Skip to main content
SpringerLink
Log in

VEGF, PF4 and PDGF are elevated in platelets of colorectal cancer patients

  • Original Paper
  • Published:
Angiogenesis Aims and scope Submit manuscript

Abstract

Platelets sequester angiogenesis regulatory proteins which suggests an avenue for developing biomarkers to monitor disease. We describe a comparison of angiogenesis regulatory proteins found in platelets of colorectal cancer patients and normal controls. Platelet and plasma content of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF), platelet factor 4 (PF4), thrombospondin-1 (TSP-1) and endostatin in 35 patients with colon cancer were compared with 84 age-matched healthy controls using ELISAs. We standardized the platelet preparation procedure, introduced process controls and normalized the respective protein levels to platelet numbers using an actin ELISA. Statistically significant differences were found in the median levels of VEGF, PF4 and PDGF in platelets of patients with cancer compared to healthy individuals. Platelet concentrations in cancer patients versus controls were: VEGF 1.3 versus 0.6 pg/106, PF4 18.5 versus 9.4 ng/106, and PDGF 34.1 versus 21.0 pg/106. Multivariable logistic regression analysis indicated that PDGF, PF4 and VEGF were independent predictors of colorectal carcinoma and as a set provided statistically significant discrimination (area under the curve = 0.893, P < .0001). No significant differences were detected for bFGF, endostatin, or TSP-1. Reference Change Value analysis determined that the differences seen were not clinically significant. Plasma levels yielded no correlations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

VEGF:

Vascular endothelial growth factor

bFGF:

Basic fibroblast growth factor

PDGF:

Platelet derived growth factor

PF4:

Platelet factor 4

TSP-1:

Thrombospondin-1

PRP:

Platelet rich plasma

PPP:

Platelet poor plasma

CBC:

Complete blood count

CRC:

Colorectal cancer

ELISA:

Enzyme linked immune sorbent assay

References

  1. Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438:932–936

    Article  PubMed  CAS  Google Scholar 

  2. Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6:273–287

    Article  PubMed  CAS  Google Scholar 

  3. Fuhrmann-Benzakein E, Ma MN, Rubbia-Brandt L et al (2000) Elevated levels of angiogenic cytokines in the plasma of cancer patients. Int J Cancer 85:40–45

    Article  PubMed  CAS  Google Scholar 

  4. Nguyen M (1997) Angiogenic factors as tumor markers. Invest New Drugs 15:29–37

    Article  PubMed  CAS  Google Scholar 

  5. Peterson JE, Zurakowski D, Italiano JE Jr et al (2010) Normal ranges of angiogenesis regulatory proteins in human platelets. Amer. J. Hematology 85:487–493

    Article  CAS  Google Scholar 

  6. Klement GL, Kikuchi L, Kieran M (2004) Early tumor detection using platelet uptake of angiogenesis regulators. Blood 104 (abstr 839)

  7. Klement GL, Yip T–T, Cassiola F et al (2009) Platelets actively sequester angiogenesis regulators. Blood 113:2835–2842

    Article  PubMed  CAS  Google Scholar 

  8. Saldago R, Benoy I, Bogers J et al (2001) Platelets and vascular endothelial growth factor (VEGF): a morphological and functional study. Angiogenesis 4:37–43

    Article  Google Scholar 

  9. Gonzalez FJ, Rueda A, Sevilla I et al (2004) Shift in the balance between circulating thrombospondin-1 and vascular endothelial growth factor in cancer patients: Relationship to platelet a-granule content and primary activation. Int J Biol Markers 19:221–228

    PubMed  CAS  Google Scholar 

  10. Hartwig JC (2008) The platelet cytoskeleton. In: Gresele P, Fuster V, López JA, Page CP, Vermylen J (eds) Platelets in hematologic and cardiovascular disorders. Cambridge University Press, New York, pp 75–97

    Google Scholar 

  11. Cervi D, Yip TT, Bhattacharya N et al (2008) Platelet-associated PF4 as a biomarker of early tumor growth. Blood 111:1201–1207

    Article  PubMed  CAS  Google Scholar 

  12. Fraser CG (2001) Changes in serial results. In: Biological variation: from principals to practice. AACC Press, Washington, DC, pp 67–90

  13. Grubbs F (1969) Procedures for detecting outlying observations in samples. Technometrics 11:1–21

    Article  Google Scholar 

  14. Altman DG (1991) Practical statistics for medical research. Chapman & Hall, Boca Raton, FL, pp 29–47

  15. Pepe MS (2003) The statistical evaluation of medical tests for classification and prediction. Oxford University Press, New York, pp 66–95

  16. Katz MH (2006) Multivariable analysis: a practical guide for clinicians, 2nd edn. Cambridge University Press, New York, pp 96–136

  17. Zaslavsky A, Baek K-H, Lynch RC et al (2010) Platelet-derived thrombospondin-1 (TSP-1) is a critical negative regulator and potential biomarker of angiogenesis. Blood 115:4605–4613

    Article  PubMed  CAS  Google Scholar 

  18. Folkman J, Browder T, Palmblad J (2001) Angiogenesis research: guidelines for translation to clinical application. Thromb Haemost 86:23–33

    PubMed  CAS  Google Scholar 

  19. George ML, Eccles SA, Tutton MG, Abulafi M, Swift RI (2000) Correlation of plasma and serum vascular endothelial growth factor levels with platelet count in colorectal cancer: Clinical Evidence of Platelet Scavenging? Clin Cancer Res 6:3147–3152

    PubMed  CAS  Google Scholar 

  20. Åkerblom B, Lindahl TL, Larsson A (2002) ADP activation induces bFGF binding to platelets in vitro. Upsala J Med Sci 107:165–171

    Article  PubMed  Google Scholar 

  21. Salgado R, Vermeulen PB, Benoy I et al (1999) Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels of advanced cancer patients, Brit. J of Cancer 80:892–897

    Article  CAS  Google Scholar 

  22. Gasic GJ, Gasic TB, Stewart CC (1968) Antimetastatic effects associated with platelet reduction. Proc Natl Acad Sci USA 61:46–52

    Article  PubMed  CAS  Google Scholar 

  23. Pedersen LM, Milman N (1996) Prognostic significance of thrombocytosis in patients with primary lung cancer. Eur Respir J 9:1826–1830

    Article  PubMed  CAS  Google Scholar 

  24. Ikeda M, Furukawa H, Imamura H et al (2002) Poor prognosis associated with thrombocytosis in patients with gastric cancer. Ann Surg Oncol 9:287–291

    Article  PubMed  Google Scholar 

  25. Verheul HM, Hoekman K, Luykx-de Bakker S et al (1997) Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 3:2187–2190

    PubMed  CAS  Google Scholar 

  26. Italiano JE Jr, Richardson JL, Patel-Hett S (2008) Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate alpha granules and differentially released. Blood 111:1227–1233

    Article  PubMed  CAS  Google Scholar 

  27. Ma L, Perini R, McKnight W et al (2005) Proteinase activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets. Proc Natl Acad Sci USA 102:216–220

    Article  PubMed  CAS  Google Scholar 

  28. Ellis LM, Takahashi Y, Liu W, Shaheen R (2000) Vascular endothelial growth factor in human colon cancer: Biology and therapeutic implications. Oncologist 5(suppl 1):11–15

    Article  PubMed  CAS  Google Scholar 

  29. Zetter BR (1998) Angiogenesis and tumor metastasis. Annu Rev Med 49:407–424

    Article  PubMed  CAS  Google Scholar 

  30. Lindmark G, Sundberg C, Glimelius B (1993) Stromal expression of platelet-derived growth factor beta-receptor and platelet-derived growth factor B-chain in colorectal cancer. Lab Invest 69(6):682–689

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This paper is dedicated to Judah Folkman, MD. We thank Dr. Marsha Moses of Children’s Hospital Boston for a helpful review of this manuscript. We thank Betsy Valles of Massachusetts General Hospital and Sean Downing of Children’s Hospital Boston and for their work in collecting and archiving cancer patient samples. We thank Dennis Robords of Ortho Clinical Diagnostics, Abdo Abou-Slaybi and Marlieke de Bruin of Children’s Hospital Boston for technical assistance. We thank Sean Downing of Children’s Hospital Boston and Lucius (Tad) Fox and John Backus of Ortho Clinical Diagnostics for discussions. We also thank John Backus for providing colonoscopy samples from Mayo Clinic. Ortho Clinical Diagnostics provided the funding for this work.

Conflict of interest

Jon Peterson was—and Marsha Oenick is—employed by and compensated by Ortho Clinical Diagnostics. Joseph Italiano and David Zurakowski were compensated as consultants to Ortho Clinical Diagnostics. No others have anything to disclose.

Author information

Author notes

  1. Jon E. Peterson

    Present address: Salimetrics, LLC, State College, PA, 16803, USA

Authors and Affiliations

  1. Department of Research and Development, Ortho Clinical Diagnostics, 100 Indigo Creek Drive, Rochester, NY, 14626, USA

    Jon E. Peterson, Lea V. Michel & Marsha Oenick

  2. The Vascular Biology Program, Children’s Hospital Boston, Boston, USA

    Jon E. Peterson, Joseph E. Italiano Jr, Susan Connors, Robert J. D’Amato & Judah Folkman

  3. Department of Surgery, Harvard Medical School and Children’s Hospital Boston, Boston, MA, 02115, USA

    Jon E. Peterson, Joseph E. Italiano Jr, Susan Connors, Robert J. D’Amato & Judah Folkman

  4. Departments of Anesthesia and Surgery, Children’s Hospital Boston, Harvard Medical School, Boston, MA, 02115, USA

    David Zurakowski

  5. Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Joseph E. Italiano Jr

  6. Department of Chemistry, Rochester Institute of Technology, Rochester, NY, 14623, USA

    Lea V. Michel

  7. Department of Ophthalmology, Harvard Medical School and Children’s Hospital Boston, Boston, MA, 02115, USA

    Robert J. D’Amato

  8. Division of Pediatric Hematology/Oncology, Pediatrics Department, Floating Hospital for Children, Tufts University School of Medicine, Boston, MA, 02111, USA

    Giannoula L. Klement

Authors
  1. Jon E. Peterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Zurakowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joseph E. Italiano Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lea V. Michel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Susan Connors
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marsha Oenick
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert J. D’Amato
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Giannoula L. Klement
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Judah Folkman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jon E. Peterson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peterson, J.E., Zurakowski, D., Italiano, J.E. et al. VEGF, PF4 and PDGF are elevated in platelets of colorectal cancer patients. Angiogenesis 15, 265–273 (2012). https://doi.org/10.1007/s10456-012-9259-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-012-9259-z

Keywords

Search

Navigation