrics and Gynecology, University of Hong Kong, Hong Kong, China.
| | - Jing-Jing Wang
- Department of Obstetrics and Gynecology, University of Hong Kong, Hong Kong, China.
| | - Thomas H Y Leung
- Department of Obstetrics and Gynecology, University of Hong Kong, Hong Kong, China.
| | - Chae Young Han
- Department of Obstetrics and Gynecology and Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8L6, Canada.
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
| | - Benjamin K Tsang
- Department of Obstetrics and Gynecology and Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8L6, Canada.
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao, China.
| | - Annie N Y Cheung
- Department of Pathology, University of Hong Kong, Hong Kong, China.
| | - Hextan Y S Ngan
- Department of Obstetrics and Gynecology, University of Hong Kong, Hong Kong, China.
| | - Karen K L Chan
- Department of Obstetrics and Gynecology, University of Hong Kong, Hong Kong, China.
| |
Collapse
|
|
13
|
He X, Xu X, Zhu G, Ye H. Circulating uPA as a potential prognostic biomarker for resectable esophageal squamous cell carcinoma. Medicine (Baltimore) 2019; 98:e14717. [PMID: 30817615 PMCID: PMC6831346 DOI: 10.1097/md.0000000000014717] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Previous research showed that the 4 genes of matrix metallopeptidase 9 (MMP9), cyto-keratin 20 (CK20), cyto-keratin 19 (CK19) and urokinase type plasminogen activator (uPA) are detectable in the peripheral blood. All the 4 genes are related to tumor invasion and metastasis. However, whether their expression is associated with clinicopathologic factors and the prognosis of patients with esophageal squamous cell carcinoma (ESCC) is still confused. Expression levels of MMP9, CK20, CK19, and uPA were evaluated by quantificational real-time polymerase chain reaction (qRT-PCR) in peripheral blood of 205 ESCC patients who received radical resection. The cut-off value was 1000 copy numbers. Their impacts on clinicopathologic factors and survival were investigated. The uPA expression positively correlated with gender (P = .046) and tumor size (P = .046). Meanwhile, CK19 expression positively correlated with tumor size (P = .029), vascular invasion (P = .024), and CK20 expression positively correlated with tumor size (P = .035) and degrees of differentiation (P = .032). Moreover, the overexpression of MMP9 has a correlation with postoperative radiotherapy (P = .041) and chemotherapy (P = .012). Among the 4 genes, only uPA is a prognostic indicator for disease-free survival and overall survival both in univariate analysis and multivariate analysis (P = .015). This study suggests that circulating uPA mRNA in peripheral blood can serve as a potential unfavorable prognosis biomarker in ESCC. Further perspective, multi-center and large-scale study is still needed.
Collapse
Affiliation(s)
- Xiao He
- Department of Radiotherapy, Lishui People's Hospital, Lishui
| | - Xiaoling Xu
- Key Laboratory of Diagnosis and Treatment Technology for Thoracic Cancer, Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Zhejiang Cancer Center, Hangzhou, People's Republic of China
| | - Guanxia Zhu
- Key Laboratory of Diagnosis and Treatment Technology for Thoracic Cancer, Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Zhejiang Cancer Center, Hangzhou, People's Republic of China
| | - Hong Ye
- Department of Radiotherapy, Lishui People's Hospital, Lishui
| |
Collapse
|
|
14
|
The prognostic relevance of urokinase-type plasminogen activator (uPA) in the blood of patients with metastatic breast cancer. Sci Rep 2019; 9:2318. [PMID: 30783124 PMCID: PMC6381129 DOI: 10.1038/s41598-018-37259-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 12/04/2018] [Indexed: 12/01/2022] Open
Abstract
In breast cancer (BC), elevated levels of urokinase-type plasminogen activator (uPA) in tumor tissue have been confirmed as a strong prognostic factor in level-of-evidence-1 studies. The aim of the present study was to evaluate the clinical relevance of uPA levels in serum of metastatic BC patients and to compare uPA with other blood-based biomarkers. 252 patients were enrolled in this prospective, multicentre study. Blood samples were collected before begin of first-line or later-line systemic treatment. Serum uPA was quantified by a commercially available ELISA. Circulating tumor cells (CTCs) were detected using CellSearch; other biomarkers (EGFR, VEGF, HER2, RAS p21, TIMP1, CAIX) by ELISA. Using the ROC analysis, the optimal cut-off value (determined by the Youden index) of serum uPA was 2.52 ng/ml. Using this value, 26% of patients had elevated uPA levels. Patients with visceral metastasis and more than one metastatic site were significantly more likely to present with elevated uPA levels. CTC status, serum HER2, RAS p21, CAIX, TIMP1 and VEGF correlated significantly with uPA levels. Elevated uPA levels predicted shorter overall and progression-free survival in univariate analysis (median OS: 7.5 months [95%-CI 4.5–10.5 months] vs. not reached, p < 0.001; PFS: 4.8 [95%-CI: 3.1–6.5] vs. 9.1 [7.4–10.8] months, p < 0.001). In multivariate analysis, elevated uPA, presence of ≥5 CTCs, elevated RAS p21, higher grading and higher line of therapy were independent predictors of shorter OS, while elevated CTC counts, higher line of therapy and negative estrogen receptor status were independent predictors of shorter PFS. In conclusion, elevated uPA levels independently predict reduced overall survival and improved prognostication in patients with known CTC status. Whether high serum uPA might identify patients most likely to benefit from therapies targeting uPA, remains to be evaluated in future trials.
Collapse
|
|
15
|
Plasminogen Activator Inhibitor Type 1 in Blood at Onset of Chemotherapy Unfavorably Affects Survival in Primary Ovarian Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1153:47-54. [DOI: 10.1007/5584_2019_353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
|
|
16
|
Impacts of Cancer on Platelet Production, Activation and Education and Mechanisms of Cancer-Associated Thrombosis. Cancers (Basel) 2018; 10:cancers10110441. [PMID: 30441823 PMCID: PMC6266827 DOI: 10.3390/cancers10110441] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 10/31/2018] [Accepted: 11/10/2018] [Indexed: 12/12/2022] Open
Abstract
Platelets are small anucleate cells that are traditionally described as the major effectors of hemostasis and thrombosis. However, increasing evidence indicates that platelets play several roles in the progression of malignancies and in cancer-associated thrombosis. A notable cross-communication exists between platelets and cancer cells. On one hand, cancer can “educate” platelets, influencing their RNA profiles, the numbers of circulating platelets and their activation states. On the other hand, tumor-educated platelets contain a plethora of active biomolecules, including platelet-specific and circulating ingested biomolecules, that are released upon platelet activation and participate in the progression of malignancy. The numerous mechanisms by which the primary tumor induces the production, activation and aggregation of platelets (also known as tumor cell induced platelet aggregation, or TCIPA) are directly related to the pro-thrombotic state of cancer patients. Moreover, the activation of platelets is critical for tumor growth and successful metastatic outbreak. The development or use of existing drugs targeting the activation of platelets, adhesive proteins responsible for cancer cell-platelet interactions and platelet agonists should be used to reduce cancer-associated thrombosis and tumor progression.
Collapse
|
|
17
|
Tang J, Wang J, Fan L, Li X, Liu N, Luo W, Wang J, Wang Y, Wang Y. cRGD inhibits vasculogenic mimicry formation by down-regulating uPA expression and reducing EMT in ovarian cancer. Oncotarget 2018; 7:24050-62. [PMID: 26992227 PMCID: PMC5029683 DOI: 10.18632/oncotarget.8079] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 02/29/2016] [Indexed: 11/25/2022] Open
Abstract
Vasculogenic minicry (VM), an alternative blood supply modality except to endothelial cells-mediated vascular network, is a potential therapeutic target for ovarian cancer due to VM correlated with poor prognosis in ovarian cancer patients. Accelerated extracellular matrix (ECM) degradation is prerequisite for VM formation induced by epithelial-mesenchymal transition (EMT). Previous reports demonstrate uPA has ability to degrade ECM thereby promoting tumor angiogenesis. Also, exogenous cRGD sequence enables to modulate uPA expression, attenuate EMT and suppress endothelial-lined channels. Till now, the correlation of uPA and VM formation and the effect of exogenous cRGD on VM formation remain unknown. Herein, we validate uPA expression is positively correlated with VM formation in ovarian cancer tissues (90 cases) and ovarian cancer cells (SKOV-3, OVCAR-3 and A2780 cells). In particular, silencing uPA experiments show that down-regulated uPA causes notable decrease for the complete channels formed by SKOV-3 and OVCAR-3 cells. Mechanism study discloses uPA promotes VM formation by regulating AKT/mTOR/MMP-2/Laminin5γ2 signal pathway. The result demonstrates uPA may serve as therapeutic target of VM for ovarian cancer. Also, it is found exogenous cRGD enables to inhibit VM formation in ovarian cancer via not only down-regulating uPA expression but also reducing EMT. Exogenous cRGD may be a promising angiogenic inhibitor for ovarian cancer therapy due to its inhibiting effect on VM formation as well as endothelial cells-mediated vascular network.
Collapse
Affiliation(s)
- Jiao Tang
- Department of Obstetrics & Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.,Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jianguo Wang
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Lin Fan
- Department of Reproductive Medicine Center, The Women and Children Hospital of Guangdong, Guangzhou Medical University, Guangzhou 511442, China
| | - Xiaoxuan Li
- Department of Obstetrics & Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Na Liu
- Department of Obstetrics & Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Wanxian Luo
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jihui Wang
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yifeng Wang
- Department of Obstetrics & Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Ying Wang
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| |
Collapse
|
|
18
|
Weidle UH, Birzele F, Kollmorgen G, Nopora A. Potential microRNA-related Targets for Therapeutic Intervention with Ovarian Cancer Metastasis. Cancer Genomics Proteomics 2018; 15:1-15. [PMID: 29275359 PMCID: PMC5822180 DOI: 10.21873/cgp.20061] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 10/09/2017] [Accepted: 10/17/2017] [Indexed: 02/06/2023] Open
Abstract
Treatment of disseminated epithelial ovarian cancer (EOC) is an unmet medical need. Therefore, the identification along with preclinical and clinical validation of new targets is an issue of high importance. In this review we focus on microRNAs that mediate metastasis of EOC. We summarize up-regulated metastasis-promoting and down-regulated metastasis-suppressing microRNAs. We focus on preclinical in vitro and in vivo functions as well as their metastasis-related clinical correlations. Finally, we outline modalities for therapeutic intervention and critical issues of microRNA-based therapeutics in the context of metastatic EOC.
Collapse
Affiliation(s)
- Ulrich H Weidle
- Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany
| | - Fabian Birzele
- Roche Innovation Center Basel, F. Hofman La Roche, Basel, Switzerland
| | - Gwen Kollmorgen
- Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany
| | - Adam Nopora
- Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany
| |
Collapse
|
|
19
|
Kugaevskaya E, Gureeva T, Timoshenko O, Solovyeva N. The urokinase-type plasminogen activator system and its role in tumor progression. ACTA ACUST UNITED AC 2018; 64:472-486. [DOI: 10.18097/pbmc20186406472] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
In the multistage process of carcinogenesis, the key link in the growth and progression of the tumor is the invasion of malignant cells into normal tissue and their distribution and the degree of destruction of tissues. The most important role in the development of these processes is played by the system of urokinase-type plasminogen activator (uPA system), which consists of several components: serine proteinase – uPA, its receptor – uPAR and its two endogenous inhibitors – PAI-1 and PAI-2. The components of the uPA system are expressed by cancer cells to a greater extent than normal tissue cells. uPA converts plasminogen into broad spectrum, polyfunctional protease plasmin, which, in addition to the regulation of fibrinolysis, can hydrolyze a number of components of the connective tissue matrix (СTM), as well as activate the zymogens of secreted matrix metalloproteinases (MMР) – pro-MMР. MMРs together can hydrolyze all the main components of the СTM, and thus play a key role in the development of invasive processes, as well as to perform regulatory functions by activating and releasing from STM a number of biologically active molecules that are involved in the regulation of the main processes of carcinogenesis. The uPA system promotes tumor progression not only through the proteolytic cascade, but also through uPAR, PAI-1 and PAI-2, which are involved in both the regulation of uPA/uPAR activity and are involved in proliferation, apoptosis, chemotaxis, adhesion, migration and activation of epithelial-mesenchymal transition pathways. All of the above processes are aimed at regulating invasion, metastasis and angiogenesis. The components of the uPA system are used as prognostic and diagnostic markers of many cancers, as well as serve as targets for anticancer therapy.
Collapse
Affiliation(s)
| | - T.A. Gureeva
- Institute of Biomedical Chemistry, Moscow, Russia
| | | | | |
Collapse
|
|
20
|
Ramos SC, de Matos AJ, Ribeiro JN, Leite-Martins LR, Ferreira RRF, Viegas I, Santos AA. Serum levels of urokinase-type plasminogen activator in healthy dogs and oncologic canine patients. Vet World 2017; 10:918-923. [PMID: 28919683 PMCID: PMC5591479 DOI: 10.14202/vetworld.2017.918-923] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 03/03/2017] [Indexed: 02/06/2023] Open
Abstract
AIM Urokinase plasminogen activator (uPA) has been scarcely studied in veterinary oncology. The aim of this study was to determine the uPA serum concentrations in healthy and oncologic canine patients and to investigate its potential value as a tumor biomarker. MATERIALS AND METHODS Serum uPA concentrations of healthy and oncologic canine patients were measured by enzyme-linked immunosorbent assay. Their relationships with the dogs' health status and tumor characteristics were analyzed through ANOVA and independent t-test. RESULTS There were no significant differences between mean serum values (±standard deviation) of healthy dogs (0.19±0.13 ng/ml) and oncologic canine patients (0.22±0.33 ng/ml), or between dogs with benign or malignant tumors, and with or without metastases, although the latter tended to show higher uPA serum levels. CONCLUSION This is the first study describing the uPA serum levels in dogs. Although its results do not support uPA as a tumor biomarker, higher uPA levels in dogs with metastatic neoplasms may reflect the role of the enzyme in tumor progression.
Collapse
Affiliation(s)
- Sofia C. Ramos
- Department of Veterinary Clinics, Faculty of Veterinary Medicine of the University Lusófona of Humanities and Technologies, Campo Grande 376, Lisbon, Portugal
| | - Augusto J. de Matos
- Department of Veterinary Clinics of the Biomedical Sciences Institute of Abel Salazar (ICBAS), University of Porto, R. Jorge Viterbo Ferreira no. 228, Porto, Portugal
- Animal Science and Study Centre/Food and Agrarian Sciences and Technologies Institute (CECA/ICETA), P. Gomes Teixeira, Portugal
| | - João Niza Ribeiro
- Department of Population Studies, Biomedical Sciences Institute of Abel Salazar (ICBAS), University of Porto, R. Jorge Viterbo Ferreira no. 228, Porto, Portugal
- Institute of Public Health, University of Porto, R. das Taipas 135, Porto, Portugal
| | - Liliana R. Leite-Martins
- Department of Veterinary Clinics of the Biomedical Sciences Institute of Abel Salazar (ICBAS), University of Porto, R. Jorge Viterbo Ferreira no. 228, Porto, Portugal
| | - Rui R. F. Ferreira
- Animal Science and Study Centre/Food and Agrarian Sciences and Technologies Institute (CECA/ICETA), P. Gomes Teixeira, Portugal
- Animal Blood Bank (BSA), R. Jorge Viterbo Ferreira no. 228, Porto, Portugal
| | - Inês Viegas
- Department of Veterinary Clinics, Faculty of Veterinary Medicine of the University Lusófona of Humanities and Technologies, Campo Grande 376, Lisbon, Portugal
| | - Andreia A. Santos
- Department of Veterinary Clinics, Faculty of Veterinary Medicine of the University Lusófona of Humanities and Technologies, Campo Grande 376, Lisbon, Portugal
- Animal Science and Study Centre/Food and Agrarian Sciences and Technologies Institute (CECA/ICETA), P. Gomes Teixeira, Portugal
| |
Collapse
|
|
21
|
Ghasemi A, Hashemy SI, Aghaei M, Panjehpour M. RhoA/ROCK pathway mediates leptin-induced uPA expression to promote cell invasion in ovarian cancer cells. Cell Signal 2017; 32:104-114. [PMID: 28104444 DOI: 10.1016/j.cellsig.2017.01.020] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2016] [Revised: 01/09/2017] [Accepted: 01/14/2017] [Indexed: 12/11/2022]
Abstract
Previous studies have shown that leptin, an adipocyte-secreted hormone, stimulates ovarian cancer invasion. Here, we investigated the contribution of uPA in leptin-induced ovarian cancer cell invasion. The cell invasion and migration experiments were carried out using matrigel invasion and wound healing assays in ovarian cancer cell lines (OVCAR3, SKOV3and CaoV-3). The mechanism underlying the invasive effect of leptin was examined using cell transfection with Ob-Rb siRNA, pre-treatment with a specific inhibitor of RhoA and ROCK, RhoA activation assay, OB-Rb, Rock and upA protein expression. Our results show that leptin induced ovarian cancer cell invasion via up-regulating upA in a time and dose-dependent manner, which was attenuated using knockdown of OB-Rb by siRNA. Moreover, pre-incubation with C3 (inhibitor of RhoA) and Y-27632 (inhibitor of ROCK) effectively attenuated leptin-induced upA expression and inhibited invasive ability of ovarian cancer cells. We also found that pretreatment with inhibitors of PI3K/AKT (LY294002), JAK/STAT (AG490) and NF-kB (BAY 11-7082) significantly reduced leptin-induced upA expression. Collectively, our findings demonstrate that OB-Rb, RhoA/ROCK, PI3K/AKT, JAK/STAT pathways and NF-kB activation are involved in leptin-induced upA expression. These results may provide a new mechanism that facilitates leptin-induced ovarian cancer invasion.
Collapse
Affiliation(s)
- Ahmad Ghasemi
- Department of Biochemistry and Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Seyed Isaac Hashemy
- Surgical Oncology Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Aghaei
- Department of Biochemistry and Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mojtaba Panjehpour
- Department of Biochemistry and Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
| |
Collapse
|
|
22
|
Ferraresi A, Phadngam S, Morani F, Galetto A, Alabiso O, Chiorino G, Isidoro C. Resveratrol inhibits IL-6-induced ovarian cancer cell migration through epigenetic up-regulation of autophagy. Mol Carcinog 2016; 56:1164-1181. [PMID: 27787915 DOI: 10.1002/mc.22582] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 10/19/2016] [Accepted: 10/24/2016] [Indexed: 12/16/2022]
Abstract
Interleukin-6 (IL-6), a pro-inflammatory cytokine released by cancer-associated fibroblasts, has been linked to the invasive and metastatic behavior of ovarian cancer cells. Resveratrol is a naturally occurring polyphenol with the potential to inhibit cancer cell migration. Here we show that Resveratrol and IL-6 affect in an opposite manner the expression of RNA messengers and of microRNAs involved in cell locomotion and extracellular matrix remodeling associated with the invasive properties of ovarian cancer cells. Among the several potential candidates responsible for the anti-invasive effect promoted by Resveratrol, here we focused our attention on ARH-I (DIRAS3), that encodes a Ras homolog GTPase of 26-kDa. This protein is known to inhibit cell motility, and it has been shown to regulate autophagy by interacting with BECLIN 1. IL-6 down-regulated the expression of ARH-I and inhibited the formation of LC3-positive autophagic vacuoles, while promoting cell migration. On opposite, Resveratrol could counteract the IL-6 induction of cell migration in ovarian cancer cells through induction of autophagy in the cells at the migration front, which was paralleled by up-regulation of ARH-I and down-regulation of STAT3 expression. Spautin 1-mediated disruption of BECLIN 1-dependent autophagy abrogated the effects of Resveratrol, while promoting cell migration. The present data indicate that Resveratrol elicits its anti-tumor effect through epigenetic mechanisms and support its inclusion in the chemotherapy regimen for highly aggressive ovarian cancers. © 2016 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Alessandra Ferraresi
- Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy
| | - Suratchanee Phadngam
- Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy
| | - Federica Morani
- Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy
| | - Alessandra Galetto
- Unit of Oncology, Department of Translational Medicine, Università del Piemonte Orientale "A. Avogadro", Novara, Italy
| | - Oscar Alabiso
- Unit of Oncology, Department of Translational Medicine, Università del Piemonte Orientale "A. Avogadro", Novara, Italy
| | - Giovanna Chiorino
- Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia, Biella, Italy
| | - Ciro Isidoro
- Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy
| |
Collapse
|
|
23
|
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
|
|
24
|
Tumor microenvironment: The culprit for ovarian cancer metastasis? Cancer Lett 2016; 377:174-82. [DOI: 10.1016/j.canlet.2016.04.038] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 04/23/2016] [Accepted: 04/25/2016] [Indexed: 01/08/2023]
|
|
25
|
van Dam PA, Coelho A, Rolfo C. Is there a role for urokinase-type plasminogen activator inhibitors as maintenance therapy in patients with ovarian cancer? Eur J Surg Oncol 2016; 43:252-257. [PMID: 27345498 DOI: 10.1016/j.ejso.2016.06.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 05/27/2016] [Accepted: 06/04/2016] [Indexed: 10/21/2022] Open
Abstract
There is abundant evidence that the urokinase-type plasminogen activator (uPA), its inhibitors PAI-1 and PAI-2 (plasminogen activator inhibitor type-1 and type-2) and its cells surface receptor (uPA-R, CD87) play a fundamental role in tumor invasion and metastasis and are of significant prognostic significance for many tumor types. We performed a systematic Med-line search on uPA, PAI, uPA-R and (epithelial) ovarian cancer (EOC). The majority of malignant EOC specimens show moderate to strong immunostating of tumor and stromal cells. Overexpression of u-PA and PAI-1 can be found in more the 75% of primary ovarian carcinomas, in most metastatic EOC samples and all examined epithelial ovarian cancer cell lines. uPA overexpression in primary specimens was significantly associated with tumor stage, grade, residual disease status after cytoreductive surgery, and poor clinical outcome. This may be explained by increased chemoresistance, a lower resectability and more aggressive tumor biology and tumor dissemination in patients with high uPA and PAI-1. Several therapeutical approaches aimed at inhibiting the uPA/uPAR functions have shown to possess anti-tumor effects in vitro and in animal models. When treating a patient with advanced ovarian cancer it may to be assumed that inhibiting the progression of established (micro) metastases may be more therapeutically relevant than trying to destroy all tumor cells which is not possible in most cases with current systemic treatment modalities. Taking into account the role of uPA and PAI in cell detachment, formation of new stroma, tumor cell reimplantation and metastasis uPA inhibition should be further investigated as maintenance treatment in patients with advanced EOC.
Collapse
Affiliation(s)
- P A van Dam
- Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Edegem, B2650, Belgium; Centre of Oncologic Research (CORE), Antwerp University, Edegem, B2650, Belgium.
| | - A Coelho
- Centre of Oncologic Research (CORE), Antwerp University, Edegem, B2650, Belgium; Phase I-Early Trials Unit, Antwerp University Hospital, Edegem, Belgium
| | - C Rolfo
- Centre of Oncologic Research (CORE), Antwerp University, Edegem, B2650, Belgium; Phase I-Early Trials Unit, Antwerp University Hospital, Edegem, Belgium
| |
Collapse
|
|
26
|
Qureshi T, Goswami S, McClintock CS, Ramsey MT, Peterson CB. Distinct encounter complexes of PAI-1 with plasminogen activators and vitronectin revealed by changes in the conformation and dynamics of the reactive center loop. Protein Sci 2015; 25:499-510. [PMID: 26548921 DOI: 10.1002/pro.2841] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 11/05/2015] [Indexed: 11/07/2022]
Abstract
UNLABELLED Plasminogen activator inhibitor-1 (PAI-1) is a biologically important serine protease inhibitor (serpin) that, when overexpressed, is associated with a high risk for cardiovascular disease and cancer metastasis. Several of its ligands, including vitronectin, tissue-type and urokinase-type plasminogen activator (tPA, uPA), affect the fate of PAI-1. Here, we measured changes in the solvent accessibility and dynamics of an important unresolved functional region, the reactive center loop (RCL), upon binding of these ligands. Binding of the catalytically inactive S195A variant of tPA to the RCL causes an increase in fluorescence, indicating greater solvent protection, at its C-terminus, while mobility along the loop remains relatively unchanged. In contrast, a fluorescence increase and large decrease in mobility at the N-terminal RCL is observed upon binding of S195A-uPA to PAI-1. At a site distant from the RCL, binding of vitronectin results in a modest decrease in fluorescence at its proximal end without restricting overall loop dynamics. These results provide the new evidence for ligand effects on RCL conformation and dynamics and differences in the Michaelis complex with plasminogen activators that can be used for the development of more specific inhibitors to PAI-1. This study is also the first to use electron paramagnetic resonance (EPR) spectroscopy to investigate PAI-1 dynamics. SIGNIFICANCE Balanced blood homeostasis and controlled cell migration requires coordination between serine proteases, serpins, and cofactors. These ligands form noncovalent complexes, which influence the outcome of protease inhibition and associated physiological processes. This study reveals differences in binding via changes in solvent accessibility and dynamics within these complexes that can be exploited to develop more specific drugs in the treatment of diseases associated with unbalanced serpin activity.
Collapse
Affiliation(s)
- Tihami Qureshi
- Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, 37996
| | - Sumit Goswami
- Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, 37996
| | - Carlee S McClintock
- Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, 37996
| | - Matthew T Ramsey
- Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, 37996
| | - Cynthia B Peterson
- Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, 37996
| |
Collapse
|
|
27
|
Short-term uvb-irradiation leads to putative limbal stem cell damage and niche cell-mediated upregulation of macrophage recruiting cytokines. Stem Cell Res 2015; 15:643-654. [DOI: 10.1016/j.scr.2015.10.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 10/16/2015] [Indexed: 01/17/2023] Open
|
|
28
|
Jesionowska A, Cecerska-Heryc E, Matoszka N, Dolegowska B. Lysophosphatidic acid signaling in ovarian cancer. J Recept Signal Transduct Res 2015; 35:578-84. [PMID: 26393967 DOI: 10.3109/10799893.2015.1026444] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Lysophosphatidic acid (LPA) is a bioactive phospholipid that is involved in signal transduction between cells. Plasma and ascites levels of LPA are increased in ovarian cancer patients even in the early stages and thus LPA is considered as a potential diagnostic marker for this disease. This review presents the current knowledge regarding LPA signaling in epithelial ovarian cancer. LPA stimulates proliferation, migration and invasion of ovarian cancer cells through regulation of vascular endothelial growth factor, matrix metalloproteinases, urokinase plasminogen activator, interleukin-6, interleukin-8, CXC motif chemokine ligand 12/CXC receptor 4, COX2, cyclin D1, Hippo-Yap and growth-regulated oncogene α concentrations. In this article, all of these targets and signal pathways involved in LPA influence are described.
Collapse
Affiliation(s)
| | - Elzbieta Cecerska-Heryc
- b Department of Laboratory Diagnostics and Molecular Medicine , Pomeranian Medical University , Szczecin , Poland
| | - Natalia Matoszka
- b Department of Laboratory Diagnostics and Molecular Medicine , Pomeranian Medical University , Szczecin , Poland
| | - Barbara Dolegowska
- b Department of Laboratory Diagnostics and Molecular Medicine , Pomeranian Medical University , Szczecin , Poland
| |
Collapse
|
|
29
|
Mitra AK, Chiang CY, Tiwari P, Tomar S, Watters KM, Peter ME, Lengyel E. Microenvironment-induced downregulation of miR-193b drives ovarian cancer metastasis. Oncogene 2015; 34:5923-32. [PMID: 25798837 PMCID: PMC4580483 DOI: 10.1038/onc.2015.43] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 11/24/2014] [Accepted: 12/01/2014] [Indexed: 12/14/2022]
Abstract
The cross-talk between ovarian cancer (OvCa) cells and the metastatic microenvironment is an essential determinant of successful colonization. Micro(mi)RNAs play several critical roles during metastasis; however, the role of microenvironmental cues in the regulation of miRNAs in metastasizing cancer cells has not been studied. Using a 3D culture model that mimics the human omentum, one of the principal sites of OvCa metastasis, we identified and characterized the microenvironment-induced downregulation of a tumor suppressor miRNA, miR-193b, in metastasizing OvCa cells. The direct interaction of the OvCa cells with mesothelial cells, which cover the surface of the omentum, caused a DNA methyltransferase 1 (DNMT1) mediated decrease in the expression of miR-193b. The reduction in miR-193b enabled the metastasizing cancer cells to invade and proliferate into human omental pieces ex vivo and into the omentum of a mouse xenograft model of OvCa metastasis. The functional effects of miR-193b were mediated, in large part, by the concomitant increased expression of its target, urokinase-type plasminogen activator (uPA), a known tumor-associated protease. These findings link paracrine signals from the microenvironment with the regulation of a key miRNA that is essential for the initial steps of OvCa metastatic colonization. Targeting miR-193b could prove effective in the treatment of OvCa metastasis.
Collapse
Affiliation(s)
- A K Mitra
- Department of Obstetrics and Gynecology, Section of Gynecologic Oncology - Center for Integrative Science, University of Chicago, Chicago, IL, USA.,Medical Sciences Program, Indiana University School of Medicine, Indiana University, Bloomington, IN, USA
| | - C Y Chiang
- Department of Obstetrics and Gynecology, Section of Gynecologic Oncology - Center for Integrative Science, University of Chicago, Chicago, IL, USA
| | - P Tiwari
- Department of Obstetrics and Gynecology, Section of Gynecologic Oncology - Center for Integrative Science, University of Chicago, Chicago, IL, USA
| | - S Tomar
- Medical Sciences Program, Indiana University School of Medicine, Indiana University, Bloomington, IN, USA
| | - K M Watters
- Department of Obstetrics and Gynecology, Section of Gynecologic Oncology - Center for Integrative Science, University of Chicago, Chicago, IL, USA
| | - M E Peter
- Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - E Lengyel
- Department of Obstetrics and Gynecology, Section of Gynecologic Oncology - Center for Integrative Science, University of Chicago, Chicago, IL, USA
| |
Collapse
|
|
30
|
Mashiko S, Kitatani K, Toyoshima M, Ichimura A, Dan T, Usui T, Ishibashi M, Shigeta S, Nagase S, Miyata T, Yaegashi N. Inhibition of plasminogen activator inhibitor-1 is a potential therapeutic strategy in ovarian cancer. Cancer Biol Ther 2015; 16:253-60. [PMID: 25587663 PMCID: PMC4623014 DOI: 10.1080/15384047.2014.1001271] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 10/14/2014] [Accepted: 12/18/2014] [Indexed: 10/22/2022] Open
Abstract
Plasminogen activator inhibitor (PAI)-1 is predictive of poor outcome in several types of cancer. The present study investigated the biological role for PAI-1 in ovarian cancer and potential of targeted pharmacotherapeutics. In patients with ovarian cancer, PAI-1 mRNA expression in tumor tissues was positively correlated with poor prognosis. To determine the role of PAI-1 in cell proliferation in ovarian cancer, the effects of PAI-1 inhibition were examined in PAI-1-expressing ovarian cancer cells. PAI-1 knockdown by small interfering RNA resulted in significant suppression of cell growth accompanied with G2/M cell cycle arrest and intrinsic apoptosis. Similarly, treatment with the small molecule PAI-1 inhibitor TM5275 effectively blocked cell proliferation of ovarian cancer cells that highly express PAI-1. Together these results suggest that PAI-1 promotes cell growth in ovarian cancer. Interestingly, expression of PAI-1 was increased in ovarian clear cell carcinoma compared with that in serous tumors. Our results suggest that PAI-1 inhibition promotes cell cycle arrest and apoptosis in ovarian cancer and that PAI-1 inhibitors potentially represent a novel class of anti-tumor agents.
Collapse
Affiliation(s)
- Satsuki Mashiko
- Department of Obstetrics and Gynecology; Tohoku University Graduate School of Medicine; Sendai, Japan
| | - Kazuyuki Kitatani
- Department of Obstetrics and Gynecology; Tohoku University Graduate School of Medicine; Sendai, Japan
- Tohoku Medical Megabank Organization; Tohoku University; Sendai, Japan
| | - Masafumi Toyoshima
- Department of Obstetrics and Gynecology; Tohoku University Graduate School of Medicine; Sendai, Japan
| | - Atsuhiko Ichimura
- Division of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Dan
- Division of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toshinori Usui
- Department of Obstetrics and Gynecology; Tohoku University Graduate School of Medicine; Sendai, Japan
- Tohoku Medical Megabank Organization; Tohoku University; Sendai, Japan
| | - Masumi Ishibashi
- Department of Obstetrics and Gynecology; Tohoku University Graduate School of Medicine; Sendai, Japan
| | - Shogo Shigeta
- Department of Obstetrics and Gynecology; Yamagata University Faculty of Medicine; Yamagata, Japan
| | - Satoru Nagase
- Department of Obstetrics and Gynecology; Tohoku University Graduate School of Medicine; Sendai, Japan
| | - Toshio Miyata
- Division of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Nobuo Yaegashi
- Department of Obstetrics and Gynecology; Tohoku University Graduate School of Medicine; Sendai, Japan
| |
Collapse
|
|
31
|
Serafin AM, Akudugu JM, Bohm L. Influence of freeze-drying on the recovery of the tumour invasion markers uPA and PAI-1 from prostate cancer resections. Ann Clin Biochem 2014; 52:387-94. [DOI: 10.1177/0004563214559546] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/21/2014] [Indexed: 12/29/2022]
Abstract
Background Urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) have been shown to be of merit as biomarkers for a variety of cancers. Prostate tissue resections from patients with prostate cancer (PCa) and benign prostatic hyperplasia were analysed to determine the influence of freeze-drying on the recovery of uPA and PAI-1 and their predictive performance. Methods Prostate tissue was frozen in liquid nitrogen and homogenised into a fine powder in a precooled stainless steel punch homogeniser. One aliquot of the powder was extracted directly, and a second aliquot was freeze-dried overnight and then extracted. The extracts were analysed by FEMTELLE assay to determine the concentrations of uPA and PAI-1. uPA/PAI-1 ratios were calculated for each sample, and the mean ratios for the frozen and the lyophilised tissue were compared. Results The concentrations of uPA measured for the frozen and lyophilised samples are strongly correlated ( R = 0.90 ± 0.05). The same applies to the PAI-1 measured ( R = 0.89 ± 0.03). The uPA/PAI-1 ratios for the lyophilised and frozen samples were strongly correlated. The uPA/PAI-1 ratios for frozen and lyophilised samples were found to be essentially the same with values of 0.0344 ± 0.0066 and 0.0340 ± 0.0068, respectively ( P = 0.9633). Conclusion The recovery of uPA and PAI-1 from a deep frozen prostate tissue homogenate followed by freeze-drying proceeds with a loss of 10 and 11%, respectively, with no influence on the uPA/PAI-1 ratio. Lyophilisation is a safe procedure for the preservation of frozen prostate tissue samples as it permits recovery of the markers without compromising their use for diagnostic purposes.
Collapse
Affiliation(s)
- AM Serafin
- Division of Radiobiology, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
| | - JM Akudugu
- Division of Radiobiology, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
| | - L Bohm
- Division of Radiobiology, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
| |
Collapse
|
|
32
|
ZHANG LUOSHENG, WEI LIXIA, SHEN GUANZHU, HE BENFU, GONG WEI, MIN NA, ZHANG LI, DUAN YUXIN, XIE JINGRAN, LUO HUIYAN, GAO XINGWANG. Cathepsin L is involved in proliferation and invasion of ovarian cancer cells. Mol Med Rep 2014; 11:468-74. [DOI: 10.3892/mmr.2014.2706] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 09/04/2014] [Indexed: 11/06/2022] Open
|
|
33
|
Dorn J, Beaufort N, Schmitt M, Diamandis EP, Goettig P, Magdolen V. Function and clinical relevance of kallikrein-related peptidases and other serine proteases in gynecological cancers. Crit Rev Clin Lab Sci 2014; 51:63-84. [PMID: 24490956 DOI: 10.3109/10408363.2013.865701] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gynecological cancers, including malignant tumors of the ovaries, the endometrium and the cervix, account for approximately 10% of tumor-associated deaths in women of the Western world. For screening, diagnosis, prognosis, and therapy response prediction, the group of enzymes known as serine (Ser-)proteases show great promise as biomarkers. In the present review, following a summary of the clinical facts regarding malignant tumors of the ovaries, the endometrium and the cervix, and characterization of the most important Ser-proteases, we thoroughly review the current state of knowledge relating to the use of proteases as biomarkers of the most frequent gynecological cancers. Within the Ser-protease group, the kallikrein-related peptidase (KLK) family, which encompasses a subgroup of 15 members, holds particular promise, with some acting via a tumor-promoting mechanism and others behaving as protective factors. Further, the urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 (plasminogen activator inhibitor-1) seem to play an unfavorable role in gynecological tumors, while down-regulation of high-temperature requirement proteins A 1, 2 and 3 (HtrA1,2,3) is associated with malignant disease and cancer progression. Expression/activity levels of other Ser-proteases, including the type II transmembrane Ser-proteases (TTSPs) matriptase, hepsin (TMPRSS1), and the hepsin-related protease (TMPRSS3), as well as the glycosyl-phosphatidylinositol (GPI)-anchored Ser-proteases prostasin and testisin, may be of clinical relevance in gynecological cancers. In conclusion, proteases are a rich source of biomarkers of gynecological cancer, though the enzymes' exact roles and functions merit further investigation.
Collapse
Affiliation(s)
- Julia Dorn
- Klinische Forschergruppe der Frauenklinik der Technischen Universität München, Klinikum rechts der Isar , Munich , Germany
| | | | | | | | | | | |
Collapse
|
|
34
|
Jeon YJ, Kim YR, Lee BE, Cha SH, Moon MJ, Oh D, Lee WS, Kim NK. Association of five common polymorphisms in the plasminogen activator inhibitor-1 gene with primary ovarian insufficiency. Fertil Steril 2013; 101:825-32. [PMID: 24355042 DOI: 10.1016/j.fertnstert.2013.11.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Revised: 10/25/2013] [Accepted: 11/11/2013] [Indexed: 01/22/2023]
Abstract
OBJECTIVE To investigate the association between potentially functional plasminogen activator inhibitor-1 (PAI-1) genetic polymorphisms and primary ovarian insufficiency (POI). DESIGN Case-control study. SETTING Urban university-based hospital. PATIENT(S) A cohort of 137 POI patients and 227 controls. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Genotyping of five PAI-1 polymorphisms (-844G>A [rs2227631], -675 4G/5G [rs1799889], 43G>A (Ala>Thr) [rs6092], 9785G>A [rs2227694], and 11053T>G [rs7242]) was assessed by polymerase chain reaction-restriction fragment length polymorphism assay. RESULT(S) PAI-1 polymorphisms 9785GA+AA, -844A/9785A, 4G/9785A, and 9785A/11053G were associated with POI occurrence. Moreover, -844GA+AA and 11053TG+GG were associated with lower serum E2 levels in controls. CONCLUSION(S) We have identified an association between five PAI-1 polymorphisms and POI occurrence. However, the mechanism underlying the function of these polymorphisms in POI remains to be determined. Further studies are needed to improve understanding of the roles of PAI-1 polymorphisms and genes in related pathways, using a larger and more heterogeneous cohort.
Collapse
Affiliation(s)
- Young Joo Jeon
- Institute for Clinical Research, CHA Bundang Medical Center, School of Medicine, CHA University, Seongnam 463-712, South Korea
| | - Young Ran Kim
- Department of Obstetrics and Gynecology, CHA Bundang Medical Center, School of Medicine, CHA University, Seongnam 463-712, South Korea
| | - Bo Eun Lee
- Institute for Clinical Research, CHA Bundang Medical Center, School of Medicine, CHA University, Seongnam 463-712, South Korea
| | - Sun Hee Cha
- Department of Obstetrics and Gynecology, CHA Bundang Medical Center, School of Medicine, CHA University, Seongnam 463-712, South Korea
| | - Myoung-Jin Moon
- Department of Obstetrics and Gynecology, CHA Bundang Medical Center, School of Medicine, CHA University, Seongnam 463-712, South Korea
| | - Doyeun Oh
- Department of Internal Medicine, CHA Bundang Medical Center, School of Medicine, CHA University, Seongnam 463-712, South Korea
| | - Woo Sik Lee
- Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul 135-081, South Korea
| | - Nam Keun Kim
- Institute for Clinical Research, CHA Bundang Medical Center, School of Medicine, CHA University, Seongnam 463-712, South Korea.
| |
Collapse
|
|
35
|
Chen L, Lu X, Zeng T, Chen Y, Chen Q, Wu W, Yan X, Cai H, Zhang Z, Shao Q, Qin W. Enhancement of DEN-induced liver tumourigenesis in hepatocyte-specific Lass2-knockout mice coincident with upregulation of the TGF-β1-Smad4-PAI-1 axis. Oncol Rep 2013; 31:885-93. [PMID: 24337404 DOI: 10.3892/or.2013.2908] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Accepted: 11/12/2013] [Indexed: 11/05/2022] Open
Abstract
Longevity assurance homolog 2 of yeast LAG1 (Lass2) gene is capable of suppressing the proliferation and metastasis of several types of tumours including liver cancer. In the present study, hepatocyte-specific Lass2-knockout (Lass2 KO) and wild-type (WT) mice were exposed to the carcinogen, diethylnitrosamine (DEN), to induced liver tumours. At week 23 following DEN injection, tumours were produced in 100% of the Lass2 KO mice and 21.4% of the WT mice. At week 40, 100% of the Lass2 KO mice and 78.6% of the WT mice developed tumours, with no distinct significant difference in tumour occurrences between the two genotypes; yet, tumours in the Lass2 KO mouse livers were more numerous and larger in size. Hepatocellular carcinoma (HCC) was confirmed by α-fetoprotein (AFP). PCNA and EdU assays indicated more active proliferation whereas TUNEL assay revealed decreased apoptosis in Lass2 KO livers, when compared with the WT control. The expression of plasminogen activator inhibitor type-1 (PAI-1), a tumour-promoting gene, in the liver tissues of the 2 genotypes was detected using qPCR and western blotting, showing that PAI-1 levels were significantly elevated in Lass2 KO livers at week 40 following DEN introduction. Moreover, the expression of PAI-1-related TGF-β1, Smad-4 and -7 was detected, displaying an elevation in TGF-β1 and Smad-4 (not including Smad-7) in the Lass2 KO livers. Our data demonstrates that i) Lass2 is a protective gene against DEN-induced liver tumourigenesis; and ii) upregulation of the TGF-β1-Smad4-PAI-1 axis may contribute to the vulnerability of Lass2-knockout mice to DEN.
Collapse
Affiliation(s)
- Lufang Chen
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China
| | - Xiaodong Lu
- School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Tiantian Zeng
- School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Yuanyuan Chen
- School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Qian Chen
- School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Weijiang Wu
- School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Xun Yan
- School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Honghua Cai
- School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Zhijian Zhang
- School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Qixiang Shao
- School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Wenxin Qin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China
| |
Collapse
|
|
36
|
Jacobson O, Chen X. Interrogating tumor metabolism and tumor microenvironments using molecular positron emission tomography imaging. Theranostic approaches to improve therapeutics. Pharmacol Rev 2013; 65:1214-56. [PMID: 24064460 PMCID: PMC3799232 DOI: 10.1124/pr.113.007625] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Positron emission tomography (PET) is a noninvasive molecular imaging technology that is becoming increasingly important for the measurement of physiologic, biochemical, and pharmacological functions at cellular and molecular levels in patients with cancer. Formation, development, and aggressiveness of tumor involve a number of molecular pathways, including intrinsic tumor cell mutations and extrinsic interaction between tumor cells and the microenvironment. Currently, evaluation of these processes is mainly through biopsy, which is invasive and limited to the site of biopsy. Ongoing research on specific target molecules of the tumor and its microenvironment for PET imaging is showing great potential. To date, the use of PET for diagnosing local recurrence and metastatic sites of various cancers and evaluation of treatment response is mainly based on [(18)F]fluorodeoxyglucose ([(18)F]FDG), which measures glucose metabolism. However, [(18)F]FDG is not a target-specific PET tracer and does not give enough insight into tumor biology and/or its vulnerability to potential treatments. Hence, there is an increasing need for the development of selective biologic radiotracers that will yield specific biochemical information and allow for noninvasive molecular imaging. The possibility of cancer-associated targets for imaging will provide the opportunity to use PET for diagnosis and therapy response monitoring (theranostics) and thus personalized medicine. This article will focus on the review of non-[(18)F]FDG PET tracers for specific tumor biology processes and their preclinical and clinical applications.
Collapse
Affiliation(s)
- Orit Jacobson
- Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD.
| | | |
Collapse
|
|
37
|
Li PG, Mu TH, Deng L. Anticancer effects of sweet potato protein on human colorectal cancer cells. World J Gastroenterol 2013; 19:3300-3308. [PMID: 23745032 PMCID: PMC3671082 DOI: 10.3748/wjg.v19.i21.3300] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2012] [Revised: 03/25/2013] [Accepted: 04/28/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of proteins purified from sweet potato storage roots on human colorectal cancer cell lines.
METHODS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Hoechst 33258 nuclear staining and Boyden transwell chamber methods were used to determine whether purified sweet potato protein (SPP) from fresh sweet potato roots affected proliferation, migration and invasion, respectively, of human colorectal cancer SW480 cells in vitro. The inhibitory effects of SPP on growth of human colorectal cancer HCT-8 cells intraperitoneally xenografted in nude mice and spontaneous lung metastasis of murine Lewis lung carcinoma 3LL cells subcutaneously transplanted in C57 BL/6 mice were also investigated in vivo.
RESULTS: SPP inhibited the proliferation of SW480 cells in a dose-dependent manner, with an IC50 value of 38.732 μmol/L (r2 = 0.980, P = 0.003) in the MTT assay. Hoechst 33258 nuclear staining further revealed inhibition of cell viability and induction of apoptosis by SPP. The transwell assay disclosed significant reduction in migrated cells/field by 8 μmol/L SPP (8.4 ± 2.6 vs 23.3 ± 5.4, P = 0.031) and invaded cells/field through the ECMatrix by 0.8 μmol/L SPP, compared with the control (25.2 ± 5.2 vs 34.8 ± 6.1, P = 0.038). Both intraperitoneal (ip) and intragastric (ig) administration of SPP led to significant suppression of growth of intraperitoneally inoculated HCT-8 cells in nude mice to 58.0% ± 5.9% (P = 0.037) and 43.5% ± 7.1% (P = 0.004) of the controls, respectively, after 9 d treatment. Bloody ascites additionally disappeared after ip injection of trypsin inhibitor. Notably, ig and ip administration of SPP induced a significant decrease in spontaneous pulmonary metastatic nodule formation in C57 BL/6 mice (21.0 ± 12.3 and 27.3 ± 12.7 nodules/lung vs 42.5 ± 4.5 nodules/lung in controls, respectively, P < 0.05) after 25 d treatment. Moreover, the average weight of primary tumor nodules in the hind leg of mice decreased from 8.2 ± 1.3 g/mice in the control to 6.1 ± 1.4 g/mice in the ip group (P = 0.035).
CONCLUSION: SPP exerts significant antiproliferative and antimetastatic effects on human colorectal cancer cell lines, both in vitro and in vivo.
Collapse
|
|
38
|
Ceruti P, Principe M, Capello M, Cappello P, Novelli F. Three are better than one: plasminogen receptors as cancer theranostic targets. Exp Hematol Oncol 2013; 2:12. [PMID: 23594883 PMCID: PMC3640925 DOI: 10.1186/2162-3619-2-12] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Accepted: 03/28/2013] [Indexed: 12/22/2022] Open
Abstract
Activation of plasminogen on the cell surface initiates a cascade of protease activity with important implications for several physiological and pathological events. In particular, components of the plasminogen system participate in tumor growth, invasion and metastasis. Plasminogen receptors are in fact expressed on the cell surface of most tumors, and their expression frequently correlates with cancer diagnosis, survival and prognosis. Notably, they can trigger multiple specific immune responses in cancer patients, highlighting their role as tumor-associated antigens. In this review, three of the most characterized plasminogen receptors involved in tumorigenesis, namely Annexin 2 (ANX2), Cytokeratin 8 (CK8) and alpha-Enolase (ENOA), are analyzed to ascertain an overall view of their role in the most common cancers. This analysis emphasizes the possibility of delineating new personalized therapeutic strategies to counteract tumor growth and metastasis by targeting plasminogen receptors, as well as their potential application as cancer predictors.
Collapse
Affiliation(s)
- Patrizia Ceruti
- Center for Experimental Research and Medical Studies (CeRMS), Azienda Ospedaliera Città della Salute e della Scienza, Via Cherasco 15, Turin, 10126, Italy.,Department of Molecular Biotechnology and Health Science, University of Turin, Turin, Italy
| | - Moitza Principe
- Center for Experimental Research and Medical Studies (CeRMS), Azienda Ospedaliera Città della Salute e della Scienza, Via Cherasco 15, Turin, 10126, Italy.,Department of Molecular Biotechnology and Health Science, University of Turin, Turin, Italy
| | - Michela Capello
- Center for Experimental Research and Medical Studies (CeRMS), Azienda Ospedaliera Città della Salute e della Scienza, Via Cherasco 15, Turin, 10126, Italy.,Department of Molecular Biotechnology and Health Science, University of Turin, Turin, Italy
| | - Paola Cappello
- Center for Experimental Research and Medical Studies (CeRMS), Azienda Ospedaliera Città della Salute e della Scienza, Via Cherasco 15, Turin, 10126, Italy.,Department of Molecular Biotechnology and Health Science, University of Turin, Turin, Italy
| | - Francesco Novelli
- Center for Experimental Research and Medical Studies (CeRMS), Azienda Ospedaliera Città della Salute e della Scienza, Via Cherasco 15, Turin, 10126, Italy.,Department of Molecular Biotechnology and Health Science, University of Turin, Turin, Italy
| |
Collapse
|