Skip to main content
Top
Published in: Annals of Surgical Oncology 3/2019

01-03-2019 | Pancreatic Tumors

Thrombospondin-2 is a Highly Specific Diagnostic Marker and is Associated with Prognosis in Pancreatic Cancer

Authors: Hsuan-Yu Peng, PhD, Ming-Chu Chang, MD, PhD, Chun-Mei Hu, PhD, Hwai-I Yang, PhD, Wen-Hwa Lee, PhD, Yu-Ting Chang, MD, MS, PhD

Published in: Annals of Surgical Oncology | Issue 3/2019

Login to get access

Abstract

Background

Thrombospondin-2 (TSP-2) has been reported as an early diagnostic marker for pancreatic ductal adenocarcinoma (PDAC) in Caucasian populations. This study was designed to validateTSP-2 as a diagnostic marker in a large Taiwan cohort and to investigate the association of TSP-2 with the clinical outcomes of PDAC patients.

Methods

The serum TSP-2 levels in 263 PDAC patients and 230 high-risk individuals (HRIs) were measured via an enzyme-linked immunosorbent assay. The sensitivity, specificity, and accuracy of TSP-2 as a diagnostic marker to discriminating PDAC patients from HRIs and correlations between TSP-2 levels and prognosis of PDAC patients were analyzed.

Results

Serum TSP-2 levels were significantly higher in patients with PDAC (44.90 ± 40.70 ng/ml) than in the HRIs (17.52 ± 6.23 ng/ml). At a level of ≥ 29.8 ng/ml, TSP-2 exhibited 100% specificity, 55.9% sensitivity, 100% positive predictive value (PPV), and 66.5% negative predictive value (NPV) for discriminating PDAC patients from HRIs. The Cox regression analysis showed that higher serum TSP-2 levels were significantly associated with poor outcomes in PDAC patients (hazard ratio = 1.54, 95% confidence interval = 1.143–2.086, P = 0.005). Combining the carbohydrate antigen 19-9 (CA19-9) (cutoff value of 62.0 U/ml) and TSP-2 (cutoff value of 29.8 ng/ml) levels yielded 98.7% specificity, 90.5% sensitivity, 98.8% PPV, and 90.1% NPV for discriminating patients with PDAC from HRIs.

Conclusions

TSP-2 is a highly specific diagnostic marker and an independent prognostic marker in patients with PDAC. A combined biomarker panel, including TSP-2 and CA19-9, may facilitate future PDAC screening.
Appendix
Available only for authorised users
Literature
1.
go back to reference Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913–21.CrossRef Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913–21.CrossRef
2.
go back to reference Ilic M, Ilic I. Epidemiology of pancreatic cancer. World J Gastroenterol. 2016;22(44):9694–705.CrossRef Ilic M, Ilic I. Epidemiology of pancreatic cancer. World J Gastroenterol. 2016;22(44):9694–705.CrossRef
3.
go back to reference Duffy MJ, Sturgeon C, Lamerz R, et al. Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report. Ann Oncol. 2010;21(3):441–7.CrossRef Duffy MJ, Sturgeon C, Lamerz R, et al. Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report. Ann Oncol. 2010;21(3):441–7.CrossRef
4.
go back to reference Poruk KE, Gay DZ, Brown K, et al. The clinical utility of CA 19-9 in pancreatic adenocarcinoma: diagnostic and prognostic updates. Curr Mol Med. 2013;13(3):340–51.PubMedPubMedCentral Poruk KE, Gay DZ, Brown K, et al. The clinical utility of CA 19-9 in pancreatic adenocarcinoma: diagnostic and prognostic updates. Curr Mol Med. 2013;13(3):340–51.PubMedPubMedCentral
5.
go back to reference Locker GY, Hamilton S, Harris J, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 2006;24(33):5313–5327.CrossRef Locker GY, Hamilton S, Harris J, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 2006;24(33):5313–5327.CrossRef
6.
go back to reference Gui JC, Yan WL, Liu XD. CA19-9 and CA242 as tumor markers for the diagnosis of pancreatic cancer: a meta-analysis. Clin Exp Med. 2014;14(2):225–33.CrossRef Gui JC, Yan WL, Liu XD. CA19-9 and CA242 as tumor markers for the diagnosis of pancreatic cancer: a meta-analysis. Clin Exp Med. 2014;14(2):225–33.CrossRef
7.
go back to reference Ghatnekar O, Andersson R, Svensson M, et al. Modelling the benefits of early diagnosis of pancreatic cancer using a biomarker signature. Int J Cancer. 2013;133(10):2392–7.CrossRef Ghatnekar O, Andersson R, Svensson M, et al. Modelling the benefits of early diagnosis of pancreatic cancer using a biomarker signature. Int J Cancer. 2013;133(10):2392–7.CrossRef
8.
go back to reference Mayerle J, Kalthoff H, Reszka R, et al. Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis. Gut. 2018;67(1):128–37.CrossRef Mayerle J, Kalthoff H, Reszka R, et al. Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis. Gut. 2018;67(1):128–37.CrossRef
9.
go back to reference Yee KO, Connolly CM, Duquette M, Kazerounian S, Washington R, Lawler J. The effect of thrombospondin-1 on breast cancer metastasis. Breast Cancer Res Treat. 2009;114(1):85–96.CrossRef Yee KO, Connolly CM, Duquette M, Kazerounian S, Washington R, Lawler J. The effect of thrombospondin-1 on breast cancer metastasis. Breast Cancer Res Treat. 2009;114(1):85–96.CrossRef
10.
go back to reference WeilerGuettler H, Aird WC, Rayburn H, Husain M, Rosenberg RD. Developmentally regulated gene expression of thrombomodulin in postimplantation mouse embryos. Development. 1996;122(7):2271–81. WeilerGuettler H, Aird WC, Rayburn H, Husain M, Rosenberg RD. Developmentally regulated gene expression of thrombomodulin in postimplantation mouse embryos. Development. 1996;122(7):2271–81.
11.
go back to reference Suehiro T, Shimada M, Matsumata T, Taketomi A, Yamamoto K, Sugimachi K. Thrombomodulin inhibits intrahepatic spread in human hepatocellular-carcinoma. Hepatology. 1995;21(5):1285–90.CrossRef Suehiro T, Shimada M, Matsumata T, Taketomi A, Yamamoto K, Sugimachi K. Thrombomodulin inhibits intrahepatic spread in human hepatocellular-carcinoma. Hepatology. 1995;21(5):1285–90.CrossRef
12.
go back to reference Nakazawa F, Koyama T, Shibamiya A, Hirosawa S. Characterization of thrombomodulin gene mutations of the 5’-regulatory region. Atherosclerosis. 2002;164(2):385–7.CrossRef Nakazawa F, Koyama T, Shibamiya A, Hirosawa S. Characterization of thrombomodulin gene mutations of the 5’-regulatory region. Atherosclerosis. 2002;164(2):385–7.CrossRef
13.
go back to reference Liauw J, Hoang S, Choi M, et al. Thrombospondins 1 and 2 are necessary for synaptic plasticity and functional recovery after stroke. J Cereb Blood Flow Metab. 2008;28(10):1722–32.CrossRef Liauw J, Hoang S, Choi M, et al. Thrombospondins 1 and 2 are necessary for synaptic plasticity and functional recovery after stroke. J Cereb Blood Flow Metab. 2008;28(10):1722–32.CrossRef
14.
go back to reference Bornstein P, Agah A, Kyriakides TR. The role of thrombospondins 1 and 2 in the regulation of cell-matrix interactions, collagen fibril formation, and the response to injury. Int J Biochem Cell Biol. 2004;36(6):1115–25.CrossRef Bornstein P, Agah A, Kyriakides TR. The role of thrombospondins 1 and 2 in the regulation of cell-matrix interactions, collagen fibril formation, and the response to injury. Int J Biochem Cell Biol. 2004;36(6):1115–25.CrossRef
15.
go back to reference Adams JC, Lawler J. The thrombospondins. Int J Biochem Cell Biol. 2004;36(6):961–8.CrossRef Adams JC, Lawler J. The thrombospondins. Int J Biochem Cell Biol. 2004;36(6):961–8.CrossRef
16.
go back to reference Lopes N, Gregg D, Vasudevan S, Hassanain H, Goldschmidt-Clermont P, Kovacic H. Thrombospondin 2 regulates cell proliferation induced by Rac1 redox-dependent signaling. Mol Cell Biol. 2003;23(15):5401–8.CrossRef Lopes N, Gregg D, Vasudevan S, Hassanain H, Goldschmidt-Clermont P, Kovacic H. Thrombospondin 2 regulates cell proliferation induced by Rac1 redox-dependent signaling. Mol Cell Biol. 2003;23(15):5401–8.CrossRef
17.
go back to reference Lawler PR, Lawler J. Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2. Cold Spring Harb Perspect Med. 2012;2(5):a006627.CrossRef Lawler PR, Lawler J. Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2. Cold Spring Harb Perspect Med. 2012;2(5):a006627.CrossRef
18.
go back to reference Kazerounian S, Yee KO, Lawler J. Thrombospondins in cancer. Cell Mol Life Sci. 2008;65(5):700–12.CrossRef Kazerounian S, Yee KO, Lawler J. Thrombospondins in cancer. Cell Mol Life Sci. 2008;65(5):700–12.CrossRef
19.
go back to reference Rendtlew Danielsen JM, Knudsen LM, Dahl IM, Lodahl M, Rasmussen T. Dysregulation of CD47 and the ligands thrombospondin 1 and 2 in multiple myeloma. Br J Haematol. 2007;138(6):756–60.CrossRef Rendtlew Danielsen JM, Knudsen LM, Dahl IM, Lodahl M, Rasmussen T. Dysregulation of CD47 and the ligands thrombospondin 1 and 2 in multiple myeloma. Br J Haematol. 2007;138(6):756–60.CrossRef
20.
go back to reference Zhang J, Hao N, Liu W, et al. In-depth proteomic analysis of tissue interstitial fluid for hepatocellular carcinoma serum biomarker discovery. Br J Cancer. 2017;117(11):1676–84.CrossRef Zhang J, Hao N, Liu W, et al. In-depth proteomic analysis of tissue interstitial fluid for hepatocellular carcinoma serum biomarker discovery. Br J Cancer. 2017;117(11):1676–84.CrossRef
21.
go back to reference Naumnik W, Ossolinska M, Plonska I, Chyczewska E, Niklinski J. Circulating Thrombospondin-2 and FGF-2 in patients with advanced non-small cell lung cancer: correlation with survival. Adv Exp Med Biol. 2015;833:9–14.CrossRef Naumnik W, Ossolinska M, Plonska I, Chyczewska E, Niklinski J. Circulating Thrombospondin-2 and FGF-2 in patients with advanced non-small cell lung cancer: correlation with survival. Adv Exp Med Biol. 2015;833:9–14.CrossRef
22.
go back to reference Chen PC, Tang CH, Lin LW, et al. Thrombospondin-2 promotes prostate cancer bone metastasis by the up-regulation of matrix metalloproteinase-2 through down-regulating miR-376c expression. J Hematol Oncol. 2017;10(1):33.CrossRef Chen PC, Tang CH, Lin LW, et al. Thrombospondin-2 promotes prostate cancer bone metastasis by the up-regulation of matrix metalloproteinase-2 through down-regulating miR-376c expression. J Hematol Oncol. 2017;10(1):33.CrossRef
24.
go back to reference Chang MC, Wu CH, Yang SH, et al. Pancreatic cancer screening in different risk individuals with family history of pancreatic cancer-a prospective cohort study in Taiwan. Am J Cancer Res. 2017;7(2):357–69.PubMedPubMedCentral Chang MC, Wu CH, Yang SH, et al. Pancreatic cancer screening in different risk individuals with family history of pancreatic cancer-a prospective cohort study in Taiwan. Am J Cancer Res. 2017;7(2):357–69.PubMedPubMedCentral
26.
go back to reference Kamochi J, Tokunaga T, Tomii Y, et al. Overexpression of the thrombospondin 2 (TSP2) gene modulated by the matrix metalloproteinase family expression and production in human colon carcinoma cell line. Oncol Rep. 2003;10(4):881–4.PubMed Kamochi J, Tokunaga T, Tomii Y, et al. Overexpression of the thrombospondin 2 (TSP2) gene modulated by the matrix metalloproteinase family expression and production in human colon carcinoma cell line. Oncol Rep. 2003;10(4):881–4.PubMed
27.
go back to reference Chang IW, Li CF, Lin VC, et al. Prognostic impact of Thrombospodin-2 (THBS2) overexpression on patients with urothelial carcinomas of upper urinary tracts and bladders. J Cancer. 2016;7(11):1541–9.CrossRef Chang IW, Li CF, Lin VC, et al. Prognostic impact of Thrombospodin-2 (THBS2) overexpression on patients with urothelial carcinomas of upper urinary tracts and bladders. J Cancer. 2016;7(11):1541–9.CrossRef
Metadata
Title
Thrombospondin-2 is a Highly Specific Diagnostic Marker and is Associated with Prognosis in Pancreatic Cancer
Authors
Hsuan-Yu Peng, PhD
Ming-Chu Chang, MD, PhD
Chun-Mei Hu, PhD
Hwai-I Yang, PhD
Wen-Hwa Lee, PhD
Yu-Ting Chang, MD, MS, PhD
Publication date
01-03-2019
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 3/2019
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-018-07109-6

Other articles of this Issue 3/2019

Annals of Surgical Oncology 3/2019 Go to the issue