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Midkine as a prognostic marker for gastrointestinal stromal tumors

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Abstract

Purpose

Midkine (MK), a heparin-binding growth factor, has an important role in cancer progression. The outcome of patients with gastrointestinal stromal tumors (GISTs) is correlated with tumor size and mitotic count. The aim of this study was to determine MK expression in GISTs.

Methods

Midkine was detected in 31 (55%) of 57 surgically resected GISTs by immunohistochemistry with a rabbit antibody against MK and peroxidase method.

Results

A significant worse outcome of MK-positive patients was found (P < 0.05; log rank test). Multivariate Cox regression analysis showed an independent prognostic impact (relative risk for overall survival 3.64; P < 0.05). Interestingly, MK expression was significantly associated with mitotic rate (P < 0.05; Chi-squared test), but not with tumor size (P = 0.97).

Conclusions

Taken together, MK is a prognostic marker for GIST patients. MK might also be a useful peripheral tumor marker since it can be detected in peripheral serum. Future studies should involve higher GIST patient numbers including tumor and serum samples for detection of MK.

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References

  • DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF (2000) Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 231:51–58

    Article  PubMed  CAS  Google Scholar 

  • Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480

    Article  PubMed  CAS  Google Scholar 

  • Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O’Leary TJ, Remotti H, Rubin BP, Shmookler B, Sobin LH, Weiss SW (2002a) Diagnosis of gastrointestinal stromal tumors: a consensus approach. Int J Surg Pathol 10:81–89

    Google Scholar 

  • Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O’Leary TJ, Remotti H, Rubin BP, Shmookler B, Sobin LH, Weiss SW (2002b) Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 33:459–465

    Article  Google Scholar 

  • Friedrich C, Holtkamp N, Cinatl J Jr, Sakuma S, Mautner VF, Wellman S, Michaelis M, Henze G, Kurtz A, Driever PH (2005) Overexpression of Midkine in malignant peripheral nerve sheath tumor cells inhibits apoptosis and increases angiogenic potency. Int J Oncol 27:1433–1440

    PubMed  CAS  Google Scholar 

  • Graadt van Roggen JF, van Velthuysen ML, Hogendoorn PC (2001) The histopathological differential diagnosis of gastrointestinal stromal tumours. J Clin Pathol 54:96–102

    Article  Google Scholar 

  • Ikematsu S, Nakagawara A, Nakamura Y, Sakuma S, Wakai K, Muramatsu T, Kadomatsu K (2003) Correlation of elevated level of blood midkine with poor prognostic factors of human neuroblastomas. Br J Cancer 88:1522–1526

    Article  PubMed  CAS  Google Scholar 

  • Kadomatsu K (2000) [Recent progress of midkine research on cancer]. Nippon Rinsho 58:1337–1347

    PubMed  CAS  Google Scholar 

  • Kadomatsu K, Muramatsu T (2004) Midkine and pleiotrophin in neural development and cancer. Cancer Lett 204:127–143

    Article  PubMed  CAS  Google Scholar 

  • Kaifi JT, Strelow A, Schurr PG, Reichelt U, Yekebas EF, Wachowiak R, Quaas A, Strate T, Schaefer H, Sauter G, Schachner M, Izbicki JR (2006) L1 (CD171) is highly expressed in gastrointestinal stromal tumors. Mod Pathol 19:399–406

    Article  PubMed  CAS  Google Scholar 

  • Miettinen M, El-Rifai W, HL Sobin L, Lasota J (2002a) Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. Hum Pathol 33:478–483

    Article  CAS  Google Scholar 

  • Miettinen M, Majidi M, Lasota J (2002b) Pathology and diagnostic criteria of gastrointestinal stromal tumors (GISTs): a review. Eur J Cancer 38(Suppl 5):S39–S51

    Article  Google Scholar 

  • Mirkin BL, Clark S, Zheng X, Chu F, White BD, Greene M, Rebbaa A (2005) Identification of midkine as a mediator for intercellular transfer of drug resistance. Oncogene 24:4965–4974

    Article  PubMed  CAS  Google Scholar 

  • Muramatsu T (2002) Midkine and pleiotrophin: two related proteins involved in development, survival, inflammation and tumorigenesis. J Biochem (Tokyo) 132:359–371

    CAS  Google Scholar 

  • Muramatsu H, Shirahama H, Yonezawa S, Maruta H, Muramatsu T (1993) Midkine, a retinoic acid-inducible growth/differentiation factor: immunochemical evidence for the function and distribution. Dev Biol 159:392–402

    Article  PubMed  CAS  Google Scholar 

  • Nakagawara A, Milbrandt J, Muramatsu T, Deuel TF, Zhao H, Cnaan A, Brodeur GM (1995) Differential expression of pleiotrophin and midkine in advanced neuroblastomas. Cancer Res 55:1792–1797

    PubMed  CAS  Google Scholar 

  • Obata Y, Kikuchi S, Lin Y, Yagyu K, Muramatsu T, Kumai H (2005) Serum midkine concentrations and gastric cancer. Cancer Sci 96:54–56

    Article  PubMed  CAS  Google Scholar 

  • Owada K, Sanjo N, Kobayashi T, Mizusawa H, Muramatsu H, Muramatsu T, Michikawa M (1999) Midkine inhibits caspase-dependent apoptosis via the activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase in cultured neurons. J Neurochem 73:2084–2092

    PubMed  CAS  Google Scholar 

  • Shimada H, Nabeya Y, Okazumi S, Matsubara H, Kadomatsu K, Muramatsu T, Ikematsu S, Sakuma S, Ochiai T (2003a) Increased serum midkine concentration as a possible tumor marker in patients with superficial esophageal cancer. Oncol Rep 10:411–414

    CAS  Google Scholar 

  • Shimada H, Nabeya Y, Tagawa M, Okazumi S, Matsubara H, Kadomatsu K, Muramatsu T, Ikematsu S, Sakuma S, Ochiai T (2003b) Preoperative serum midkine concentration is a prognostic marker for esophageal squamous cell carcinoma. Cancer Sci 94:628–632

    Article  CAS  Google Scholar 

  • Stoica GE, Kuo A, Powers C, Bowden ET, Sale EB, Riegel AT, Wellstein A (2002) Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types. J Biol Chem 277:35990–35998

    Article  PubMed  CAS  Google Scholar 

  • Takahashi R, Tanaka S, Kitadai Y, Sumii M, Yoshihara M, Haruma K, Chayama K (2003) Expression of vascular endothelial growth factor and angiogenesis in gastrointestinal stromal tumor of the stomach. Oncology 64:266–274

    Article  PubMed  CAS  Google Scholar 

  • Takei Y, Kadomatsu K, Yuasa K, Sato W, Muramatsu T (2005) Morpholino antisense oligomer targeting human midkine: its application for cancer therapy. Int J Cancer 114:490–497

    Article  PubMed  CAS  Google Scholar 

  • Ye C, Qi M, Fan QW, Ito K, Akiyama S, Kasai Y, Matsuyama M, Muramatsu T, Kadomatsu K (1999) Expression of midkine in the early stage of carcinogenesis in human colorectal cancer. Br J Cancer 79:179–184

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Beate Roth for excellent technical assistance. Financial support for this study was provided by research grants from the Hamburger Krebsgesellschaft e. V. (J.T.K., E.F.Y., J.R.I.).

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Authors and Affiliations

  1. Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

    Jussuf T. Kaifi, Svanheidur L. Rafnsdottir, Paulus G. Schurr, Robin Wachowiak, Helge Kleinhans, Emre F. Yekebas, Oliver Mann, Tim Strate & Jakob R. Izbicki

  2. Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Henning C. Fiegel & Dietrich Kluth

  3. Institute for Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Uta Reichelt

  4. Department of Surgery, Kagoshima University, Kagoshima, Japan

    Kuniaki Aridome

  5. Department of Health Science, Faculty of Psychological and Physical Sciences, Aichi Gakuin University, Aichi, Japan

    Keiko Ichihara-Tanaka & Takashi Muramatsu

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  1. Jussuf T. Kaifi
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  2. Henning C. Fiegel
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Correspondence to Jussuf T. Kaifi.

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Kaifi, J.T., Fiegel, H.C., Rafnsdottir, S.L. et al. Midkine as a prognostic marker for gastrointestinal stromal tumors. J Cancer Res Clin Oncol 133, 431–435 (2007). https://doi.org/10.1007/s00432-006-0180-y

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  • DOI: https://doi.org/10.1007/s00432-006-0180-y

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