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Kriebardis AG, Chardalias L, Damaskos C, Pouliakis A, Garmpis N, Fortis SP, Papailia A, Sideri C, Georgatzakou HT, Papageorgiou EG, Pittaras T, Tsourouflis G, Politou M, Papaconstantinou I, Dimitroulis D, Valsami S. Precision Oncology: Circulating Microvesicles as New Biomarkers in a Very Early Stage of Colorectal Cancer. Cancers (Basel) 2024; 16:1943. [PMID: 38792021 PMCID: PMC11119677 DOI: 10.3390/cancers16101943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 05/13/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND The release of microvesicles (MVs) is an essential phenomenon for inter-cellular signaling in health and disease. The role of MVs in cancer is multidimensional and includes cancer cell survival, proliferation, and invasion. In this prospective study, we analyzed MV levels in colorectal cancer patients and assessed the importance of MV release in early-stage colorectal cancer and survival. METHODS This study included 98 patients and 15 controls. The characterization of MVs from human plasma was performed by flow cytometry using monoclonal antibodies. RESULTS The levels of total MVs and MUC-1-positive, tissue factor (TF)-positive, and endothelial cell-derived MVs (EMVs) were statistically significantly higher in the colon cancer patients than in the controls (p < 0.001). Furthermore, the subgroup of patients with very early-stage colorectal cancer also had statistically significant differences in the levels of the abovementioned MVs compared to the controls (p < 0.01). Highly differentiated tumors had lower levels of MUC-1-positive MVs (p < 0.02), EMVs (p < 0.002), and EMV/TF combinations (p < 0.001) versus those with tumors with low/intermediate differentiation. CONCLUSIONS Our data demonstrate that the analysis of circulating MV levels in plasma could possibly become a tool for the early diagnosis of colon cancer at a very early stage of the disease.
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Affiliation(s)
- Anastasios G. Kriebardis
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, School of Health & Caring Sciences, University of West Attica (UniWA), 12243 Egaleo, Greece; (A.G.K.); (S.P.F.); (H.T.G.); (E.G.P.)
| | - Leonidas Chardalias
- 2nd Department of Surgery, Aretaieion University Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (L.C.); (A.P.); (I.P.)
| | - Christos Damaskos
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 10679 Athens, Greece; (C.D.); (N.G.); (G.T.); (D.D.)
| | - Abraham Pouliakis
- Second Department of Pathology, “Attikon” University Hospital, National and Kapodistrian University of Athens, 10679 Athens, Greece;
| | - Nikolaos Garmpis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 10679 Athens, Greece; (C.D.); (N.G.); (G.T.); (D.D.)
| | - Sotirios P. Fortis
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, School of Health & Caring Sciences, University of West Attica (UniWA), 12243 Egaleo, Greece; (A.G.K.); (S.P.F.); (H.T.G.); (E.G.P.)
| | - Aspasia Papailia
- 2nd Department of Surgery, Aretaieion University Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (L.C.); (A.P.); (I.P.)
| | - Christiana Sideri
- Hematology Laboratory-Blood Bank, Aretaieion Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece; (C.S.); (T.P.); (M.P.)
| | - Hara T. Georgatzakou
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, School of Health & Caring Sciences, University of West Attica (UniWA), 12243 Egaleo, Greece; (A.G.K.); (S.P.F.); (H.T.G.); (E.G.P.)
| | - Effie G. Papageorgiou
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, School of Health & Caring Sciences, University of West Attica (UniWA), 12243 Egaleo, Greece; (A.G.K.); (S.P.F.); (H.T.G.); (E.G.P.)
| | - Theodoros Pittaras
- Hematology Laboratory-Blood Bank, Aretaieion Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece; (C.S.); (T.P.); (M.P.)
| | - Gerasimos Tsourouflis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 10679 Athens, Greece; (C.D.); (N.G.); (G.T.); (D.D.)
| | - Marianna Politou
- Hematology Laboratory-Blood Bank, Aretaieion Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece; (C.S.); (T.P.); (M.P.)
| | - Ioannis Papaconstantinou
- 2nd Department of Surgery, Aretaieion University Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (L.C.); (A.P.); (I.P.)
| | - Dimitrios Dimitroulis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 10679 Athens, Greece; (C.D.); (N.G.); (G.T.); (D.D.)
| | - Serena Valsami
- Hematology Laboratory-Blood Bank, Aretaieion Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece; (C.S.); (T.P.); (M.P.)
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Wang L, Liu Z, Liang R, Wang W, Zhu R, Li J, Xing Z, Weng S, Han X, Sun YL. Comprehensive machine-learning survival framework develops a consensus model in large-scale multicenter cohorts for pancreatic cancer. eLife 2022; 11:e80150. [PMID: 36282174 PMCID: PMC9596158 DOI: 10.7554/elife.80150] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 10/15/2022] [Indexed: 11/13/2022] Open
Abstract
As the most aggressive tumor, the outcome of pancreatic cancer (PACA) has not improved observably over the last decade. Anatomy-based TNM staging does not exactly identify treatment-sensitive patients, and an ideal biomarker is urgently needed for precision medicine. Based on expression files of 1280 patients from 10 multicenter cohorts, we screened 32 consensus prognostic genes. Ten machine-learning algorithms were transformed into 76 combinations, of which we selected the optimal algorithm to construct an artificial intelligence-derived prognostic signature (AIDPS) according to the average C-index in the nine testing cohorts. The results of the training cohort, nine testing cohorts, Meta-Cohort, and three external validation cohorts (290 patients) consistently indicated that AIDPS could accurately predict the prognosis of PACA. After incorporating several vital clinicopathological features and 86 published signatures, AIDPS exhibited robust and dramatically superior predictive capability. Moreover, in other prevalent digestive system tumors, the nine-gene AIDPS could still accurately stratify the prognosis. Of note, our AIDPS had important clinical implications for PACA, and patients with low AIDPS owned a dismal prognosis, higher genomic alterations, and denser immune cell infiltrates as well as were more sensitive to immunotherapy. Meanwhile, the high AIDPS group possessed observably prolonged survival, and panobinostat may be a potential agent for patients with high AIDPS. Overall, our study provides an attractive tool to further guide the clinical management and individualized treatment of PACA.
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Affiliation(s)
- Libo Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou UniversityZhengzhouChina
- Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary DiseasesZhengzhouChina
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Ruopeng Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou UniversityZhengzhouChina
- Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary DiseasesZhengzhouChina
| | - Weijie Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou UniversityZhengzhouChina
- Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary DiseasesZhengzhouChina
| | - Rongtao Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou UniversityZhengzhouChina
- Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary DiseasesZhengzhouChina
| | - Jian Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou UniversityZhengzhouChina
- Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary DiseasesZhengzhouChina
| | - Zhe Xing
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Siyuan Weng
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Yu-ling Sun
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou UniversityZhengzhouChina
- Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary DiseasesZhengzhouChina
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Dai W, Wang Z, Liang X, Wang M, Ni W, Yang Y, Zang YS. Circulating lncRNA EGFR-AS1 as a diagnostic biomarker of colorectal cancer and an indicator of tumor burden. J Gastrointest Oncol 2022; 13:2439-2446. [PMID: 36388668 PMCID: PMC9660029 DOI: 10.21037/jgo-22-968] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/18/2022] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common malignancies. Although CRC treatment has been significantly improved, patient survival remains low because most patients already have advanced disease at diagnosis. Early screening and diagnosis of tumors is critical; however, the current tissue biopsy and radiological evaluation methods have very limited effectiveness. Therefore, establishing new convenient and non-invasive biomarkers is urgently needed for timely detection, therapeutic assessment, and prognostic prediction. At present, non-coding RNAs (ncRNAs) have attracted research attention owing to their potential oncological applications. METHODS The long ncRNA epidermal growth factor receptor antisense RNA 1 (EGFR-AS1) is overexpressed in multiple malignancies including CRC. The present study examined the circulating EGFR-AS1 level in CRC, and the results showed that EGFR-AS1 could be considered an indicator of tumor burden. RESULTS Elevated circulating EGFR-AS1 levels were detected in CRC cases (n=128) compared with control cases comprising endoscopy confirmed CRC-free individuals [n=64, median expression normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 1.578 vs. 0.780, P<0.001]. Individuals with larger tumors (≥5 cm) had elevated circulating EGFR-AS1 levels compared to those with smaller tumors (<5 cm, 1.739 vs. 1.290, P<0.001). The expression of serum EGFR-AS1 in stage III/IV CRC was higher than that in stage I/II CRC (1.691 vs. 1.412, P<0.05). Plasma EGFR-AS1 levels were markedly reduced following surgical resection of colorectal lesions in a subset of patients [n=32, 1.192 (pre-surgery) vs. 0.692, P<0.001]. Furthermore, the expression of EGFR-AS1 in resected CRC tissues was significantly higher than that in paracancerous tissues (n=32, 1.336 vs. 0.487, P<0.001). CONCLUSIONS These results highlight the potential of EGFR-AS1 as a diagnostic biomarker in CRC.
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Affiliation(s)
- Weiping Dai
- Department of Oncology, Second Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Zhan Wang
- Department of Oncology, Second Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Xiaoben Liang
- E.N.T. Department, Children’s Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai, China
| | - Miaomiao Wang
- Department of Oncology, Second Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Wanliu Ni
- Department of Gastroenterology, Beizhan Hospital of Shanghai, Shanghai, China
| | - Ye Yang
- Department of Gastroenterology, Beizhan Hospital of Shanghai, Shanghai, China
| | - Yuan-Sheng Zang
- Department of Oncology, Second Affiliated Hospital of Navy Medical University, Shanghai, China
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Link KH, Kornmann M, Staib L, Kreuser ED, Gaus W, Röttinger E, Suhr P, Maulbecker-Armstrong C, Danenberg P, Danenberg K, Schatz M, Sander S, Ji ZL, Li JT, Peng SY, Bittner R, Beger HG, Traub B. Patient-centered developments in colon- and rectal cancer with a multidisciplinary international team: From translational research to national guidelines. World J Gastrointest Surg 2021; 13:1597-1614. [PMID: 35070066 PMCID: PMC8727190 DOI: 10.4240/wjgs.v13.i12.1597] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 08/07/2021] [Accepted: 11/24/2021] [Indexed: 02/06/2023] Open
Abstract
Rarely, scientific developments centered around the patient as a whole are published. Our multidisciplinary group, headed by gastrointestinal surgeons, applied this research philosophy considering the most important aspects of the diseases "colon- and rectal cancer" in the long-term developments. Good expert cooperation/knowledge at the Comprehensive Cancer Center Ulm (CCCU) were applied in several phase III trials for multimodal treatments of primary tumors (MMT) and metastatic diseases (involving nearly 2000 patients and 64 centers), for treatment individualization of MMT and of metastatic disease, for psycho-oncology/quality of life involving the patients' wishes, and for disease prevention. Most of the targets initially were heavily rejected/discussed in the scientific communities, but now have become standards in treatments and national guidelines or are topics in modern translational research protocols involving molecular biology for e.g., "patient centered individualized treatment". In this context we also describe the paths we had to tread in order to realize our new goals, which at the end were highly beneficial for the patients from many points of view. This description is also important for students and young researchers who, with an actual view on our recent developments, might want to know how medical progress was achieved.
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Affiliation(s)
- Karl-Heinrich Link
- Asklepios Tumor Center (ATC) and Surgical Center, Asklepios Paulinen Klinik, Wiesbaden 65197, Germany
- FOGT (Multidisciplinary Study Group on Oncology of Gastrointestinal Tumors), University of Ulm, Ulm 89081, Germany
- Department of General and Visceral Surgery, University of Ulm, Ulm 89081, Germany
| | - Marko Kornmann
- FOGT (Multidisciplinary Study Group on Oncology of Gastrointestinal Tumors), University of Ulm, Ulm 89081, Germany
- Department of General and Visceral Surgery, University of Ulm, Ulm 89081, Germany
| | - Ludger Staib
- FOGT (Multidisciplinary Study Group on Oncology of Gastrointestinal Tumors), University of Ulm, Ulm 89081, Germany
- Department of General and Visceral Surgery, University of Ulm, Ulm 89081, Germany
| | - Ernst-Dietrich Kreuser
- FOGT (Multidisciplinary Study Group on Oncology of Gastrointestinal Tumors), University of Ulm, Ulm 89081, Germany
| | - Wilhelm Gaus
- FOGT (Multidisciplinary Study Group on Oncology of Gastrointestinal Tumors), University of Ulm, Ulm 89081, Germany
- Department of Biometry and Medical Documentation, University of Ulm, Ulm 89081, Germany
| | - Erwin Röttinger
- FOGT (Multidisciplinary Study Group on Oncology of Gastrointestinal Tumors), University of Ulm, Ulm 89081, Germany
- Department of Radiotherapy, University of Ulm, Ulm 89081, Germany
| | - Peter Suhr
- FOGT (Multidisciplinary Study Group on Oncology of Gastrointestinal Tumors), University of Ulm, Ulm 89081, Germany
- Department of Radiotherapy, University of Ulm, Ulm 89081, Germany
| | - Catharina Maulbecker-Armstrong
- Fachbereich Gesundheit, Medizinisches Management, Sozialversicherungssysteme, Internationales Versorgungsmanagement, e-Health, Technische Hochschule Mittelhessen, Giessen 35390, Germany
| | - Peter Danenberg
- Department of Biochemistry and Molecular Medicine, Keck-USC School of Medicine, Los Angeles, CA 90033, United States
| | - Kathleen Danenberg
- Norris Comprehensive Cancer Center, Keck-USC School of Medicine, Los Angeles, CA 90033, United States
| | - Miriam Schatz
- Private Practice for Psychology, Adelsdorf 91325, Germany
| | - Silvia Sander
- FOGT (Multidisciplinary Study Group on Oncology of Gastrointestinal Tumors), University of Ulm, Ulm 89081, Germany
- Department of Biometry and Medical Documentation, University of Ulm, Ulm 89081, Germany
| | - Zhen-Ling Ji
- Department of General Surgery, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Jiang-Tao Li
- Department of Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Shu-You Peng
- Department of Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Reinhard Bittner
- FOGT (Multidisciplinary Study Group on Oncology of Gastrointestinal Tumors), University of Ulm, Ulm 89081, Germany
- Surgical Clinic, Marienhospital, Stuttgart 70177, Germany
| | - Hans Günther Beger
- FOGT (Multidisciplinary Study Group on Oncology of Gastrointestinal Tumors), University of Ulm, Ulm 89081, Germany
- Department of General and Visceral Surgery, University of Ulm, Ulm 89081, Germany
| | - Benno Traub
- FOGT (Multidisciplinary Study Group on Oncology of Gastrointestinal Tumors), University of Ulm, Ulm 89081, Germany
- Department of General and Visceral Surgery, University of Ulm, Ulm 89081, Germany
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Maderer A, Fiteni F, Tanis E, Mauer M, Schmitt T, Aust DE, Lutz MP, Roelofson F, Gog C, Weinmann A, Koehne CH, Moehler M, Thomaidis T. CXCR4 and hif-1α as prognostic molecular markers for stage 3 colon cancer patients: post hoc analysis of the randomized, multicenter phase 3 PETACC-2 trial dataset. Acta Oncol 2021; 60:1543-1547. [PMID: 34355650 DOI: 10.1080/0284186x.2021.1959057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Annett Maderer
- Department of Internal Medicine, Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Frederic Fiteni
- Fellowship Programme Unit, EORTC Headquarters, Brussels, Belgium
| | - Erik Tanis
- Fellowship Programme Unit, EORTC Headquarters, Brussels, Belgium
| | - Murielle Mauer
- Statistics Department, EORTC Headquarters, Brussels, Belgium
| | - Thomas Schmitt
- Department of Internal Medicine, Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Daniela E. Aust
- Molekulare/Prädiktive Diagnostik, Koordination UCC Tumor- und Normalgewebebank Institut für Pathologie, Dresden, Germany
| | | | | | - Christiane Gog
- Klinikum der JW Goethe, Universität Frankfurt am Main, Frankfurt, Germany
| | - Arndt Weinmann
- Department of Internal Medicine, Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Claus H. Koehne
- Department of Oncology and Hematology, Klinikum Oldenburg, European Medical School Oldenburg/Groningen, Carl von Ossietzky University Oldenburg, Oldenburg, Germany
| | - Markus Moehler
- Department of Internal Medicine, Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Thomas Thomaidis
- Department of Internal Medicine, Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
- Second Department of Gastroenterology, Hygeia Hospital, Athens, Greece
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Paschke S, Hebart H, Goeb R, Staib L, Fleck U, Henne-Bruns D, Sander S, Link KH, Kornmann M. Adjuvant Chemotherapy of Locally Advanced Colon Cancer: Final Results of a Randomized Trial Comparing 5-Fluorouracil and Folinic Acid with Folfiri. Visc Med 2019; 35:124-132. [PMID: 31192246 PMCID: PMC6514490 DOI: 10.1159/000491648] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND There is still the need to optimize adjuvant treatment of colon cancer (CC). Standard adjuvant chemotherapy using 5-fluorouracil (FU) and folinic acid (FA) was compared with a combination including irinotecan (Folfiri). The aim of the present report was to analyze overall survival (OS) after long-term follow-up, to summarize final recurrence rates and toxicity data, and to identify possible clinical and pathological factors associated with prognosis. METHODS Patients (CC stage IIb and III) were randomized to a 6-month treatment with FUFA or Folfiri. The trial was closed after 275 of 588 planned patients, 269 of which were included in the intention-to-treat analysis. RESULTS 133 and 136 patients received FUFA and Folfiri, respectively. Adjuvant therapy was not completed for 16 FUFA (12.0%) and 44 Folfiri (32.4%) patients. Toxicities grade III and IV were observed in 17 (12.8%) patients treated with FUFA and in 50 (36.8%) patients treated with Folfiri. Recurrences occurred in 46 of 133 (34.6%) and in 47 of 136 (34.6%) patients who received FUFA and Folfiri, respectively. 5-year OS rates were 69.9% (95% confidence interval (CI): 61.2-77.1) for FUFA and 72.7% (95% CI: 63.9-79.8) for Folfiri. OS was associated with tumor grading (1 & 2 vs. 3), tumor sub-stage (II vs. IIIa vs. IIIb vs. IIIc), and tumor location (left vs. right colon). CONCLUSION Folfiri cannot be generally recommended for adjuvant chemotherapy of CC. Besides tumor grading and sub-staging, prognosis of CC may depend on tumor location. Left-sided tumors had a significantly better prognosis irrespective of treatment.
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Affiliation(s)
- Stephan Paschke
- Clinic of General and Visceral Surgery, University Hospital of Ulm, Ulm, Germany
| | - Holger Hebart
- Center for Internal Medicine, Stauferklinikum, Schwäbisch Gmünd, Germany
| | - Roland Goeb
- Department of General and Visceral Surgery, Katholisches Krankenhaus St. Johann Nepomuk, Erfurt, Deutschland
| | - Ludger Staib
- Department of General and Visceral Surgery, Städtisches Klinikum Esslingen, Esslingen, Germany
| | - Ullrich Fleck
- Department of General and Visceral Surgery, Krankenhaus Luckenwalde, Luckenwalde, Germany
| | - Doris Henne-Bruns
- Clinic of General and Visceral Surgery, University Hospital of Ulm, Ulm, Germany
| | - Silvia Sander
- Institute of Epidemiology and Medical Biometry, University Hospital of Ulm, Ulm, Germany
| | | | - Marko Kornmann
- Clinic of General and Visceral Surgery, University Hospital of Ulm, Ulm, Germany
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Huang CY, Wei PL, Chen WY, Chang WC, Chang YJ. Silencing Heat Shock Protein 27 Inhibits the Progression and Metastasis of Colorectal Cancer (CRC) by Maintaining the Stability of Stromal Interaction Molecule 1 (STIM1) Proteins. Cells 2018; 7:cells7120262. [PMID: 30544747 PMCID: PMC6315635 DOI: 10.3390/cells7120262] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 12/02/2018] [Accepted: 12/07/2018] [Indexed: 12/13/2022] Open
Abstract
The incidence of colorectal cancer (CRC) has significantly increased in recent decades, and this disease has become an important health issue worldwide. Currently, there is no useful prognostic or diagnostic biomarker for CRC. Heat shock protein 27 (HSP27) is a chaperone that interacts with many proteins. HSP27 has been shown to be overexpressed in many cancers, including colon cancer, and its overexpression is related to poor disease outcome. Although the importance of HSP27 as a biomarker cannot be underrated, its detailed mechanisms in colon cancer are still unclear. In vitro studies have indicated that silencing HSP27 reduces the proliferation, migration and invasion of colon cancer cells, and xenograft models have shown that silencing HSP27 decreases tumor progression. Tissue array results showed that colon cancer patients with high expression of HSP27 exhibited poor prognosis. In addition, we found a reduction of calcium influx through a decrease in STIM1 protein after HSP27 was abolished. The formation of puncta was decreased in HSP27 knockdown (HSP27KD) cells after thapsigargin (TG) treatment. Finally, we confirmed that the reduction of STIM1 after HSP27 silencing may be due to a loss of STIM1 stability instead of transcription. HSP27 may interact with STIM1 but not Orai1, as shown by immunoprecipitation assays. HSP27 and STIM1 were co-expressed in CRC specimens. Our study showed that HSP27 is a key mediator in the progression and metastasis of CRC by regulating the store-operated calcium entry. This novel pathway may provide a new direction for development of therapeutic strategies for CRC.
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Affiliation(s)
- Chien-Yu Huang
- Department of Surgery, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei 110, Taiwan.
| | - Po-Li Wei
- Department of Surgery, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
- Division of Colorectal Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan.
- Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 110, Taiwan.
| | - Wei-Yu Chen
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
- Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan.
| | - Wei-Chiao Chang
- School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, Taipei Medical University, Taipei 110, Taiwan.
| | - Yu-Jia Chang
- Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
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Jing C, Jin YH, You Z, Qiong Q, Jun Z. Prognostic value of amphiregulin and epiregulin mRNA expression in metastatic colorectal cancer patients. Oncotarget 2018; 7:55890-55899. [PMID: 27344184 PMCID: PMC5342459 DOI: 10.18632/oncotarget.10151] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 06/06/2016] [Indexed: 12/22/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) and its ligands amphiregulin (AREG) and epiregulin (EREG) play a central role in the development of colorectal cancer, but the prognostic values of AREG and EREG are controversial. We conducted a meta-analysis of studies that investigated AREG and/or EREG mRNA levels in primary tumors to determine their prognostic value in metastatic colorectal cancer (mCRC). In addition, RAS status was assessed. Relevant articles were identified by searching the EMBASE, PubMed, and Cochrane Library databases. Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated using a random-effects model. Nine studies involving 2167 patients were included in this meta-analysis. High AREG expression was associated with longer overall survival (OS) and progression-free survival (PFS). High EREG expression was also associated with prolonged OS and PFS. In RAS wild-type (WT) patients who received anti-EGFR therapy, high AREG and EREG expression was associated with longer OS. Our results indicate that high AREG and EREG mRNA expression are independent favorable prognostic biomarkers in mCRC. The expression of these ligands should be considered when evaluating prognoses in RAS-WT patients receiving anti-EGFR therapy.
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Affiliation(s)
- Chen Jing
- Department of Medical Oncology, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Yang Han Jin
- Department of Pathology, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Zhai You
- Department of Pharmacy, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Qian Qiong
- Department of Medical Oncology, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Zhou Jun
- Department of Pharmacy, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
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9
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Prediction of novel target genes and pathways involved in irinotecan-resistant colorectal cancer. PLoS One 2017; 12:e0180616. [PMID: 28749961 PMCID: PMC5531462 DOI: 10.1371/journal.pone.0180616] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 06/14/2017] [Indexed: 01/02/2023] Open
Abstract
Background Acquired drug resistance to the chemotherapeutic drug irinotecan (the active metabolite of which is SN-38) is one of the significant obstacles in the treatment of advanced colorectal cancer (CRC). The molecular mechanism or targets mediating irinotecan resistance are still unclear. It is urgent to find the irinotecan response biomarkers to improve CRC patients’ therapy. Methods Genetic Omnibus Database GSE42387 which contained the gene expression profiles of parental and irinotecan-resistant HCT-116 cell lines was used. Differentially expressed genes (DEGs) between parental and irinotecan-resistant cells, protein-protein interactions (PPIs), gene ontologies (GOs) and pathway analysis were performed to identify the overall biological changes. The most common DEGs in the PPIs, GOs and pathways were identified and were validated clinically by their ability to predict overall survival and disease free survival. The gene-gene expression correlation and gene-resistance correlation was also evaluated in CRC patients using The Cancer Genomic Atlas data (TCGA). Results The 135 DEGs were identified of which 36 were upregulated and 99 were down regulated. After mapping the PPI networks, the GOs and the pathways, nine genes (GNAS, PRKACB, MECOM, PLA2G4C, BMP6, BDNF, DLG4, FGF2 and FGF9) were found to be commonly enriched. Signal transduction was the most significant GO and MAPK pathway was the most significant pathway. The five genes (FGF2, FGF9, PRKACB, MECOM and PLA2G4C) in the MAPK pathway were all contained in the signal transduction and the levels of those genes were upregulated. The FGF2, FGF9 and MECOM expression were highly associated with CRC patients’ survival rate but not PRKACB and PLA2G4C. In addition, FGF9 was also associated with irinotecan resistance and poor disease free survival. FGF2, FGF9 and PRKACB were positively correlated with each other while MECOM correlated positively with FGF9 and PLA2G4C, and correlated negatively with FGF2 and PRKACB after doing gene-gene expression correlation. Conclusion Targeting the MAPK signal transduction pathway through the targeting of the FGF2, FGF9, MECOM, PLA2G4C and PRKACB might increase tumor responsiveness to irinotecan treatment.
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10
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Su F, Li X, You K, Chen M, Xiao J, Zhang Y, Ma J, Liu B. Expression of VEGF-D, SMAD4, and SMAD7 and Their Relationship with Lymphangiogenesis and Prognosis in Colon Cancer. J Gastrointest Surg 2016; 20:2074-2082. [PMID: 27730400 DOI: 10.1007/s11605-016-3294-9] [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: 05/12/2016] [Accepted: 09/29/2016] [Indexed: 01/31/2023]
Abstract
AIM The vascular endothelial growth factor (VEGF) and TGF-β1 pathways play important roles in cancer. However, few studies have evaluated the expression and roles of VEGF-D, SMAD4, and SMAD7 in colon cancer, and the conclusions remain controversial. To clarify the roles of VEGF-D, SMAD4, and SMAD7 in colon cancer, we examined their expression and evaluated correlations with lymphangiogenesis, prognosis, and chemotherapeutic outcome. METHODS The expression of VEGF-D, SMAD4, and SMAD7 was immunohistochemically examined in 251 primary colon cancer samples obtained from the Harbin Medical University. RESULTS The expression of VEGF-D, SMAD4, and SMAD7 was identified in 71.7, 41.0, and 69.7 % of samples, respectively. Positive expression of VEGF-D and SMAD7 and lost expression of SMAD4 were significantly correlated with lymph node metastasis and high lymphatic vessel density. VEGF-D and SMAD7 were found to be independent indicators of prognosis and chemotherapy outcome, and positive expression of either VEGF-D or SMAD7 was associated with significantly shorter overall survival and disease-free survival (OS and DFS) than negative expression in all 251 patients (P < 0.001 for OS and DFS) and patients following chemotherapy (P < 0.001 for OS and DFS). CONCLUSION VEGF-D, SMAD4, and SMAD7 were involved in lymphangiogenesis and lymph node metastasis. VEGF-D and SMAD7 can serve as predictors of prognosis and chemotherapeutic outcome in colon cancer.
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Affiliation(s)
- Fei Su
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, People's Republic of China
| | - Xuemei Li
- Department of Anatomy, Harbin Medical University, 57 Baojian Road, Harbin, 150081, People's Republic of China
| | - Kai You
- Department of Anatomy, Harbin Medical University, 57 Baojian Road, Harbin, 150081, People's Republic of China
| | - Mingwei Chen
- Department of Anatomy, Harbin Medical University, 57 Baojian Road, Harbin, 150081, People's Republic of China
| | - Jianbing Xiao
- Department of Anatomy, Harbin Medical University, 57 Baojian Road, Harbin, 150081, People's Republic of China
| | - Yafang Zhang
- Department of Anatomy, Harbin Medical University, 57 Baojian Road, Harbin, 150081, People's Republic of China
| | - Jing Ma
- Department of Anatomy, Harbin Medical University, 57 Baojian Road, Harbin, 150081, People's Republic of China
| | - Baoquan Liu
- Department of Anatomy, Harbin Medical University, 57 Baojian Road, Harbin, 150081, People's Republic of China.
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11
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Ding C, Li L, Yang T, Fan X, Wu G. Combined application of anti-VEGF and anti-EGFR attenuates the growth and angiogenesis of colorectal cancer mainly through suppressing AKT and ERK signaling in mice model. BMC Cancer 2016; 16:791. [PMID: 27729020 PMCID: PMC5059930 DOI: 10.1186/s12885-016-2834-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 10/05/2016] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Angiogenesis is generally involved during the cancer development and hematogenous metastasis. Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) are considered to have an important role in tumor-associated angiogenesis. However, the effects of simultaneously targeting on VEGF and EGFR on the growth and angiogenesis of colorectal cancer (CRC), and its underlying mechanisms remain unknown. METHODS Immunohistochemical staining was used to detect the VEGF and EGFR expression in different CRC tissue specimens, and the correlation between VEGF/EGFR expression with the clinicopathologic features was analyzed. Cell counting kit‑8 (CCK-8) and transwell assays were used to assess the cellular proliferation and invasion of CRC cells after treated with anti-VEGF antibody and/or anti-EGFR antibody in vitro, respectively. Moreover, in vivo tumor formation was performed on nude mice model, and the tumor microvessel density (MVD) was determined by anti-CD34 staining in different groups. Finally, we evaluated the impact of anti-VEGF antibody and/or anti-EGFR antibody on the activation of downstream signaling effectors using western blot. RESULTS VEGF and EGFR were upregulated in CRC tissues, and their expression levels were correlated with hepatic metastasis. Blockage on VEGF or EGFR alone could inhibit the cellular proliferation and metastasis while their combination could reach a good synergism in vitro. In addition, in vivo xenograft mice model demonstrated that the tumor formation and angiogenesis were strongly suppressed by combination treatment of anti-VEGF and anti-EGFR antibodies. Besides, the combination treatment significantly reduced the activation of AKT and ERK1/2, but barely affected the activation of c-Myc, NF-κB/p65 and IκBα in CRC cells tumors. Interestingly, anti-VEGF antibody or anti-EGFR antibody alone could attenuate the phosphorylation of STAT3 as compared with negative control group, whereas the combined application not further suppressed but at least partially restored the activation of STAT3 in vivo. CONCLUSIONS Simultaneous targeting on VEGF and EGFR does show significant inhibition on CRC tumor growth and angiogenesis in mice model, and these effects are mainly attributed to suppression of the AKT and ERK signaling pathways.
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Affiliation(s)
- Chenbo Ding
- Medical School of Southeast University, Nanjing, 210009, China
| | - Longmei Li
- Department of Immunology, Zunyi Medical University, Zunyi, 563003, China
| | - Taoyu Yang
- Department of Oncology, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, China
| | - Xiaobo Fan
- Medical School of Southeast University, Nanjing, 210009, China
| | - Guoqiu Wu
- Medical School of Southeast University, Nanjing, 210009, China. .,Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China.
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12
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Yang RW, Zeng YY, Wei WT, Cui YM, Sun HY, Cai YL, Nian XX, Hu YT, Quan YP, Jiang SL, Wang M, Zhao YL, Qiu JF, Li MX, Zhang JH, He MR, Liang L, Ding YQ, Liao WT. TLE3 represses colorectal cancer proliferation by inhibiting MAPK and AKT signaling pathways. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2016; 35:152. [PMID: 27669982 PMCID: PMC5037636 DOI: 10.1186/s13046-016-0426-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 09/13/2016] [Indexed: 01/19/2023]
Abstract
Background Transducin-like enhancer of Split3 (TLE3) serves as a transcriptional corepressor during cell differentiation and shows multiple roles in different kinds of cancers. Recently, TLE3 together with many other genes involved in Wnt/β-catenin pathway were detected hyper-methylated in colorectal cancer (CRC). However, the potential role and the underlying mechanism of TLE3 in CRC progression remain scarce. Methods Gene expression profiles were analyzed in The Cancer Genome Atlas (TCGA) microarray dataset of 41 normal colorectal intestine tissues and 465 CRC tissues. Western blot and Real-time Quantitative PCR (RT-qPCR) were respectively performed to detect protein and mRNA expression in 8 pairs of CRC tissue and matched adjacent normal mucosa. Immunohistochemistry (IHC) was conducted to evaluate TLE3 protein expression in 105 paraffin-embedded, archived human CRC tissues from patients, whose survival data were analyzed with Kaplan-Meier method. In vitro experiments including MTT assay, colony formation assay, and soft agar formation assay were used to investigate the effects of TLE3 on CRC cell growth and proliferation. Additionally, subcutaneous tumorigenesis assay was performed in nude mice to confirm the effects of TLE3 in vivo. Furthermore, gene set enrichment analysis (GSEA) was run to explore potential mechanism of TLE3 in CRC, and then we measured the distribution of CRC cell cycle phases and apoptosis by flow cytometry, as well as the impacts of TLE3 on MAPK and AKT signaling pathways by Western blot and RT-qPCR. Results TLE3 was significantly down-regulated in 465 CRC tissues compared with 41 normal tissues. Both protein and mRNA expressions of TLE3 were down-regulated in CRC compared with matched adjacent normal mucosa. Lower expression of TLE3 was significantly associated with poorer survival of patients with CRC. Besides, knock down of TLE3 promoted CRC cell growth and proliferation, while overexpression of TLE3 showed suppressive effects. Furthermore, overexpression of TLE3 caused G1-S phase transition arrest, inhibition of MAPK and AKT pathways, and up-regulation of p21Cip1/WAF1 and p27Kip1. Conclusion This study indicated that TLE3 repressed CRC proliferation partly through inhibition of MAPK and AKT signaling pathways, suggesting the possibility of TLE3 as a biomarker for CRC prognosis. Electronic supplementary material The online version of this article (doi:10.1186/s13046-016-0426-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Run-Wei Yang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Ying-Yue Zeng
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Wen-Ting Wei
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Yan-Mei Cui
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Hui-Ying Sun
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Yue-Long Cai
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Xin-Xin Nian
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Yun-Teng Hu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Yu-Ping Quan
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Sheng-Lu Jiang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Meng Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Ya-Li Zhao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Jun-Feng Qiu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Ming-Xuan Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Jia-Huan Zhang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Mei-Rong He
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Li Liang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Yan-Qing Ding
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. .,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. .,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. .,Department of Pathology, Nanfang Hospital and School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China.
| | - Wen-Ting Liao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. .,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. .,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. .,Department of Pathology, Nanfang Hospital and School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China.
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13
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Zhao L, Bi Y, Kou J, Shi J, Piao D. Phosphatidylserine exposing-platelets and microparticles promote procoagulant activity in colon cancer patients. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2016; 35:54. [PMID: 27015840 PMCID: PMC4807543 DOI: 10.1186/s13046-016-0328-9] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 03/21/2016] [Indexed: 12/13/2022]
Abstract
Background Colon cancer is invariably accompanied by altered coagulation activity; however, the precise role of phosphatidylserine (PS) in the hypercoagulable state of colon cancer patients remains unclear. We explored the exposure of PS on platelets and microparticles (MPs), and evaluate its role in procoagulant activity in colon cancer patients. Methods PS-positive platelets and MPs, mainly from platelets and endothelial cells, were detected by flow cytometry and confocal microscopy, and their procoagulant activity was assessed with purified coagulation complex assays, clotting time, and fibrin turbidity. Results Plasma levels of PS-positive platelets increased gradually from stage I to IV and were higher in all stages of the patients than in the healthy control, while PS-positive platelet-derived MPs only increased significantly in stage III/IV patients. Meanwhile, PS-positive MPs and endothelial-derived MPs in stage II/III/IV patients were markedly higher than ones in controls but no difference with stage I. Tissue factor positive MPs were higher in all 4 stages of colon cancer patients than in the healthy control. Platelets and MPs from the patients demonstrated significantly enhanced intrinsic/extrinsic FXa and thrombin generation, greatly shortened coagulation time, and increased fibrin formation. Combined treatment with PS antagonist lactadherin, strongly prolonged the coagulation time and reduced fibrin formation by inhibiting factor tenase and prothrombinase complex activity. In contrast, pretreatment with anti tissue factor antibody played a lesser role in suppression of procoagulant activity. Conclusion Our results suggest that PS-positive platelets and MPs contribute to hypercoagulability and represent a potential therapeutic target to prevent coagulation in patients with colon cancer.
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Affiliation(s)
- Liangliang Zhao
- Department of Colorectal Surgery, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China
| | - Yayan Bi
- Department of Medicine, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China
| | - Junjie Kou
- Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, Heilongjiang Province, 150086, People's Republic of China
| | - Jialan Shi
- Department of Medicine, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China. .,Department of Surgery, Brigham and Women's Hospital, VA Boston Healthcare System, Harvard Medical School, Boston, 02132, USA. .,Department of Hematology, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China.
| | - Daxun Piao
- Department of Colorectal Surgery, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China.
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