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Firpo MA, Boucher KM, Bleicher J, Khanderao GD, Rosati A, Poruk KE, Kamal S, Marzullo L, De Marco M, Falco A, Genovese A, Adler JM, De Laurenzi V, Adler DG, Affolter KE, Garrido-Laguna I, Scaife CL, Turco MC, Mulvihill SJ. Multianalyte Serum Biomarker Panel for Early Detection of Pancreatic Adenocarcinoma. JCO Clin Cancer Inform 2023; 7:e2200160. [PMID: 36913644 PMCID: PMC10530881 DOI: 10.1200/cci.22.00160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 01/10/2023] [Accepted: 02/03/2023] [Indexed: 03/14/2023] Open
Abstract
PURPOSE We determined whether a large, multianalyte panel of circulating biomarkers can improve detection of early-stage pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS We defined a biologically relevant subspace of blood analytes on the basis of previous identification in premalignant lesions or early-stage PDAC and evaluated each in pilot studies. The 31 analytes that met minimum diagnostic accuracy were measured in serum of 837 subjects (461 healthy, 194 benign pancreatic disease, and 182 early-stage PDAC). We used machine learning to develop classification algorithms using the relationship between subjects on the basis of their changes across the predictors. Model performance was subsequently evaluated in an independent validation data set from 186 additional subjects. RESULTS A classification model was trained on 669 subjects (358 healthy, 159 benign, and 152 early-stage PDAC). Model evaluation on a hold-out test set of 168 subjects (103 healthy, 35 benign, and 30 early-stage PDAC) yielded an area under the receiver operating characteristic curve (AUC) of 0.920 for classification of PDAC from non-PDAC (benign and healthy controls) and an AUC of 0.944 for PDAC versus healthy controls. The algorithm was then validated in 146 subsequent cases presenting with pancreatic disease (73 benign pancreatic disease and 73 early- and late-stage PDAC cases) and 40 healthy control subjects. The validation set yielded an AUC of 0.919 for classification of PDAC from non-PDAC and an AUC of 0.925 for PDAC versus healthy controls. CONCLUSION Individually weak serum biomarkers can be combined into a strong classification algorithm to develop a blood test to identify patients who may benefit from further testing.
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Affiliation(s)
- Matthew A. Firpo
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
| | - Kenneth M. Boucher
- Department of Oncological Sciences, School of Medicine, University of Utah, Salt Lake City, UT
| | - Josh Bleicher
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
| | - Gayatri D. Khanderao
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
| | - Alessandra Rosati
- BIOUNIVERSA s.r.l., Baronissi, Italy
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana” University of Salerno, Baronissi, Italy
| | - Katherine E. Poruk
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
| | - Sama Kamal
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
| | - Liberato Marzullo
- BIOUNIVERSA s.r.l., Baronissi, Italy
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana” University of Salerno, Baronissi, Italy
| | - Margot De Marco
- BIOUNIVERSA s.r.l., Baronissi, Italy
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana” University of Salerno, Baronissi, Italy
| | - Antonia Falco
- BIOUNIVERSA s.r.l., Baronissi, Italy
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana” University of Salerno, Baronissi, Italy
| | - Armando Genovese
- University Hospital “San Giovanni di Dio e Ruggi D'Aragona,” Salerno, Italy
| | - Jessica M. Adler
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
| | - Vincenzo De Laurenzi
- BIOUNIVERSA s.r.l., Baronissi, Italy
- Department of Medicine and Biotechnology, University G d'Annunzio and CeSI-MeT, Chieti, Italy
| | - Douglas G. Adler
- Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT
| | - Kajsa E. Affolter
- Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT
| | - Ignacio Garrido-Laguna
- Department of Oncological Sciences, School of Medicine, University of Utah, Salt Lake City, UT
| | - Courtney L. Scaife
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
| | - M. Caterina Turco
- BIOUNIVERSA s.r.l., Baronissi, Italy
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana” University of Salerno, Baronissi, Italy
| | - Sean J. Mulvihill
- Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT
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Huang HK, Lee SY, Huang SF, Lin YS, Chao SC, Huang SF, Lee SC, Cheng TH, Loh SH, Tsai YT. Isoorientin Decreases Cell Migration via Decreasing Functional Activity and Molecular Expression of Proton-Linked Monocarboxylate Transporters in Human Lung Cancer Cells. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2020; 48:201-222. [PMID: 31918564 DOI: 10.1142/s0192415x20500111] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Aggressive tumor cells mainly rely on glycolysis, and further release vast amounts of lactate and protons by monocarboxylate transporter (MCT), which causes a higher intracellular pH (pHi) and acidic extracellular pH. Isoorientin, a principle flavonoid compound extracted from several plant species, shows various pharmacological activities. However, effects of isoorientin on anticancer and MCT await to explore in human lung cancer cells. Human lung cancer tissues were obtained from cancer patients undergoing surgery, while the human lung adenocarcinoma cells (A549) were bought commercially. Change of pHi was detected by microspectrofluorometry method with a pH-sensitive fluorescent dye, BCECF. MTT and wound-healing assay were used to detect the cell viability and migration, respectively. Western blot techniques and immunocytochemistry staining were used to detect the protein expression. Our results indicated that the expression of MCTs1/4 and CD147 were upregulated significantly in human lung tissues. In experiments of A549 cells, under HEPES-buffer, the resting pHi was 7.47, and isoorientin (1-300μM) inhibited functional activity of MCT concentration-dependently (up to -42%). Pretreatment with isoorientin (3-100μM) for 24h, MCT activity and cell migration were significantly inhibited (-25% and -40%, respectively), while the cell viability was not affected. Moreover, the expression of MCTs1/4, CD147, and matrix metalloproteinase (MMP) 2/9 were significantly down regulated. In summary, MCTs1/4 and CD147 are significantly upregulated in human lung adenocarcinoma tissues, and isoorientin inhibits cells-migration by inhibiting activity/expression of MCTs1/4 and MMPs2/9 in human lung cancer cells. These novel findings suggest that isoorientin could be a promising pharmacological agent for lung cancer.
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Affiliation(s)
- Hsu-Kai Huang
- Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.,Department of Surgery, Tri-Service General Hospital, Penghu Branch, National Defense Medical Center, Taipei 11490, Taiwan
| | - Shin-Yi Lee
- Department of Pharmacology, National Defense Medical Center, Taipei 11490, Taiwan
| | - Shu-Fen Huang
- Clinical Pathology Division, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
| | - Yu-San Lin
- Department of Pharmacology, National Defense Medical Center, Taipei 11490, Taiwan
| | - Shih-Chi Chao
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan
| | - Shu-Fu Huang
- Department of Pharmacy Practice, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
| | - Shih-Chun Lee
- Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
| | - Tzu-Hurng Cheng
- Department of Pharmacology, National Defense Medical Center, Taipei 11490, Taiwan.,Department of Biochemistry, School of Medicine, College of Medicine, China Medical University, Taichung 40400, Taiwan
| | - Shih-Hurng Loh
- Department of Pharmacology, National Defense Medical Center, Taipei 11490, Taiwan.,Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan.,Department of Pharmacy Practice, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
| | - Yi-Ting Tsai
- Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
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3
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Kumar D, Vetrivel U, Parameswaran S, Subramanian KK. Structural insights on druggable hotspots in CD147: A bull's eye view. Life Sci 2019; 224:76-87. [DOI: 10.1016/j.lfs.2019.03.044] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 03/11/2019] [Accepted: 03/19/2019] [Indexed: 12/13/2022]
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4
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Kanat O, Ertas H. Shattering the castle walls: Anti-stromal therapy for pancreatic cancer. World J Gastrointest Oncol 2018; 10:202-210. [PMID: 30147846 PMCID: PMC6107476 DOI: 10.4251/wjgo.v10.i8.202] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 06/19/2018] [Accepted: 06/27/2018] [Indexed: 02/05/2023] Open
Abstract
Despite the availability of potent chemotherapy regimens, such as 5-fluorouracil, folinic acid, irinotecan, and oxaliplatin (FOLFIRINOX) and nab-paclitaxel plus gemcitabine, treatment outcomes in metastatic pancreatic cancer (PC) remain unsatisfactory. The presence of an abundant fibrous stroma in PC is considered a crucial factor for its unfavorable condition. Apparently, stroma acts as a physical barrier to restrict intratumoral cytotoxic drug penetration and creates a hypoxic environment that reduces the efficacy of radiotherapy. In addition, stroma plays a vital supportive role in the development and progression of PC, which has prompted researchers to assess the potential benefits of agents targeting several cellular (e.g., stellate cells) and acellular (e.g., hyaluronan) elements of the stroma. This study aims to briefly review the primary structural properties of PC stroma and its interaction with cancer cells and summarize the current status of anti-stromal therapies in the management of metastatic PC.
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Affiliation(s)
- Ozkan Kanat
- Department of Medical Oncology, Faculty of Medicine, Uludag University, Bursa 16059, Turkey
| | - Hulya Ertas
- Department of Medical Oncology, Faculty of Medicine, Uludag University, Bursa 16059, Turkey
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5
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Bahrami A, Khazaei M, Bagherieh F, Ghayour-Mobarhan M, Maftouh M, Hassanian SM, Avan A. Targeting stroma in pancreatic cancer: Promises and failures of targeted therapies. J Cell Physiol 2017; 232:2931-2937. [PMID: 28083912 DOI: 10.1002/jcp.25798] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 01/11/2017] [Indexed: 12/18/2022]
Abstract
Desmoplasia or abundant fibrotic stroma is a typical property of most malignancies, which has a great effect on tumorigenesis, angiogenesis, and resistance to therapy. The activated stroma cells comprises several cell types including endothelial cells, nerve cells, inflammatory/macrophages cells, stellate cells, and extracellular matrix. In other word, the interactions of cancer-stroma modulate tumorigenesis, therapy resistance, and poor delivery of drugs. Therefore, targeting the tumor stroma in combination with conventional chemotherapeutic agents could provide a promising approach in the treatment of pancreatic cancer. This review summarizes the current knowledge about pancreatic stellate cells, targeting stroma compartments with particular emphasis on preclinical, and clinical trials on targeting of stroma as an option in pancreatic cancer treatment.
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Affiliation(s)
- Afsane Bahrami
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Neurogenic Inflammatory Research Center and Department of Physiology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fariba Bagherieh
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mina Maftouh
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Cancer Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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6
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Expression of polymeric immunoglobulin receptor and stromal activity in pancreatic ductal adenocarcinoma. Pancreatology 2017; 17:295-302. [PMID: 28173980 DOI: 10.1016/j.pan.2017.01.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 01/26/2017] [Accepted: 01/30/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES Polymeric immunoglobulin receptor (pIgR) traffics Immunoglobulins (IgA and IgM) through epithelial cells in normal mucosae but neither are expressed in the normal pancreas. Recent work from our laboratory suggested pIgR may be upregulated in pancreatic ductal adenocarcinoma (PDAC). Our aim was to assess the role of pIgR in human PDAC. METHODS pIgR expression was manipulated (siRNA and shRNA) in cell lines to evaluate its subsequent effect on cell behaviour in 2D assays as well as 3D organotypics models. Tissue Microarrays of 88 patients with PDAC were analysed after pIgR, αSMA, E-Cadherin and Picrosirius Red staining to assess their role as a combined bio-marker panel. RESULTS Cytokines such as interleukin 4 (IL4) and Tumour Necrosis Factor (TNFα) could not modulate pIgR expression in PDAC cell lines despite this effect being seen in other studies. Down-regulation in pIgR expression in Capan1 cancer cell line resulted in reduction of cellular proliferation, adhesion and migration in 2D assays. In 3D physiomimetic organotypic models, pIgR downregulation resulted in reduced cancer cell invasion, alteration of apico-basal polarity and diminished stromal activity. In human PDAC, decreased E-cadherin expression correlates with increased pIgR expression through pancreatic intra-epithelial neoplasia (PanIN) progression. In combination with enhanced stromal indices (α-smooth muscle action (SMA) and Picrosirius red), low pIgR scores had a trend towards better survival. CONCLUSION pIgR may be involved in PDAC progression and may be linked stromal activity. Further work on its precise role is mandated in in vivo models, to understand its influence on cancer progression.
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Zhang WW, Zhan SH, Geng CX, Sun X, Erkan M, Kleeff J, Xie XJ. Activated leukocyte cell adhesion molecule regulates the interaction between pancreatic cancer cells and stellate cells. Mol Med Rep 2016; 14:3627-33. [PMID: 27573419 PMCID: PMC5042774 DOI: 10.3892/mmr.2016.5681] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Accepted: 07/01/2016] [Indexed: 11/22/2022] Open
Abstract
Activated leukocyte cell adhesion molecule (ALCAM/CD166) is a transmembrane glycoprotein that is involved in tumor progression and metastasis. In the present study, the expression and functional role of ALCAM in pancreatic cancer cells and pancreatic stellate cells (PSCs) was investigated. Tissue specimens were obtained from patients with pancreatic ductal adenocarcinoma (n=56) or chronic pancreatitis (CP; n=10), who underwent pancreatic resection, and from normal pancreatic tissue samples (n=10). Immunohistochemistry was used to analyze the localization and expression of ALCAM in pancreatic tissues. Subsequently, reverse transcription-quantitative polymerase chain reaction and immunoblotting were applied to assess the expression of ALCAM in pancreatic cancer Panc-1 and T3M4 cells, as well as in PSCs. An enzyme-linked immunosorbent assay was used to measure ALCAM levels in cell culture medium stimulated by hypoxia, tumor necrosis factor (TNF)-α and transforming growth factor-β. Silencing of ALCAM was performed using ALCAM small interfering (si)RNA and immunocytochemistry was used to analyze the inhibition efficiency. An invasion assay and a cell interaction assay were performed to assess the invasive ability and co-cultured adhesive potential of Panc-1 and T3M4 cells, as well as PSCs. Histologically, ALCAM expression was generally weak or absent in pancreatic cancer cells, but was markedly upregulated in PSCs in pancreatic cancer tissues. ALCAM was highly expressed in PSCs from CP tissues and PSCs surrounding pancreatic intraepithelial neoplasias, as well as in pancreatic cancer cells. ALCAM mRNA was highly expressed in PSCs, with a low to moderate expression in T3M4 and Panc-1 cells. Similar to the mRNA expression, immunoblotting demonstrated that ALCAM protein levels were high in PSCs and T3M4 cells, but low in Panc-1 cells. The expression of TNF-α increased, while hypoxia decreased the secretion of ALCAM in pancreatic cancer Panc-1 and T3M4 cells, and also in PSCs. Silencing of ALCAM by siRNA revealed no significant alteration in the invasion of pancreatic cancer cells, however, it inhibited the invasive ability of PSCs, and decreased the interaction between Panc-1 cells and PSCs. In conclusion, ALCAM is upregulated in PSCs of pancreatic cancer tissues, suggesting a potential role of ALCAM in regulating pancreatic cancer cell-PSC interactions.
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Affiliation(s)
- Wei-Wei Zhang
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, Shandong 266071, P.R. China
| | - Shu-Hui Zhan
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, Shandong 266071, P.R. China
| | - Chang-Xin Geng
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, Shandong 266071, P.R. China
| | - Xin Sun
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, Shandong 266071, P.R. China
| | - Mert Erkan
- Department of Surgery, Koc University School of Medicine, Istanbul 34450, Turkey
| | - Jörg Kleeff
- Department of Surgery, Technical University of Munich, D-80333 Munich, Germany
| | - Xiang-Jun Xie
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, Shandong 266071, P.R. China
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Lee A, Rode A, Nicoll A, Maczurek AE, Lim L, Lim S, Angus P, Kronborg I, Arachchi N, Gorelik A, Liew D, Warner FJ, McCaughan GW, McLennan SV, Shackel NA. Circulating CD147 predicts mortality in advanced hepatocellular carcinoma. J Gastroenterol Hepatol 2016; 31:459-66. [PMID: 26312403 DOI: 10.1111/jgh.13148] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 07/27/2015] [Accepted: 08/09/2015] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM The glycoprotein CD147 has a role in tumor progression, is readily detectable in the circulation, and is abundantly expressed in hepatocellular carcinoma (HCC). Advanced HCC patients are a heterogeneous group with some individuals having dismal survival. The aim of this study was to examine circulating soluble CD147 levels as a prognostic marker in HCC patients. METHODS CD147 was measured in 277 patients (110 HCC, 115 chronic liver disease, and 52 non-liver disease). Clinical data included etiology, tumor progression, Barcelona Clinic Liver Cancer (BCLC) stage, and treatment response. Patients with HCC were stratified into two groups based upon the 75th percentile of CD147 levels (24 ng/mL). RESULTS CD147 in HCC correlated inversely with poor survival (P = 0.031). Increased CD147 predicted poor survival in BCLC stages C and D (P = 0.045), and CD147 levels >24 ng/mL predicted a significantly diminished 90-day and 180-day survival time (hazard ratio [HR] = 6.1; 95% confidence interval [CI]: 2.1-63.2; P = 0.0045 and HR = 2.8; 95% CI: 1.2-12.6; P = 0.028, respectively). In BCLC stage C, CD147 predicted prognosis; levels >24 ng/mL were associated with a median survival of 1.5 months compared with 6.5 months with CD147 levels ≤24 ng/mL (P = 0.03). CD147 also identified patients with a poor prognosis independent from treatment frequency, modality, and tumor size. CONCLUSIONS Circulating CD147 is an independent marker of survival in advanced HCC. CD147 requires further evaluation as a potential new prognostic measure in HCC to identify patients with advanced disease who have a poor prognosis.
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Affiliation(s)
- Aimei Lee
- Centenary Institute of Cancer Medicine and Cell Biology, Camperdown, New South Wales, Australia.,Sydney Medical School, The University of Sydney, Camperdown, New South Wales, Australia
| | - Anthony Rode
- Department of Gastroenterology and Hepatology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Amanda Nicoll
- Department of Gastroenterology and Hepatology, Box Hill Hospital, Box Hill, Victoria, Australia
| | - Annette E Maczurek
- Centenary Institute of Cancer Medicine and Cell Biology, Camperdown, New South Wales, Australia.,Sydney Medical School, The University of Sydney, Camperdown, New South Wales, Australia
| | - Lucy Lim
- Victorian Liver Transplant Unit and Department of Gastroenterology, Austin Hospital, Melbourne, Victoria, Australia
| | - Seok Lim
- Department of Gastroenterology and Hepatology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Peter Angus
- Victorian Liver Transplant Unit and Department of Gastroenterology, Austin Hospital, Melbourne, Victoria, Australia
| | - Ian Kronborg
- Department of Gastroenterology, Western Hospital, Footscray, Victoria, Australia
| | - Niranjan Arachchi
- Department of Gastroenterology, Western Hospital, Footscray, Victoria, Australia
| | - Alexandra Gorelik
- Melbourne EpiCentre, University of Melbourne and Melbourne Health, Parkville, Victoria, Australia
| | - Danny Liew
- Melbourne EpiCentre, University of Melbourne and Melbourne Health, Parkville, Victoria, Australia
| | - Fiona J Warner
- Centenary Institute of Cancer Medicine and Cell Biology, Camperdown, New South Wales, Australia.,Sydney Medical School, The University of Sydney, Camperdown, New South Wales, Australia
| | - Geoffrey W McCaughan
- Centenary Institute of Cancer Medicine and Cell Biology, Camperdown, New South Wales, Australia.,Sydney Medical School, The University of Sydney, Camperdown, New South Wales, Australia.,A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
| | - Susan V McLennan
- Sydney Medical School, The University of Sydney, Camperdown, New South Wales, Australia.,Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
| | - Nicholas A Shackel
- Centenary Institute of Cancer Medicine and Cell Biology, Camperdown, New South Wales, Australia.,Sydney Medical School, The University of Sydney, Camperdown, New South Wales, Australia.,A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
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Abstract
![]()
Development
of novel imaging probes for cancer diagnostics remains
critical for early detection of disease, yet most imaging agents are
hindered by suboptimal tumor accumulation. To overcome these limitations,
researchers have adapted antibodies for imaging purposes. As cancerous
malignancies express atypical patterns of cell surface proteins in
comparison to noncancerous tissues, novel antibody-based imaging agents
can be constructed to target individual cancer cells or surrounding
vasculature. Using molecular imaging techniques, these agents may
be utilized for detection of malignancies and monitoring of therapeutic
response. Currently, there are several imaging modalities commonly
employed for molecular imaging. These imaging modalities include positron
emission tomography (PET), single-photon emission computed tomography
(SPECT), magnetic resonance (MR) imaging, optical imaging (fluorescence
and bioluminescence), and photoacoustic (PA) imaging. While antibody-based
imaging agents may be employed for a broad range of diseases, this
review focuses on the molecular imaging of pancreatic cancer, as there
are limited resources for imaging and treatment of pancreatic malignancies.
Additionally, pancreatic cancer remains the most lethal cancer with
an overall 5-year survival rate of approximately 7%, despite significant
advances in the imaging and treatment of many other cancers. In this
review, we discuss recent advances in molecular imaging of pancreatic
cancer using antibody-based imaging agents. This task is accomplished
by summarizing the current progress in each type of molecular imaging
modality described above. Also, several considerations for designing
and synthesizing novel antibody-based imaging agents are discussed.
Lastly, the future directions of antibody-based imaging agents are
discussed, emphasizing the potential applications for personalized
medicine.
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Affiliation(s)
- Christopher G England
- Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States
| | - Reinier Hernandez
- Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States
| | - Savo Bou Zein Eddine
- Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States
| | - Weibo Cai
- Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.,Department of Radiology, University of Wisconsin-Madison , Madison, Wisconsin 53792, United States.,University of Wisconsin Carbone Cancer Center , Madison, Wisconsin 53792, United States
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10
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Haun RS, Quick CM, Siegel ER, Raju I, Mackintosh SG, Tackett AJ. Bioorthogonal labeling cell-surface proteins expressed in pancreatic cancer cells to identify potential diagnostic/therapeutic biomarkers. Cancer Biol Ther 2015; 16:1557-65. [PMID: 26176765 DOI: 10.1080/15384047.2015.1071740] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
To develop new diagnostic and therapeutic tools to specifically target pancreatic tumors, it is necessary to identify cell-surface proteins that may serve as potential tumor-specific targets. In this study we used an azido-labeled bioorthogonal chemical reporter to metabolically label N-linked glycoproteins on the surface of pancreatic cancer cell lines to identify potential targets that may be exploited for detection and/or treatment of pancreatic cancer. Labeled glycoproteins were tagged with biotin using click chemistry, purified by streptavidin-coupled magnetic beads, separated by gel electrophoresis, and identified by liquid chromatography-tandem mass spectrometry (MS). MS/MS analysis of peptides from 3 cell lines revealed 954 unique proteins enriched in the azido sugar samples relative to control sugar samples. A comparison of the proteins identified in each sample indicated 20% of these proteins were present in 2 cell lines (193 of 954) and 17 of the proteins were found in all 3 cell lines. Five of the 17 proteins identified in all 3 cell lines have not been previously reported to be expressed in pancreatic cancer; thus indicating that novel cell-surface proteins can be revealed through glycoprotein profiling. Western analysis of one of these glycoproteins, ecto-5'-nucleotidase (NT5E), revealed it is expressed in 8 out of 8 pancreatic cancer cell lines examined. Further, immunohistochemical analysis of human pancreatic tissues indicates NT5E is significantly overexpressed in pancreatic tumors compared to normal pancreas. Thus, we have demonstrated that metabolic labeling with bioorthogonal chemical reporters can be used to selectively enrich and identify novel cell-surface glycoproteins expressed in pancreatic ductal adenocarcinomas.
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Affiliation(s)
- Randy S Haun
- a Central Arkansas Veterans Healthcare System; Little Rock , AR USA.,b Department of Pharmaceutical Sciences ; University of Arkansas for Medical Sciences; Little Rock , AR USA
| | - Charles M Quick
- c Department of Pathology; University of Arkansas for Medical Sciences; Little Rock , AR USA
| | - Eric R Siegel
- d Department of Biostatistics; University of Arkansas for Medical Sciences; Little Rock , AR USA
| | - Ilangovan Raju
- b Department of Pharmaceutical Sciences ; University of Arkansas for Medical Sciences; Little Rock , AR USA
| | - Samuel G Mackintosh
- e Department of Biochemistry & Molecular Biology; University of Arkansas for Medical Sciences; Little Rock , AR USA
| | - Alan J Tackett
- e Department of Biochemistry & Molecular Biology; University of Arkansas for Medical Sciences; Little Rock , AR USA
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11
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Kong B, Wang W, Esposito I, Friess H, Michalski CW, Kleeff J. Increased expression of Nodal correlates with reduced patient survival in pancreatic cancer. Pancreatology 2015; 15:156-61. [PMID: 25708930 DOI: 10.1016/j.pan.2015.02.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 01/12/2015] [Accepted: 02/01/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Nodal (nodal growth differentiation factor) and its inhibitor Lefty (left right determination factor), which are ligands of the TGF (transforming growth factor) β superfamily, are responsible for the determination of left-right asymmetry in vertebrates. Nodal/Lefty signaling has been suggested to play a role in the development of metastatic melanoma and breast cancer. However, it remains unclear whether this pathway is also involved in human pancreatic ductal adenocarcinoma (PDAC). METHODS Pancreatic cancer patient specimens with clinical data (n = 54) were used to investigate the clinical significance of Nodal-Lefty signaling. A set of in vitro assays were carried out in a human pancreatic cancer cell line (Colo-357) to assess the functional relevance of Nodal-Lefty signaling. RESULTS Nodal was absent in the human normal pancreas, while Lefty was present in islet cells. Though Nodal and Lefty expression were found in cancer cells at various expression levels, the cancer-associated tubular complexes were particularly positive for Lefty. Survival analysis revealed that high expression of Nodal correlated with reduced patient survival (median survival 17.8 vs 33.0 months, p = 0.013). Cultured pancreatic cancer cell lines expressed Nodal and Lefty at different levels. In vitro functional assays revealed that treatment with human recombinant Nodal inhibited cell growth and increased invasion of Colo-357 pancreatic cancer cells whereas no effect was found upon treatment with recombinant Lefty. CONCLUSION Nodal-Lefty signaling might be involved in the pathogenesis of PDAC as Nodal expression marks a subtype of PDAC with unfavorable prognosis.
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Affiliation(s)
- Bo Kong
- Department of Surgery, Technische Universität München, Munich, Germany
| | - Weibin Wang
- Department of Surgery, Technische Universität München, Munich, Germany; Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Irene Esposito
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Helmut Friess
- Department of Surgery, Technische Universität München, Munich, Germany
| | | | - Jörg Kleeff
- Department of Surgery, Technische Universität München, Munich, Germany.
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Yang X, Zhang P, Ma Q, Kong L, Li Y, Liu B, Lei D. EMMPRIN silencing inhibits proliferation and perineural invasion of human salivary adenoid cystic carcinoma cells in vitro and in vivo. Cancer Biol Ther 2014; 13:85-91. [DOI: 10.4161/cbt.13.2.18455] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Li L, Tang W, Wu X, Karnak D, Meng X, Thompson R, Hao X, Li Y, Qiao XT, Lin J, Fuchs J, Simeone DM, Chen ZN, Lawrence TS, Xu L. HAb18G/CD147 promotes pSTAT3-mediated pancreatic cancer development via CD44s. Clin Cancer Res 2013; 19:6703-15. [PMID: 24132924 DOI: 10.1158/1078-0432.ccr-13-0621] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE Signal transducer and activator of transcription 3 (STAT3) plays a critical role in initiation and progression of pancreatic cancer. However, therapeutically targeting STAT3 has failed clinically. We previously identified HAb18G/CD147 as an effective target for cancer treatment. In this study, we aimed to investigate the potential role of HAb18G/CD147 in STAT3-involved pancreatic tumorigenesis in vitro and in vivo. EXPERIMENTAL DESIGN The expression of HAb18G/CD147, pSTAT3, and CD44s was determined in tissue microarrays. The tumorigenic function and molecular signaling mechanism of HAb18G/CD147 were assessed by in vitro cellular and clonogenic growth, reporter assay, immunoblot assay, immunofluorescence staining, immunoprecipitation, and in vivo tumor formation using loss or gain-of-function strategies. RESULTS Highly expressed HAb18G/CD147 promoted cellular and clonogenic growth in vitro and tumorigenicity in vivo. Cyclophilin A (CyPA), a ligand of CD147, stimulated STAT3 phosphorylation and its downstream genes cyclin D1/survivin through HAb18G/CD147-dependent mechanisms. HAb18G/CD147 was associated and colocalized with cancer stem cell marker CD44s in lipid rafts. The inhibitors of STAT3 and survivin, as well as CD44s neutralizing antibodies suppressed the HAb18G/CD147-induced cell growth. High HAb18G/CD147 expression in pancreatic cancer was significantly correlated with the poor tumor differentiation, and the high coexpression of HAb18G/CD147-CD44s-STAT3 associated with poor survival of patients with pancreatic cancer. CONCLUSIONS We identified HAb18G/CD147 as a novel upstream activator of STAT3, which interacts with CD44s and plays a critical role in the development of pancreatic cancer. The data suggest that HAb18G/CD147 could be a promising therapeutic target for highly aggressive pancreatic cancer and a surrogate marker in the STAT3-targeted molecular therapies.
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Affiliation(s)
- Ling Li
- Authors' Affiliations: Departments of Radiation Oncology and Surgery, University of Michigan Medical Center; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan; Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an; Department of Hematology/Oncology, Hainan University Medical School, Haikou, Hainan, China; Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, Kansas; Department of Pediatrics, College of Medicine; and Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, Ohio
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Abstract
Pancreatic cancer remains a devastating disease. Over the last few years, there have been important advances in the molecular and biological understanding of pancreatic cancer. This included understanding of the genomic complexity of the disease, the role of pancreatic cancer stem cells, the relevance of the tumor microenvironment, and the unique metabolic adaptation of pancreas cancer cells to obtain nutrients under hypoxic environment. In this paper, we review the most salient developments in these few areas.
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Affiliation(s)
- M Hidalgo
- Centro Nacional de Investigaciones Oncologicas, Madrid, Spain.
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Charo C, Holla V, Arumugam T, Hwang R, Yang P, Dubois RN, Menter DG, Logsdon CD, Ramachandran V. Prostaglandin E2 regulates pancreatic stellate cell activity via the EP4 receptor. Pancreas 2013; 42:467-74. [PMID: 23090667 PMCID: PMC3600062 DOI: 10.1097/mpa.0b013e318264d0f8] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Pancreatic stellate cells are source of dense fibrotic stroma, a constant pathological feature of chronic pancreatitis and pancreatic adenocarcinoma. We observed correlation between levels of cyclooxygenase 2 (COX-2) and its product prostaglandin E2 (PGE2) and the extent of pancreatic fibrosis. The aims of this study were to delineate the effects of PGE2 on immortalized human pancreatic stellate cells (HPSCs) and to identify the receptor involved. METHODS Immunohistochemistry, reverse transcription-polymerase chain reaction and quantitative reverse transcription-polymerase chain reaction were used to assess COX-2, extracellular matrix, and matrix metalloproteinase gene expression. Eicosanoid profile was determined by liquid chromatography-tandem mass spectrometry. Human pancreatic stellate cell proliferation was assessed by MTS assay, migration by Boyden chamber assay, and invasion using an invasion chamber. Transient silencing was obtained by small interfering RNA. RESULTS Human pancreatic stellate cells express COX-2 and synthesize PGE2. Prostaglandin E2 stimulated HPSC proliferation, migration, and invasion and stimulated expression of both extracellular matrix and matrix metalloproteinase genes. Human pancreatic stellate cells expressed all 4 EP receptors. Only blocking the EP4 receptor resulted in abrogation of PGE2-mediated HPSC activation. Specificity of EP4 for the effects of PGE2 on stellate cells was confirmed using specific antagonists. CONCLUSIONS Our data indicate that PGE2 regulates pancreatic stellate cell profibrotic activities via EP4 receptor, thus suggesting EP4 receptor as useful therapeutic target for pancreatic cancer to reduce desmoplasia.
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Affiliation(s)
- Chantale Charo
- Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX
| | - Vijaykumar Holla
- Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX
| | | | - Rosa Hwang
- Department of Surgical Oncology, UT MD Anderson Cancer Center, Houston, TX
| | - Peiying Yang
- Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX
| | - Raymond N. Dubois
- Department of Cancer Biology and Gastrointestinal Oncology, UT MD Anderson Cancer Center, Houston, TX
| | - David G. Menter
- Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX
| | - Craig D. Logsdon
- Department of Cancer Biology and Medical Oncology, UT MD Anderson Cancer Center, Houston, TX
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Tang D, Wang D, Yuan Z, Xue X, Zhang Y, An Y, Chen J, Tu M, Lu Z, Wei J, Jiang K, Miao Y. Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma. Int J Cancer 2013; 132:993-1003. [PMID: 22777597 DOI: 10.1002/ijc.27715] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2012] [Revised: 06/20/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumors with poor prognosis due to extremely high malignancy, low rate of eligibility for surgical resection and chemoradiation resistance. Increasing evidence indicate that the interaction between activated pancreatic stellate cells (PSCs) and PDAC cells plays an important role in the development of PDAC. By producing high levels of cytokines, chemotactic factors, growth factors and excessive extracellular matrix (ECM), PSCs create desmoplasia and a hypoxic microenvironment that promote the initiation, development, evasion of immune surveillance, invasion, metastasis and resistance to chemoradiation of PDAC. Therefore, targeting the interaction between PSCs and PDAC cells may represent a novel therapeutic approach to advanced PDAC, especially therapies that target PSCs of the pancreatic tumor microenvironment.
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Affiliation(s)
- Dong Tang
- Department of Gastrointestinal Surgery, Subei People's Hospital of Jiangsu Province (Clinical Medical College of Yangzhou University), Yangzhou, People's Republic of China
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Hidalgo M, Von Hoff DD. Translational therapeutic opportunities in ductal adenocarcinoma of the pancreas. Clin Cancer Res 2013; 18:4249-56. [PMID: 22896691 DOI: 10.1158/1078-0432.ccr-12-1327] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDA) remains a devastating disease with nearly equal incidence and mortality rates. Over the past few decades, a litany of randomized clinical trials has failed to improve the outcome of this disease. More recently, the combination chemotherapy regimen FOLFIRINOX has shown improvement in overall survival over the single agent gemcitabine, and nab-paclitaxel (an albumin-coated formulation of paclitaxel) in combination with gemcitabine has shown promising results in phase II studies. Despite limited impact on patient care as of yet, the molecular and biologic understanding of PDA has advanced substantially. This includes understanding the genomic complexity of the disease, the potential importance of the tumor microenvironment, the metabolic adaptation of PDA cells to obtain nutrients in a hypoxic environment, and the role of pancreatic cancer stem cells. These fundamental discoveries are starting to be translated into clinical studies. In this overview, we discuss the implications of biologic understanding of PDA in clinical research and provide insights for future development of novel approaches and agents in this disease.
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Affiliation(s)
- Manuel Hidalgo
- Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
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Morrison M. Pancreatic cancer and diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 771:229-39. [PMID: 23393682 DOI: 10.1007/978-1-4614-5441-0_18] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Diabetes studies have increasingly been associated with several types of cancer. Diabetes and pancreatic cancer have a unique relationship. Genetic mutations, such as activation of the KRAS2 oncogene, inactivation of the tumor-suppressor gene CDKN2A, inactivation of the tumor-suppressor gene TP53 and deleted in pancreatic cancer 4 (DPC4) gene defects are seen in those with pancreatic cancer. Approximately 80% of those patients, diagnosed with pancreatic cancer, are identified as having concomitant diabetes with a poor prognostic factor. Damaged pancreatic tissue, secondary to pancreatic cancer, leads to diabetes as islet cells and beta cells are taken over by malignancy. Additionally, those on certain anti-diabetic regimens are shown to be at a higher risk of developing pancreatic cancer due to the effect of stimulation on the pancreatic beta and islet cells. Therefore, diabetes is thought to be both a potential cause and effect of pancreatic cancer. Diabetes has become a pandemic, and pancreatic cancer is one of the most lethal forms of malignancy known. In order to better understand these diseases and how they are associated, more research needs to be done. Particularly, research focusing on different types of diabetes in the setting of pancreatic cancer will be an important issue for further understanding of the link between diabetes and pancreatic cancer.
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Affiliation(s)
- Maureen Morrison
- Swedish Organ Transplant Division, Swedish Medical Center, Seattle, Washington, USA.
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Liu H, Ma Q, Xu Q, Lei J, Li X, Wang Z, Wu E. Therapeutic potential of perineural invasion, hypoxia and desmoplasia in pancreatic cancer. Curr Pharm Des 2012; 18:2395-403. [PMID: 22372500 DOI: 10.2174/13816128112092395] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Accepted: 01/18/2012] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer is one of the most fatal human malignancies. Though a relatively rare malignancy, it remains one of the deadliest tumors, with an extremely high mortality rate. The prognosis of patients with pancreatic cancer remains poor; only patients with small tumors and complete resection have a chance of a complete cure. Pancreatic cancer responds poorly to conventional therapies, including chemotherapy and irradiation. Tumor-specific targeted therapy is a relatively recent addition to the arsenal of anti-cancer therapies. It is important to find novel targets to distinguish tumor cells from their normal counterparts in therapeutic approaches. In the past few decades, studies have revealed the molecular mechanisms of pancreatic tumorigenesis, growth, invasion and metastasis. The proteins that participate in the pathophysiological processes of pancreatic cancer might be potential targets for therapy. This review describes the main players in perineural invasion, hypoxia and desmoplasia and the molecular mechanisms of these pathophysiological processes.
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Affiliation(s)
- Han Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, China
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Erkan M, Hausmann S, Michalski CW, Fingerle AA, Dobritz M, Kleeff J, Friess H. The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol 2012; 9:454-67. [PMID: 22710569 DOI: 10.1038/nrgastro.2012.115] [Citation(s) in RCA: 481] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the five most lethal malignancies worldwide and survival has not improved substantially in the past 30 years. Desmoplasia (abundant fibrotic stroma) is a typical feature of PDAC in humans, and stromal activation commonly starts around precancerous lesions. It is becoming clear that this stromal tissue is not a bystander in disease progression. Cancer-stroma interactions effect tumorigenesis, angiogenesis, therapy resistance and possibly the metastatic spread of tumour cells. Therefore, targeting the tumour stroma, in combination with chemotherapy, is a promising new option for the treatment of PDAC. In this Review, we focus on four issues. First, how can stromal activity be used to detect early steps of pancreatic carcinogenesis? Second, what is the effect of perpetual pancreatic stellate cell activity on angiogenesis and tissue perfusion? Third, what are the (experimental) antifibrotic therapy options in PDAC? Fourth, what lessons can be learned from Langton's Ant (a simple mathematical model) regarding the unpredictability of genetically engineered mouse models?
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Affiliation(s)
- Mert Erkan
- Department of General Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 12, 81675 Munich, Germany.
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The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. J Gastrointest Cancer 2012; 40:1-9. [PMID: 22710569 DOI: 10.1007/s12029-009-9071-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2009] [Accepted: 05/27/2009] [Indexed: 12/18/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the five most lethal malignancies worldwide and survival has not improved substantially in the past 30 years. Desmoplasia (abundant fibrotic stroma) is a typical feature of PDAC in humans, and stromal activation commonly starts around precancerous lesions. It is becoming clear that this stromal tissue is not a bystander in disease progression. Cancer-stroma interactions effect tumorigenesis, angiogenesis, therapy resistance and possibly the metastatic spread of tumour cells. Therefore, targeting the tumour stroma, in combination with chemotherapy, is a promising new option for the treatment of PDAC. In this Review, we focus on four issues. First, how can stromal activity be used to detect early steps of pancreatic carcinogenesis? Second, what is the effect of perpetual pancreatic stellate cell activity on angiogenesis and tissue perfusion? Third, what are the (experimental) antifibrotic therapy options in PDAC? Fourth, what lessons can be learned from Langton's Ant (a simple mathematical model) regarding the unpredictability of genetically engineered mouse models?
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Bhagirath D, Abrol N, Khan R, Sharma M, Seth A, Sharma A. Expression of CD147, BIGH3 and Stathmin and their potential role as diagnostic marker in patients with urothelial carcinoma of the bladder. Clin Chim Acta 2012; 413:1641-6. [PMID: 22626996 DOI: 10.1016/j.cca.2012.05.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Revised: 05/03/2012] [Accepted: 05/08/2012] [Indexed: 01/31/2023]
Abstract
BACKGROUND Urothelial carcinoma of the bladder is characterised by very high recurrence rate, followed up by cystoscopy which being invasive technique makes the need for non-invasive markers important for Transitional Cell Carcinoma (TCC) detection. CD147 is a transmembrane protein highly expressed in tumour cells which aids in tumour invasion and growth. BIGH3, an Extracellular matrix protein (ECM) which interacts with various ECM component in different tissue system and Stathmin(STMN1) is cytosolic microtubule destabilising protein also called as Oncoprotein18 due to its role in tumour promotion. So far the expression of BIGH3 and STMN1 remains undetermined in cancer subjects including TCC. We therefore studied the levels and molecular expression of these molecules in TCC patients, to evaluate their usefulness as diagnostic markers. METHODS Thirty consecutive TCC patients and two sets of control- 15 Benign prostatic hyperplasia (BPH) patient and 15 healthy were taken. Serum and urine levels of these molecules were estimated by ELISA and relative mRNA expression by Q-PCR from tumour and normal urothelium. Post-Hoc analysis and ROC curve were determined to evaluate the significance and sensitivity and specificity. RESULTS The mean concentrations of these molecules were found to be significantly increased (p<0.001) in the serum and urine of TCC patients, with varying significance in each grade for different molecules. The urinary levels of CD147 (67 pg/ml) and serum STMN1 concentration (1.38 ng/ml) showed a specific increase as compared to the controls, while BIGH3 was elevated in both serum and urine samples. Molecular (mRNA) expression was elevated in the high grade (Muscle Invasive) stage of the disease for all the molecules, with a significant 3-fold increase that correlated with disease severity being observed for STMN1. ROC analysis gave optimal combination of sensitivity and specificity for diagnosis of the disease in urine and serum sample for STMN1. CONCLUSION Of CD147, BIGH3 and STMN1, significant results were obtained for STMN1 and it could serve as the best possible diagnostic marker for TCC detection in future.
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Affiliation(s)
- Divya Bhagirath
- Department of Biochemistry, All India Institute of Medical Sciences-AIIMS, New Delhi, India
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Kim H, Zhai G, Samuel SL, Rigell CJ, Umphrey HR, Rana S, Stockard CR, Fineberg NS, Zinn KR. Dual combination therapy targeting DR5 and EMMPRIN in pancreatic adenocarcinoma. Mol Cancer Ther 2011; 11:405-15. [PMID: 22203731 DOI: 10.1158/1535-7163.mct-11-0581] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The goal of the study was to assess the efficacy of combined extracellular matrix metalloprotease inducer (EMMPRIN)- and death receptor 5 (DR5)-targeted therapy for pancreatic adenocarcinoma in orthotopic mouse models with multimodal imaging. Cytotoxicity of anti-EMMPRIN antibody and anti-DR5 antibody (TRA-8) in MIA PaCa-2 and PANC-1 cell lines was measured by ATPlite assay in vitro. The distributions of Cy5.5-labeled TRA-8 and Cy3-labeled anti-EMMPRIN antibody in the 2 cell lines were analyzed by fluorescence imaging in vitro. Groups 1 to 12 of severe combined immunodeficient mice bearing orthotopic MIA PaCa-2 (groups 1-8) or PANC-1 (groups 9-12) tumors were used for in vivo studies. Dynamic contrast-enhanced-MRI was applied in group 1 (untreated) or group 2 (anti-EMMPRIN antibody). The tumor uptake of Tc-99m-labeled TRA-8 was measured in group 3 (untreated) and group 4 (anti-EMMPRIN antibody). Positron emission tomography/computed tomography imaging with (18)F-FDG was applied in groups 5 to 12. Groups 5 to 8 (or groups 9 to 12) were untreated or treated with anti-EMMPRIN antibody, TRA-8, and combination, respectively. TRA-8 showed high killing efficacy for both MIA PaCa-2 and PANC-1 cells in vitro, but additional anti-EMMPRIN treatment did not improve the cytotoxicity. Cy5.5-TRA-8 formed cellular caps in both the cell lines, whereas the maximum signal intensity was correlated with TRA-8 cytotoxicity. Anti-EMMPRIN therapy significantly enhanced the tumor delivery of the MR contrast agent, but not Tc-99m-TRA-8. Tumor growth was significantly suppressed by the combination therapy, and the additive effect of the combination was shown in both MIA PaCa-2 and PANC-1 tumor models.
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Affiliation(s)
- Hyunki Kim
- Department of Radiology, University of Alabama at Birmingham, 1670 University Blvd, Birmingham, AL 35294, USA.
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Vasseur S, Tomasini R, Tournaire R, Iovanna JL. Hypoxia induced tumor metabolic switch contributes to pancreatic cancer aggressiveness. Cancers (Basel) 2010; 2:2138-52. [PMID: 24281221 PMCID: PMC3840441 DOI: 10.3390/cancers2042138] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2010] [Revised: 12/07/2010] [Accepted: 12/13/2010] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumors with an overall five-year survival rate of only 3-5%. Its aggressive biology and resistance to conventional and targeted therapeutic agents lead to a typical clinical presentation of incurable disease once diagnosed. The disease is characterized by the presence of a dense stroma of fibroblasts and inflammatory cells, termed desmoplasia, which limits the oxygen diffusion in the organ, creating a strong hypoxic environment within the tumor. In this review, we argue that hypoxia is responsible for the highly aggressive and metastatic characteristics of this tumor and drives pancreatic cancer cells to oncogenic and metabolic changes facilitating their proliferation. However, the molecular changes leading to metabolic adaptations of pancreatic cancer cells remain unclear. Cachexia is a hallmark of this disease and illustrates that this cancer is a real metabolic disease. Hence, this tumor must harbor metabolic pathways which are probably tied in a complex inter-organ dialog during the development of this cancer. Such a hypothesis would better explain how under fuel source limitation, pancreatic cancer cells are maintained, show a growth advantage, and develop metastasis.
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Affiliation(s)
- Sophie Vasseur
- INSERM U624, Stress Cellulaire, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, BP 915¸13288 Marseille cedex 9, France.
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Interaction of stellate cells with pancreatic carcinoma cells. Cancers (Basel) 2010; 2:1661-82. [PMID: 24281180 PMCID: PMC3837330 DOI: 10.3390/cancers2031661] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2010] [Revised: 09/02/2010] [Accepted: 09/02/2010] [Indexed: 12/21/2022] Open
Abstract
Pancreatic cancer is characterized by its late detection, aggressive growth, intense infiltration into adjacent tissue, early metastasis, resistance to chemo- and radiotherapy and a strong “desmoplastic reaction”. The dense stroma surrounding carcinoma cells is composed of fibroblasts, activated stellate cells (myofibroblast-like cells), various inflammatory cells, proliferating vascular structures, collagens and fibronectin. In particular the cellular components of the stroma produce the tumor microenvironment, which plays a critical role in tumor growth, invasion, spreading, metastasis, angiogenesis, inhibition of anoikis, and chemoresistance. Fibroblasts, myofibroblasts and activated stellate cells produce the extracellular matrix components and are thought to interact actively with tumor cells, thereby promoting cancer progression. In this review, we discuss our current understanding of the role of pancreatic stellate cells (PSC) in the desmoplastic response of pancreas cancer and the effects of PSC on tumor progression, metastasis and drug resistance. Finally we present some novel ideas for tumor therapy by interfering with the cancer cell-host interaction.
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Abstract
RNA interference (RNAi) is an evolutionary conserved mechanism for specific gene silencing. This mechanism has great potential for use in targeted cancer therapy. Understanding the RNAi mechanism has led to the development of several novel RNAi-based therapeutic approaches currently in the early phases of clinical trials. It remains difficult to effectively deliver the nucleic acids required in vivo to initiate RNAi, and intense effort is under way in developing effective and targeted systemic delivery systems for RNAi. Description of in vivo delivery systems is not the focus of this review. In this review, we cover the rationale for pursuing personalised cancer therapy with RNAi, briefly review the mechanism of each major RNAi therapeutic technique, summarise and sample recent results with animal models applying RNAi for cancer, and provide an update on current clinical trials with RNAi-based therapeutic agents for cancer therapy. RNAi-based cancer therapy is still in its infancy, and there are numerous obstacles and issues that need to be resolved before its application in personalised therapy focusing on patient-cancer-specific targets can become standard cancer treatment, either alone or in combination with other treatments.
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Kong B, Michalski CW, Hong X, Valkovskaya N, Rieder S, Abiatari I, Streit S, Erkan M, Esposito I, Friess H, Kleeff J. AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling. Oncogene 2010; 29:5146-58. [PMID: 20581862 DOI: 10.1038/onc.2010.258] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Epithelial-to-mesenchymal transdifferentiation (EMT) mediated by transforming growth factor-β (TGF-β) signaling leads to aggressive cancer progression. In this study, we identified zinc-α2-glycoprotein (AZGP1, ZAG) as a tumor suppressor in pancreatic ductal adenocarcinoma whose expression is lost due to histone deacetylation. In vitro, ZAG silencing strikingly increased invasiveness of pancreatic cancer cells accompanied by the induction of a mesenchymal phenotype. Expression analysis of a set of EMT markers showed an increase in the expression of mesenchymal markers (vimentin (VIM) and integrin-α5) and a concomitant reduction in the expression of epithelial markers (cadherin 1 (CDH1), desmoplakin and keratin-19). Blockade of endogenous TGF-β signaling inhibited these morphological changes and the downregulation of CDH1, as elicited by ZAG silencing. In a ZAG-negative cell line, human recombinant ZAG (rZAG) specifically inhibited exogenous TGF-β-mediated tumor cell invasion and VIM expression. Furthermore, rZAG blocked TGF-β-mediated ERK2 phosphorylation. PCR array analysis revealed that ZAG-induced epithelial transdifferentiation was accompanied by a series of concerted cellular events including a shift in the energy metabolism and prosurvival signals. Thus, epigenetically regulated ZAG is a novel tumor suppressor essential for maintaining an epithelial phenotype.
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Affiliation(s)
- B Kong
- Department of Surgery, Technische Universität München, Munich, Germany
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Moonsom S, Tayapiwatana C, Wongkham S, Kongtawelert P, Kasinrerk W. A Competitive ELISA for quantifying serum CD147: reduction of soluble CD147 levels in cancer patient sera. Hybridoma (Larchmt) 2010; 29:45-52. [PMID: 20199151 DOI: 10.1089/hyb.2009.0096] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) is a cell surface glycoprotein that displays increased expression in many cancers. It has been previously demonstrated to participate in cancer metastasis and progression. In this study we used an anti-CD147 monoclonal antibody and a recombinant CD147 protein generated in our laboratory to establish a competitive ELISA for quantifying serum CD147 levels. Unexpectedly, the CD147 level was highest in sera of normal subjects and significantly reduced in sera of cancer patients. There was no significant difference in serum CD147 level between benign, non-metastatic, and metastatic stages of cancers. In regard to liver diseases, the maximal CD147 level was observed in sera of patients with hepatitis and hepatocellular carcinoma, and significantly decreased in patients with liver cirrhosis and cholangiocarcinoma. Our results imply that there may be homeostasis of CD147 levels in sera under normal physiological conditions, while such a level is altered in cancer patients.
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Affiliation(s)
- Seangdeun Moonsom
- Biomedical Technology Research Center, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency at the Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
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30
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Affiliation(s)
- Manuel Hidalgo
- Centro Nacional de Investigaciones Oncológicas and Hospital de Madrid, Madrid.
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31
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Qu X, Yang W, Jiang M, Han T, Han L, Qu Y, Wang G, Shi D, Xu G. CD147 expression in pituitary adenomas and its significance for clinical outcome. Hum Pathol 2010; 41:1165-71. [PMID: 20381119 DOI: 10.1016/j.humpath.2009.10.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2009] [Revised: 10/22/2009] [Accepted: 10/23/2009] [Indexed: 01/07/2023]
Abstract
CD147, a transmembrane glycoprotein member of the immunoglobulin superfamily of receptors, is involved in invasion and angiogenesis of some types of tumors; but its roles and clinicopathologic significance in pituitary adenomas are not clear. Using immunohistochemistry and quantitative reverse transcriptase polymerase chain reaction, we measured the expression of CD147, matrix metalloproteinase-2, and Ki-67 in 74 pituitary adenomas and evaluated the associations of CD147 with matrix metalloproteinase-2, Ki-67 labeling index, clinicopathologic characteristics, and prognosis. The CD147 protein was expressed in 35 (87.5%) of 40 invasive and in 16 (47.1%) of 34 noninvasive pituitary adenomas; and matrix metalloproteinase-2, in 32 (80.0%) and in 14 (41.2%) of 34, respectively. The Ki-67 labeling index was 3.93% +/- 2.48% for invasive samples and 1.32% +/- 1.04% for noninvasive ones. In addition, the expression of CD147 was positively correlated with matrix metalloproteinase-2, Ki-67 labeling index, or both in invasive pituitary adenomas (P< .01 and P< .01, respectively). All of the 4 recurrent adenomas were concurrently positive for CD147 and matrix metalloproteinase-2, and the Ki-67 labeling indexes of all were greater than 3%. Thus, CD147 may play a pivotal role in the development and progression of invasive pituitary adenomas and also be a useful prognostic biomarker.
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Affiliation(s)
- Xin Qu
- Department of Neurosurgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, China
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Kennedy KM, Dewhirst MW. Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation. Future Oncol 2010; 6:127-48. [PMID: 20021214 DOI: 10.2217/fon.09.145] [Citation(s) in RCA: 217] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Tumor metabolism consists of complex interactions between oxygenation states, metabolites, ions, the vascular network and signaling cascades. Accumulation of lactate within tumors has been correlated with poor clinical outcomes. While its production has negative implications, potentially contributing to tumor progression, the implications of the ability of tumors to utilize lactate can offer new therapeutic targets for the future. Monocarboxylate transporters (MCTs) of the SLC16A gene family influence substrate availability, the metabolic path of lactate and pH balance within the tumor. CD147, a chaperone to some MCT subtypes, contributes to tumor progression and metastasis. The implications and consequences of lactate utilization by tumors are currently unknown; therefore future research is needed on the intricacies of tumor metabolism. The possibility of metabolic modification of the tumor microenvironment via regulation or manipulation of MCT1 and CD147 may prove to be promising avenues of therapeutic options.
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Affiliation(s)
- Kelly M Kennedy
- Pathology department, Research Drive, Duke University Medical Center, NC 27710, USA
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33
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Zhu H, Evans B, O'Neill P, Ren X, Xu Z, Hait WN, Yang JM. A role for p53 in the regulation of extracellular matrix metalloproteinase inducer in human cancer cells. Cancer Biol Ther 2009; 8:1722-8. [PMID: 19597352 DOI: 10.4161/cbt.8.18.9207] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
EMMPRIN, a transmembrane glycoprotein known to promote survival, invasion and metastasis of tumor cells through multiple pathways and mechanisms, has been found to be overexpressed in various types of cancer cells. Here we report that loss of the function of p53, a tumor suppressor protein that is mutated in approximately 50% of human cancers, contributes to the upregulation of EMMPRIN protein. We observed an inverse association between the activity of p53 and the level of EMMPRIN protein in several cancer cell lines. We further demonstrated that p53 is able to negatively regulate EMMPRIN protein, but downregulation of EMMPRIN by p53 is independent of repression of the EMMPRIN transcription. Furthermore, downregulation of EMMPRIN by p53 can be rescued by chloroquine, a lysosome inhibitor, but not by MG132, a proteasome inhibitor, suggesting an involvement of the lysosomal pathway in the p53-regulated degradation of EMMPRIN. Downregulation of EMMPRIN by p53 leads to a decrease in the activity of MMP-9 and an inhibition of tumor cell invasion. Our study suggests that the upregulation of EMMPRIN seen in many cancers can be attributed to, at least in part, the dysfunction of p53 and thus provides new evidence for the roles of p53 in tumor development and progression.
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Affiliation(s)
- Hua Zhu
- Department of Pharmacology and The Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033-0850, USA
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34
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Cancer-stellate cell interactions perpetuate the hypoxia-fibrosis cycle in pancreatic ductal adenocarcinoma. Neoplasia 2009; 11:497-508. [PMID: 19412434 DOI: 10.1593/neo.81618] [Citation(s) in RCA: 226] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2008] [Revised: 01/27/2009] [Accepted: 03/02/2009] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIMS Although both cancer and stellate cells (PSCs) secrete proangiogenic factors, pancreatic cancer is a scirrhous and hypoxic tumor. The impact of cancer-PSCs interactions on angiogenesis was analyzed. METHODS Expression of periostin, CD31, and alpha-smooth muscle actin was assessed by immunohistochemistry. Human PSCs and cancer cells were cultivated under normoxia and hypoxia alone, or in coculture, to analyze the changes in their angiogenic and fibrogenic attributes, using enzyme-linked immunosorbent assay, immunoblot, and quantitative polymerase chain reaction analyses and growth of cultured endothelial cells in vitro. RESULTS On the invasive front of the activated stroma, PSCs deposited a periostin-rich matrix around the capillaries in the periacinar spaces. Compared with the normal pancreas, there was a significant reduction in the microvessel density in chronic pancreatitis (five-fold, P < .001) and pancreatic cancer (four-fold, P < .01) tissues. In vitro, hypoxia increased PSCs' activity and doubled the secretion of periostin, type I collagen, fibronectin, and vascular endothelial growth factor (VEGF). Cancer cells induced VEGF secretion of PSCs (390 +/- 60%, P < .001), whereas PSCs increased the endostatin production of cancer cells (210 +/- 14%, P < .001) by matrix metalloproteinase-dependent cleavage. In vitro, PSCs increased the endothelial cell growth, whereas cancer cells alone, or their coculture with PSCs, suppressed it. CONCLUSIONS Although PSCs are the dominant producers of VEGF and increase endothelial cell growth in vitro, in the peritumoral stroma, they contribute to the fibrotic/hypoxic milieu through abnormal extracellular matrix deposition and by amplifying endostatin production of cancer cells.
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Venkatesan B, Valente AJ, Reddy VS, Siwik DA, Chandrasekar B. Resveratrol blocks interleukin-18-EMMPRIN cross-regulation and smooth muscle cell migration. Am J Physiol Heart Circ Physiol 2009; 297:H874-86. [PMID: 19561311 DOI: 10.1152/ajpheart.00311.2009] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Vascular smooth muscle cell (SMC) migration is an important mechanism in atherogenesis and postangioplasty arterial remodeling. Previously, we demonstrated that the proinflammatory cytokine interleukin (IL)-18 is a potent inducer of SMC migration. Since extracellular matrix metalloproteinase inducer (EMMPRIN) stimulates ECM degradation and facilitates cell migration, we investigated whether IL-18 and EMMPRIN regulate each other's expression, whether their cross talk induces SMC migration, and whether the phytoalexin resveratrol inhibits IL-18-EMMPRIN signaling and SMC migration. Our studies demonstrate that 1) IL-18 induces EMMPRIN mRNA and protein expressions and stimulates EMMPRIN secretion from human aortic SMCs; 2) IL-18 stimulates EMMPRIN expression via oxidative stress and phosphatidylinositol 3-kinase (PI3K)-Akt-ERK signaling; 3) IL-18-stimulated SMC migration is significantly blunted by EMMPRIN knockdown, EMMPRIN function-blocking antibodies, or adenoviral transduction of mutant EMMPRIN; 4) conversely, EMMPRIN stimulates IL-18 expression and secretion via PI3K, Akt, and ERK; and 5) resveratrol attenuates IL-18- and EMMPRIN-mediated PI3K, Akt, and ERK activations; blunts IL-18-mediated oxidative stress; blocks IL-18-EMMPRIN cross-regulation; and inhibits SMC migration. Collectively, our results demonstrate that the coexpression and regulation of IL-18 and EMMPRIN in the vessel wall may amplify the inflammatory cascade and promote atherosclerosis and remodeling. Resveratrol, via its antioxidant and anti-inflammatory properties, has the potential to inhibit the progression of atherosclerosis by blocking IL-18 and EMMPRIN cross-regulation and SMC migration.
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Affiliation(s)
- Balachandar Venkatesan
- Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA
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36
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Abiatari I, DeOliveira T, Kerkadze V, Schwager C, Esposito I, Giese NA, Huber P, Bergman F, Abdollahi A, Friess H, Kleeff J. Consensus transcriptome signature of perineural invasion in pancreatic carcinoma. Mol Cancer Ther 2009; 8:1494-504. [PMID: 19509238 DOI: 10.1158/1535-7163.mct-08-0755] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Perineural invasion, the growth of tumor cells along nerves, is a key feature of pancreatic cancer. The cardinal symptom of pancreatic cancer, abdominal pain often radiating to the back, as well as the high frequency of local tumor recurrence following resection are both attributed to the unique ability of pancreatic tumor cells to invade the neuronal system. The molecular mechanisms underlying the neuroaffinity of pancreatic tumors are not completely understood. In this study, we developed a novel method to monitor ex vivo perineural invasion into surgically resected rat vagal nerves by different human pancreatic tumor cell lines. Genome-wide transcriptional analyses were employed to identify the consensus set of genes differentially regulated in all highly nerve-invasive (nerve invasion passage 3) versus less invasive (nerve invasion passage 0) pancreatic tumor cells. The critical involvement of kinesin family member 14 (KIF14) and Rho-GDP dissociation inhibitor beta (ARHGDIbeta) in perineural invasion was confirmed on RNA and protein levels in human pancreatic tumor specimens. We found significant up-regulation of KIF14 and ARHGDIbeta mRNA levels in patients with pancreatic cancer, and both proteins were differentially expressed in tumor cells invading the perineural niche of pancreatic cancer patients as detected by immunohistochemistry. Moreover, functional knockdown of KIF14 and ARHGDIbeta using small interfering RNA resulted in altered basal and/or perineural invasion of pancreatic tumor cells. Our work provides novel insights into the molecular determinants of perineural invasion in pancreatic cancer. The established nerve invasion model and the consensus signature of perineural invasion could be instrumental in the identification of novel therapeutic targets of pancreatic cancer as exemplified by KIF14 and ARHGDIbeta.
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Affiliation(s)
- Ivane Abiatari
- Department of General Surgery, Technische Universität München, Ismaningerstrasse 22, Munich, Germany
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Jiang X, Abiatari I, Kong B, Erkan M, De Oliveira T, Giese NA, Michalski CW, Friess H, Kleeff J. Pancreatic islet and stellate cells are the main sources of endocrine gland-derived vascular endothelial growth factor/prokineticin-1 in pancreatic cancer. Pancreatology 2008; 9:165-72. [PMID: 19077468 DOI: 10.1159/000178888] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2007] [Accepted: 04/28/2008] [Indexed: 12/11/2022]
Abstract
AIMS Endocrine gland-derived vascular endothelial growth factor (EG-VEGF)/prokineticins have been identified as tissue-specific angiogenic factors. This study investigates the expression and localization of EG-VEGF and its receptors in pancreatic tissues and pancreatic stellate cells (PSCs). METHODS mRNA levels of EG-VEGF/prokineticin 1 (PK1), prokineticin 2 (PK2) and their receptors 1 (PKR1) and 2 (PKR2) were measured in pancreatic tissues, pancreatic cancer cell lines and PSCs by quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR). Protein expression of PK1, PKR1 and PKR2 was assessed in pancreatic tissues by immunohistochemistry. Growth factor-induced secretion of EG-VEGF was measured by ELISA. RESULTS QRT-PCR analysis in bulk tissues of normal pancreas, chronic pancreatitis and pancreatic ductal adenocarcinoma showed no significant difference of PK1 mRNA levels, whereas PK2 mRNA was barely detectable. High PK1 mRNA levels were observed only in cultured PSCs and microdissected islet cells, but not in cancer cells, and PK1 protein was localized mainly in islets and cancer-associated stromal cells. PKR1 and PKR2 proteins were present in endothelial cells of small blood vessels. TGF-beta(1) and PDGF-BB specifically stimulated PK1 secretion in PSCs. CONCLUSIONS Islet and/or PSC-derived PK1 might act through its receptors on endothelial cells to increase angiogenesis in pancreatic diseases.
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Affiliation(s)
- Xiaohua Jiang
- Department of Surgery, Technische Universität München, Munich, Germany
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Newman JR, Helman EE, Safavy S, Zhang W, Rosenthal EL. EMMPRIN expression is required for response to bevacizumab therapy in HNSCC xenografts. Cancer Lett 2008; 274:313-8. [PMID: 18990485 DOI: 10.1016/j.canlet.2008.09.033] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2008] [Revised: 09/15/2008] [Accepted: 09/24/2008] [Indexed: 11/17/2022]
Abstract
The HNSCC cell line, FaDu was stably transfected with control vector (FaDu) or with plasmid expressing small interfering RNA against EMMPRIN (FaDu/siE). Tumor cells were treated with bevacizumab (0, 25, 50, and 75 ng/ml) in vitro, and then cell counts were performed at 72 h. For in vivo analysis, tumor cells were xenografted onto the flank of SCID mice, and were treated with 100 microg bevacizumab twice weekly for three weeks. Xenograft samples from the control and treatment groups were analyzed for microvessel density. Escalating doses of bevacizumab had no effect on the growth of tumor cells in vitro (P.or=0.086). However, tumor xenografts expressing EMMPRIN responded to bevacizumab treatment (P=0.0013), whereas the EMMPRIN knockdown cell line did not (P=0.7942). Immunohistochemical analysis demonstrated that microvascular density was reduced in the treated FaDu tumors (P=0.005), but not in the FaDu/siE tumors (P=0.48). Currently there is limited information on biomarkers to predict response to bevacizumab. By demonstrating effectiveness of bevacizumab therapy in tumors that express EMMPRIN, but not in tumors with silenced EMMPRIN expression, this study suggests that EMMPRIN may serve as a biomarker for response to bevacizumab treatment.
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Affiliation(s)
- J Robert Newman
- Department of Surgery, Division of Otolaryngology - Head and Neck Surgery, University of Alabama at Birmingham, BDB Suit 563, 1808 7th Avenue South, Birmingham, AL 358294-0012, USA
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Erkan M, Michalski CW, Rieder S, Reiser-Erkan C, Abiatari I, Kolb A, Giese NA, Esposito I, Friess H, Kleeff J. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol 2008; 6:1155-61. [PMID: 18639493 DOI: 10.1016/j.cgh.2008.05.006] [Citation(s) in RCA: 346] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2007] [Revised: 04/12/2008] [Accepted: 05/02/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with an innate resistance to therapy. Pancreatic stellate cells (PSCs) produce this excessively desmoplastic microenvironment. The impact of PSC activity on PDAC behavior in vivo is analyzed. METHODS 233 patients who underwent surgery for PDAC were evaluated by immunohistochemistry using antibodies against alpha-smooth muscle actin as a marker of PSC activity. Aniline was used to stain collagen deposition. The ratio of alpha-smooth muscle actin-stained area to collagen-stained area was defined as the activated stroma index (ASI). Survival analysis was performed using the Kaplan-Meier method. Prognostic factors were determined in a multivariable analysis using a Cox proportional hazards model. RESULTS Four major patterns of collagen deposition were defined with regard to PSC activity. The combination of high stromal activity and low collagen deposition was associated with a worse prognosis, whereas the combination of high collagen deposition and low stromal activity indicated a better prognosis. Patients with the lowest ASI had the best median survival rate (25.7 mo). The highest ASI was found in patients with the worst median survival rate (16.1 mo; P = .007; lowest vs highest ASI: hazard ratio, 1.61; 95% confidence interval, 1.014-2.562). ASI was an independent prognostic marker in multivariable survival analysis comparable with the nodal status of cancer. CONCLUSIONS The activated stroma index is a novel independent prognostic marker in PDAC in cases undergoing surgery. This finding highlights the impact of the microenvironment in cancer progression and on patient survival.
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Affiliation(s)
- Mert Erkan
- Department of General Surgery, Technische Universität München, Munich, Germany
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Hanata K, Yamaguchi N, Yoshikawa K, Mezaki Y, Miura M, Suzuki S, Senoo H, Ishikawa K. Soluble EMMPRIN (extra-cellular matrix metalloproteinase inducer) stimulates the migration of HEp-2 human laryngeal carcinoma cells, accompanied by increased MMP-2 production in fibroblasts. ACTA ACUST UNITED AC 2008; 70:267-77. [PMID: 18431027 DOI: 10.1679/aohc.70.267] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The basement membrane functions as a barrier against the invasion of cancer cells. It is therefore important to investigate the mechanism of basement membrane degradation by matrix metalloproteinases (MMPs). Previously, cancer cells were long considered to be the major source of MMPs; however, current evidence indicates that most MMPs in cancer tissue are produced by stromal rather than cancer cells. A glycoprotein highly expressed on the cancer-cell membrane, EMMPRIN (extra-cellular matrix metalloproteinase inducer), exhibits the potential role of the MMP inductor in stromal cells. Depending on the cell type, EMMPRIN can stimulate the production of MMP-1, MMP-2, and MMP-3. We here report that soluble full-length EMMPRIN is liberated from HEp-2 human laryngeal epidermoid carcinoma cells, probably via microvesicle shedding. Soluble EMMPRIN stimulates human fibroblasts to produce MMP-2, after which the augmented migration of HEp-2 cells occurs, as observed in an invasion chamber assay with separately cultured fibroblasts. An anti-EMMPRIN function-blocking antibody reduced MMP-2 activity in the conditioned medium and inhibited the migration of HEp-2; obviously, EMMPRIN activity contributes to cancer-cell migration. We postulate that soluble EMMPRIN probably triggers the promotion of cancer invasion in vivo.
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Affiliation(s)
- Kyoshi Hanata
- Department of Otolaryngology, Akita University School of Medicine, Akita, Japan.
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Tragoolpua K, Intasai N, Kasinrerk W, Mai S, Yuan Y, Tayapiwatana C. Generation of functional scFv intrabody to abate the expression of CD147 surface molecule of 293A cells. BMC Biotechnol 2008; 8:5. [PMID: 18226275 PMCID: PMC2258298 DOI: 10.1186/1472-6750-8-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2007] [Accepted: 01/29/2008] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Expression of intracellular antibodies (intrabodies) has become a broadly applicable technology for generation of phenotypic knockouts in vivo. The method uses surface depletion of cellular membrane proteins to examine their biological function. In this study, we used this strategy to block the transport of cell surface molecule CD147 to the cell membrane. Phage display technology was introduced to generate the functional antibody fragment to CD147, and we subsequently constructed a CD147-specific scFv that was expressed intracellularly and retained in the endoplasmic reticulum by adenoviral gene transfer. RESULTS The recombinant antibody fragments, Fab and scFv, of the murine monoclonal antibody (clone M6-1B9) reacted specifically to CD147 by indirect enzyme-linked immunosorbent assays (ELISA) using a recombinant CD147-BCCP as a target. This indicated that the Fab- and scFv-M6-1B9 displaying on phage surfaces were correctly folded and functionally active. We subsequently constructed a CD147-specific scFv, scFv-M6-1B9-intrabody, in 293A cells. The expression of CD147 on 293A cell surface was monitored at 36 h after transduction by flow cytometry and demonstrated remarkable reduction. Colocalization of scFv-M6-1B9 intrabody with CD147 in the ER network was depicted using a 3D deconvolution microscopy system. CONCLUSION The results suggest that our approach can generate antibody fragments suitable for decreasing the expression of CD147 on 293A cells. This study represents a step toward understanding the role of the cell surface protein, CD147.
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Affiliation(s)
- Khajornsak Tragoolpua
- Division of Clinical Immunology, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand.
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