Skip to main content
Top
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

Extracellular matrix specific protein fingerprints measured in serum can separate pancreatic cancer patients from healthy controls

Authors: Nicholas Willumsen, Cecilie L Bager, Diana J Leeming, Victoria Smith, Morten A Karsdal, David Dornan, Anne-Christine Bay-Jensen

Published in: BMC Cancer | Issue 1/2013

Login to get access

Abstract

Background

Pancreatic cancer (PC) is an aggressive disease with an urgent need for biomarkers. Hallmarks of PC include increased collagen deposition (desmoplasia) and increased matrix metalloproteinase (MMP) activity. The aim of this study was to investigate whether protein fingerprints of specific MMP-generated collagen fragments differentiate PC patients from healthy controls when measured in serum.

Methods

The levels of biomarkers reflecting MMP-mediated degradation of type I (C1M), type III (C3M) and type IV (C4M, C4M12a1) collagen were assessed in serum samples from PC patients (n = 15) and healthy controls (n = 33) using well-characterized and validated competitive ELISAs.

Results

The MMP-generated collagen fragments were significantly elevated in serum from PC patients as compared to controls. The diagnostic power of C1M, C3M, C4M and C4M12 were ≥83% (p < 0.001) and when combining all biomarkers 99% (p < 0.0001).

Conclusions

A panel of serum biomarkers reflecting altered MMP-mediated collagen turnover is able to differentiate PC patients from healthy controls. These markers may increase the understanding of mode of action of the disease and, if validated in larger clinical studies, provide an improved and additional tool in the PC setting.
Appendix
Available only for authorised users
Literature
1.
go back to reference Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 2013, 63: 11-30. 10.3322/caac.21166.CrossRefPubMed Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 2013, 63: 11-30. 10.3322/caac.21166.CrossRefPubMed
2.
go back to reference Malvezzi M, Bertuccio P, Levi F, La VC, Negri E: European cancer mortality predictions for the year 2013. Ann Oncol. 2013, 24: 792-800. 10.1093/annonc/mdt010.CrossRefPubMed Malvezzi M, Bertuccio P, Levi F, La VC, Negri E: European cancer mortality predictions for the year 2013. Ann Oncol. 2013, 24: 792-800. 10.1093/annonc/mdt010.CrossRefPubMed
3.
go back to reference Olson P, Hanahan D: Cancer. Breaching the cancer fortress. Science. 2009, 324: 1400-1401. 10.1126/science.1175940.CrossRefPubMed Olson P, Hanahan D: Cancer. Breaching the cancer fortress. Science. 2009, 324: 1400-1401. 10.1126/science.1175940.CrossRefPubMed
4.
go back to reference Chu D, Kohlmann W, Adler DG: Identification and screening of individuals at increased risk for pancreatic cancer with emphasis on known environmental and genetic factors and hereditary syndromes. JOP. 2010, 11: 203-212.PubMed Chu D, Kohlmann W, Adler DG: Identification and screening of individuals at increased risk for pancreatic cancer with emphasis on known environmental and genetic factors and hereditary syndromes. JOP. 2010, 11: 203-212.PubMed
5.
go back to reference Kessenbrock K, Plaks V, Werb Z: Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010, 141: 52-67. 10.1016/j.cell.2010.03.015.CrossRefPubMedPubMedCentral Kessenbrock K, Plaks V, Werb Z: Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010, 141: 52-67. 10.1016/j.cell.2010.03.015.CrossRefPubMedPubMedCentral
6.
go back to reference Karsdal MA, Nielsen MJ, Sand JM, Henriksen K, Genovese F, Bay-Jensen AC, et al: Extracellular matrix remodeling: the common denominator in connective tissue diseases. Possibilities for evaluation and current understanding of the matrix as more than a passive architecture, but a key player in tissue failure. Assay Drug Dev Technol. 2013, 11: 70-92. 10.1089/adt.2012.474.CrossRefPubMedPubMedCentral Karsdal MA, Nielsen MJ, Sand JM, Henriksen K, Genovese F, Bay-Jensen AC, et al: Extracellular matrix remodeling: the common denominator in connective tissue diseases. Possibilities for evaluation and current understanding of the matrix as more than a passive architecture, but a key player in tissue failure. Assay Drug Dev Technol. 2013, 11: 70-92. 10.1089/adt.2012.474.CrossRefPubMedPubMedCentral
7.
go back to reference Shields MA, Dangi-Garimella S, Redig AJ, Munshi HG: Biochemical role of the collagen-rich tumour microenvironment in pancreatic cancer progression. Biochem J. 2012, 441: 541-552. 10.1042/BJ20111240.CrossRefPubMed Shields MA, Dangi-Garimella S, Redig AJ, Munshi HG: Biochemical role of the collagen-rich tumour microenvironment in pancreatic cancer progression. Biochem J. 2012, 441: 541-552. 10.1042/BJ20111240.CrossRefPubMed
8.
go back to reference Sawai H, Okada Y, Funahashi H, Takahashi H, Matsuo Y, Yasuda A, et al: Basement membrane proteins play an important role in the invasive processes of human pancreatic cancer cells. J Surg Res. 2008, 144: 117-123. 10.1016/j.jss.2007.03.023.CrossRefPubMed Sawai H, Okada Y, Funahashi H, Takahashi H, Matsuo Y, Yasuda A, et al: Basement membrane proteins play an important role in the invasive processes of human pancreatic cancer cells. J Surg Res. 2008, 144: 117-123. 10.1016/j.jss.2007.03.023.CrossRefPubMed
9.
go back to reference Ohlund D, Franklin O, Lundberg E, Lundin C, Sund M: Type IV collagen stimulates pancreatic cancer cell proliferation, migration, and inhibits apoptosis through an autocrine loop. BMC Cancer. 2013, 13: 154-10.1186/1471-2407-13-154.CrossRefPubMedPubMedCentral Ohlund D, Franklin O, Lundberg E, Lundin C, Sund M: Type IV collagen stimulates pancreatic cancer cell proliferation, migration, and inhibits apoptosis through an autocrine loop. BMC Cancer. 2013, 13: 154-10.1186/1471-2407-13-154.CrossRefPubMedPubMedCentral
10.
go back to reference Karsdal MA, Delvin E, Christiansen C: Protein fingerprints - relying on and understanding the information of serological protein measurements. Clin Biochem. 2011, 44: 1278-1279. 10.1016/j.clinbiochem.2011.08.1135.CrossRefPubMed Karsdal MA, Delvin E, Christiansen C: Protein fingerprints - relying on and understanding the information of serological protein measurements. Clin Biochem. 2011, 44: 1278-1279. 10.1016/j.clinbiochem.2011.08.1135.CrossRefPubMed
11.
go back to reference Leeming D, He Y, Veidal S, Nguyen Q, Larsen D, Koizumi M, et al: A novel marker for assessment of liver matrix remodeling: an enzyme-linked immunosorbent assay (ELISA) detecting a MMP generated type I collagen neo-epitope (C1M). Biomarkers. 2011, 16: 616-628. 10.3109/1354750X.2011.620628.CrossRefPubMed Leeming D, He Y, Veidal S, Nguyen Q, Larsen D, Koizumi M, et al: A novel marker for assessment of liver matrix remodeling: an enzyme-linked immunosorbent assay (ELISA) detecting a MMP generated type I collagen neo-epitope (C1M). Biomarkers. 2011, 16: 616-628. 10.3109/1354750X.2011.620628.CrossRefPubMed
12.
go back to reference Barascuk N, Veidal SS, Larsen L, Larsen DV, Larsen MR, Wang J, et al: A novel assay for extracellular matrix remodeling associated with liver fibrosis: An enzyme-linked immunosorbent assay (ELISA) for a MMP-9 proteolytically revealed neo-epitope of type III collagen. Clin Biochem. 2010, 43: 899-904. 10.1016/j.clinbiochem.2010.03.012.CrossRefPubMed Barascuk N, Veidal SS, Larsen L, Larsen DV, Larsen MR, Wang J, et al: A novel assay for extracellular matrix remodeling associated with liver fibrosis: An enzyme-linked immunosorbent assay (ELISA) for a MMP-9 proteolytically revealed neo-epitope of type III collagen. Clin Biochem. 2010, 43: 899-904. 10.1016/j.clinbiochem.2010.03.012.CrossRefPubMed
13.
go back to reference Veidal SS, Karsdal MA, Nawrocki A, Larsen MR, Dai Y, Zheng Q, et al: Assessment of proteolytic degradation of the basement membrane: a fragment of type IV collagen as a biochemical marker for liver fibrosis. Fibrogenesis Tissue Repair. 2011, 4: 22-10.1186/1755-1536-4-22.CrossRefPubMedPubMedCentral Veidal SS, Karsdal MA, Nawrocki A, Larsen MR, Dai Y, Zheng Q, et al: Assessment of proteolytic degradation of the basement membrane: a fragment of type IV collagen as a biochemical marker for liver fibrosis. Fibrogenesis Tissue Repair. 2011, 4: 22-10.1186/1755-1536-4-22.CrossRefPubMedPubMedCentral
14.
go back to reference Sand JM, Larsen L, Hogaboam CM, Martinez FJ, Han M, Larsen MR, et al: MMP mediated degradation of type IV collagen alpha 1 and alpha 3 chains reflects basement membrane remodeling in experimental and clinical fibrosis – Validation of two novel biomarker assays. PLoS One. 2013, in press Sand JM, Larsen L, Hogaboam CM, Martinez FJ, Han M, Larsen MR, et al: MMP mediated degradation of type IV collagen alpha 1 and alpha 3 chains reflects basement membrane remodeling in experimental and clinical fibrosis – Validation of two novel biomarker assays. PLoS One. 2013, in press
15.
go back to reference Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, et al: Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009, 139: 891-906. 10.1016/j.cell.2009.10.027.CrossRefPubMedPubMedCentral Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, et al: Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009, 139: 891-906. 10.1016/j.cell.2009.10.027.CrossRefPubMedPubMedCentral
16.
go back to reference Ohlund D, Lundin C, Ardnor B, Oman M, Naredi P, Sund M: Type IV collagen is a tumour stroma-derived biomarker for pancreas cancer. Br J Cancer. 2009, 101: 91-97. 10.1038/sj.bjc.6605107.CrossRefPubMedPubMedCentral Ohlund D, Lundin C, Ardnor B, Oman M, Naredi P, Sund M: Type IV collagen is a tumour stroma-derived biomarker for pancreas cancer. Br J Cancer. 2009, 101: 91-97. 10.1038/sj.bjc.6605107.CrossRefPubMedPubMedCentral
17.
go back to reference Nurmenniemi S, Koivula MK, Nyberg P, Tervahartiala T, Sorsa T, Mattila PS, et al: Type I and III collagen degradation products in serum predict patient survival in head and neck squamous cell carcinoma. Oral Oncol. 2012, 48: 136-140. 10.1016/j.oraloncology.2011.09.002.CrossRefPubMed Nurmenniemi S, Koivula MK, Nyberg P, Tervahartiala T, Sorsa T, Mattila PS, et al: Type I and III collagen degradation products in serum predict patient survival in head and neck squamous cell carcinoma. Oral Oncol. 2012, 48: 136-140. 10.1016/j.oraloncology.2011.09.002.CrossRefPubMed
18.
go back to reference Nicoloff G, Deliiyski T, Nikolov A: Detection of Serum Collagen Type IV and Elastin Derived Peptides in Patients With Breast Cancer. Diabetol Croat. 2010, 39: 81-112. Nicoloff G, Deliiyski T, Nikolov A: Detection of Serum Collagen Type IV and Elastin Derived Peptides in Patients With Breast Cancer. Diabetol Croat. 2010, 39: 81-112.
19.
go back to reference Mazouni C, Arun B, Andre F, Ayers M, Krishnamurthy S, Wang B, et al: Collagen IV levels are elevated in the serum of patients with primary breast cancer compared to healthy volunteers. Br J Cancer. 2008, 99: 68-71. 10.1038/sj.bjc.6604443.CrossRefPubMedPubMedCentral Mazouni C, Arun B, Andre F, Ayers M, Krishnamurthy S, Wang B, et al: Collagen IV levels are elevated in the serum of patients with primary breast cancer compared to healthy volunteers. Br J Cancer. 2008, 99: 68-71. 10.1038/sj.bjc.6604443.CrossRefPubMedPubMedCentral
20.
go back to reference Hong WS, Hong SI, Park SY, Son Y, Lee YS, Chung YH, et al: Elevation of serum type IV collagen in liver cancer as well as liver cirrhosis. Anticancer Res. 1995, 15: 2777-2780.PubMed Hong WS, Hong SI, Park SY, Son Y, Lee YS, Chung YH, et al: Elevation of serum type IV collagen in liver cancer as well as liver cirrhosis. Anticancer Res. 1995, 15: 2777-2780.PubMed
21.
go back to reference Nystrom H, Naredi P, Hafstrom L, Sund M: Type IV collagen as a tumour marker for colorectal liver metastases. Eur J Surg Oncol. 2011, 37: 611-617. 10.1016/j.ejso.2011.04.010.CrossRefPubMed Nystrom H, Naredi P, Hafstrom L, Sund M: Type IV collagen as a tumour marker for colorectal liver metastases. Eur J Surg Oncol. 2011, 37: 611-617. 10.1016/j.ejso.2011.04.010.CrossRefPubMed
22.
go back to reference Kubo S, Tsukamoto T, Hirohashi K, Tanaka H, Shuto T, Takemura S, et al: Correlation between preoperative serum concentration of type IV collagen 7 s domain and hepatic failure following resection of hepatocellular carcinoma. Ann Surg. 2004, 239: 186-193. 10.1097/01.sla.0000109152.48425.4d.CrossRefPubMedPubMedCentral Kubo S, Tsukamoto T, Hirohashi K, Tanaka H, Shuto T, Takemura S, et al: Correlation between preoperative serum concentration of type IV collagen 7 s domain and hepatic failure following resection of hepatocellular carcinoma. Ann Surg. 2004, 239: 186-193. 10.1097/01.sla.0000109152.48425.4d.CrossRefPubMedPubMedCentral
23.
go back to reference Mason SD, Joyce JA: Proteolytic networks in cancer. Trends Cell Biol. 2011, 21: 228-237. 10.1016/j.tcb.2010.12.002.CrossRefPubMed Mason SD, Joyce JA: Proteolytic networks in cancer. Trends Cell Biol. 2011, 21: 228-237. 10.1016/j.tcb.2010.12.002.CrossRefPubMed
24.
go back to reference Martin MD, Matrisian LM: The other side of MMPs: protective roles in tumor progression. Cancer Metastasis Rev. 2007, 26: 717-724. 10.1007/s10555-007-9089-4.CrossRefPubMed Martin MD, Matrisian LM: The other side of MMPs: protective roles in tumor progression. Cancer Metastasis Rev. 2007, 26: 717-724. 10.1007/s10555-007-9089-4.CrossRefPubMed
25.
go back to reference Zucker S, Cao J: Matrix Metalloproteinases and Cancer Cell Invasion/Metastasis. The tumor microenviroment. Edited by: Bagley RG. 2010, New York: Springer Science+Business Media, LLC, 531-554.CrossRef Zucker S, Cao J: Matrix Metalloproteinases and Cancer Cell Invasion/Metastasis. The tumor microenviroment. Edited by: Bagley RG. 2010, New York: Springer Science+Business Media, LLC, 531-554.CrossRef
26.
go back to reference Overall CM, Kleifeld O: Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006, 6: 227-239. 10.1038/nrc1821.CrossRefPubMed Overall CM, Kleifeld O: Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006, 6: 227-239. 10.1038/nrc1821.CrossRefPubMed
27.
go back to reference Xu J, Rodriguez D, Petitclerc E, Kim JJ, Hangai M, Moon YS, et al: Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo. J Cell Biol. 2001, 154: 1069-1079. 10.1083/jcb.200103111.CrossRefPubMedPubMedCentral Xu J, Rodriguez D, Petitclerc E, Kim JJ, Hangai M, Moon YS, et al: Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo. J Cell Biol. 2001, 154: 1069-1079. 10.1083/jcb.200103111.CrossRefPubMedPubMedCentral
28.
go back to reference Xu J, Rodriguez D, Kim JJ, Brooks PC: Generation of monoclonal antibodies to cryptic collagen sites by using subtractive immunization. Hybridoma. 2000, 19: 375-385. 10.1089/02724570050198893.CrossRefPubMed Xu J, Rodriguez D, Kim JJ, Brooks PC: Generation of monoclonal antibodies to cryptic collagen sites by using subtractive immunization. Hybridoma. 2000, 19: 375-385. 10.1089/02724570050198893.CrossRefPubMed
30.
go back to reference Zucker S, Cao J, Chen WT: Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene. 2000, 19: 6642-6650. 10.1038/sj.onc.1204097.CrossRefPubMed Zucker S, Cao J, Chen WT: Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene. 2000, 19: 6642-6650. 10.1038/sj.onc.1204097.CrossRefPubMed
31.
go back to reference Pannala R, Basu A, Petersen GM, Chari ST: New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol. 2009, 10: 88-95. 10.1016/S1470-2045(08)70337-1.CrossRefPubMedPubMedCentral Pannala R, Basu A, Petersen GM, Chari ST: New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol. 2009, 10: 88-95. 10.1016/S1470-2045(08)70337-1.CrossRefPubMedPubMedCentral
32.
go back to reference Gangi S, Fletcher JG, Nathan MA, Christensen JA, Harmsen WS, Crownhart BS, et al: Time interval between abnormalities seen on CT and the clinical diagnosis of pancreatic cancer: retrospective review of CT scans obtained before diagnosis. AJR Am J Roentgenol. 2004, 182: 897-903. 10.2214/ajr.182.4.1820897.CrossRefPubMed Gangi S, Fletcher JG, Nathan MA, Christensen JA, Harmsen WS, Crownhart BS, et al: Time interval between abnormalities seen on CT and the clinical diagnosis of pancreatic cancer: retrospective review of CT scans obtained before diagnosis. AJR Am J Roentgenol. 2004, 182: 897-903. 10.2214/ajr.182.4.1820897.CrossRefPubMed
33.
go back to reference Miyamoto H, Murakami T, Tsuchida K, Sugino H, Miyake H, Tashiro S: Tumor-stroma interaction of human pancreatic cancer: acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins. Pancreas. 2004, 28: 38-44. 10.1097/00006676-200401000-00006.CrossRefPubMed Miyamoto H, Murakami T, Tsuchida K, Sugino H, Miyake H, Tashiro S: Tumor-stroma interaction of human pancreatic cancer: acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins. Pancreas. 2004, 28: 38-44. 10.1097/00006676-200401000-00006.CrossRefPubMed
34.
go back to reference Kaur S, Baine MJ, Jain M, Sasson AR, Batra SK: Early diagnosis of pancreatic cancer: challenges and new developments. Biomark Med. 2012, 6: 597-612. 10.2217/bmm.12.69.CrossRefPubMedPubMedCentral Kaur S, Baine MJ, Jain M, Sasson AR, Batra SK: Early diagnosis of pancreatic cancer: challenges and new developments. Biomark Med. 2012, 6: 597-612. 10.2217/bmm.12.69.CrossRefPubMedPubMedCentral
36.
go back to reference Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, Macdonald JS, et al: ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 2006, 24: 5313-5327. 10.1200/JCO.2006.08.2644.CrossRefPubMed Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, Macdonald JS, et al: ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 2006, 24: 5313-5327. 10.1200/JCO.2006.08.2644.CrossRefPubMed
37.
go back to reference Bhat K, Wang F, Ma Q, Li Q, Mallik S, Hsieh TC, et al: Advances in biomarker research for pancreatic cancer. Curr Pharm Des. 2012, 18: 2439-2451. 10.2174/13816128112092439.CrossRefPubMedPubMedCentral Bhat K, Wang F, Ma Q, Li Q, Mallik S, Hsieh TC, et al: Advances in biomarker research for pancreatic cancer. Curr Pharm Des. 2012, 18: 2439-2451. 10.2174/13816128112092439.CrossRefPubMedPubMedCentral
38.
go back to reference Wingren C, Sandstrom A, Segersvard R, Carlsson A, Andersson R, Lohr M, et al: Identification of serum biomarker signatures associated with pancreatic cancer. Cancer Res. 2012, 72: 2481-2490. 10.1158/0008-5472.CAN-11-2883.CrossRefPubMed Wingren C, Sandstrom A, Segersvard R, Carlsson A, Andersson R, Lohr M, et al: Identification of serum biomarker signatures associated with pancreatic cancer. Cancer Res. 2012, 72: 2481-2490. 10.1158/0008-5472.CAN-11-2883.CrossRefPubMed
Metadata
Title
Extracellular matrix specific protein fingerprints measured in serum can separate pancreatic cancer patients from healthy controls
Authors
Nicholas Willumsen
Cecilie L Bager
Diana J Leeming
Victoria Smith
Morten A Karsdal
David Dornan
Anne-Christine Bay-Jensen
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-554

Other articles of this Issue 1/2013

BMC Cancer 1/2013 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine