Skip to main content

Advertisement

Log in

Bone morphogenetic protein-2 levels are elevated in the patients with gastric cancer and correlate with disease progression

  • Original paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Bone morphogenetic protein-2 (BMP-2) was reported to enhance migration, invasion, and metastasis at the various types of cancer cells. The purpose of this study is to identify the role of BMP-2 in progression of gastric cancer. Forty-four patients with operable gastric cancer were enrolled. Also, twenty healthy volunteers were enrolled as control group. All patients received gastrectomy with D2 lymphadenectomy, and surgical staging was performed. Whole blood was obtained preoperatively in all patients, and serum BMP-2 levels were quantified by commercially available ELISA kit. Immunohistochemical stain for BMP-2 in all gastric cancer tissues was performed using tissue microarray. All patients showed increased serum BMP-2 levels compared with control group, when upper normal limit was defined as the mean of control serum level + 2 × standard deviation. The mean serum BMP-2 level of lymph node positive group was significantly elevated than that of lymph node-negative group (382.7 pg/ml, 95% CI 341.99–423.4 pg/ml vs 211.69 pg/ml, 95% CI 191.09–232.29 pg/ml, P < 0.001). The serum BMP-2 was strongly correlated with the depth of invasion (T stage) and the extent of regional lymph node involvement (N stage) (r = 0.662, P < 0.001 and r = 0.831, P < 0.001, respectively). Moreover, the serum BMP-2 was correlated with the grade of tumor histology(r = 0.421, P = 0.008). Immunohistochemical stain showed the specific expression of BMP-2 in cancer cells compared with normal gastric mucosa. In conclusion, serum BMP-2 is associated with progression from early localized gastric cancer to locally advanced gastric cancer.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, et al. Novel regulators of bone formation: molecular clones and activities. Science. 1988;242(4885):1528–34.

    Article  CAS  PubMed  Google Scholar 

  2. Sampath TK, Maliakal JC, Hauschka PV, Jones WK, Sasak H, Tucker RF, et al. Recombinant human osteogenic protein-1 (hOP-1) induces new bone formation in vivo with a specific activity comparable with natural bovine osteogenic protein and stimulates osteoblast proliferation and differentiation in vitro. J Biol Chem. 1992;267(28):20352–62.

    CAS  PubMed  Google Scholar 

  3. Hogan BL. Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev. 1996;10(13):1580–94.

    Article  CAS  PubMed  Google Scholar 

  4. LI M, Eriksen EF, Bunger C. Bone morphogenetic protein-2 but not bone morphogenetic protein-4 and -6 stimulates chemotactic migration of human osteoblasts, human marrow osteoblasts, and U2-OS cells. Bone. 1996;18(1):53–7.

    Article  Google Scholar 

  5. Massague J. TGFbeta signaling: receptors, transducers, and mad proteins. Cell. 1996;85(7):947–50.

    Article  CAS  PubMed  Google Scholar 

  6. Nissinen L, Pirila L, Heino J. Bone morphogenetic protein-2 is a regulator of cell adhesion. Exp Cell Res. 1997;230(2):377–85.

    Article  CAS  PubMed  Google Scholar 

  7. Cao X, Chen D. The BMP signaling and in vivo bone formation. Gene. 2005;357(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  8. Derynck R, Zhang Y, Feng XH. Smads: transcriptional activators of TGF-beta responses. Cell. 1998;95(6):737–40.

    Article  CAS  PubMed  Google Scholar 

  9. Hoodless PA, Haerry T, Abdollah S, Stapleton M, O’Connor MB, Attisano L, et al. MADR1, a MAD-related protein that functions in BMP2 signaling pathways. Cell. 1996;85(4):489–500.

    Article  CAS  PubMed  Google Scholar 

  10. Yang S, Zhong C, Frenkel B, Reddi AH, Roy-Burman P. Diverse biological effect and Smad signaling of bone morphogenetic protein 7 in prostate tumor cells. Cancer Res. 2005;65(13):5769–77.

    Article  CAS  PubMed  Google Scholar 

  11. Deng H, Makizumi R, Ravikumar TS, Dong H, Yang W, Yang WL. Bone morphogenetic protein-4 is overexpressed in colonic adenocarcinomas and promotes migration and invasion of HCT116 cells. Exp Cell Res. 2007;313(5):1033–44.

    Article  CAS  PubMed  Google Scholar 

  12. Kleeff J, Maruyama H, Ishiwata T, Sawhney H, Friess H, Buchler MW, et al. Bone morphogenetic protein 2 exerts diverse effects on cell growth in vitro and is expressed in human pancreatic cancer in vivo. Gastroenterology. 1999;116(5):1202–16.

    Article  CAS  PubMed  Google Scholar 

  13. Kim IY, Kim SJ. Role of bone morphogenetic proteins in transitional cell carcinoma cells. Cancer Lett. 2006;241(1):118–23.

    Article  CAS  PubMed  Google Scholar 

  14. Feeley BT, Krenek L, Liu N, Hsu WK, Gamradt SC, Schwarz EM, et al. Overexpression of noggin inhibits BMP-mediated growth of osteolytic prostate cancer lesions. Bone. 2006;38(2):154–66.

    Article  CAS  PubMed  Google Scholar 

  15. Rothhammer T, Poser I, Soncin F, Bataille F, Moser M, Bosserhoff AK. Bone morphogenic proteins are overexpressed in malignant melanoma and promote cell invasion and migration. Cancer Res. 2005;65(2):448–56.

    CAS  PubMed  Google Scholar 

  16. Langenfeld EM, Calvano SE, Abou-Nukta F, Lowry SF, Amenta P, Langenfeld J. The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells. Carcinogenesis. 2003;24(9):1445–54.

    Article  CAS  PubMed  Google Scholar 

  17. Arnold SF, Tims E, McGrath BE. Identification of bone morphogenetic proteins and their receptors in human breast cancer cell lines: importance of BMP2. Cytokine. 1999;11(12):1031–7.

    Article  CAS  PubMed  Google Scholar 

  18. Feeley BT, Gamradt SC, Hsu WK, Liu N, Krenek L, Robbins P, et al. Influence of BMPs on the formation of osteoblastic lesions in metastatic prostate cancer. J Bone Miner Res. 2005;20(12):2189–99.

    Article  CAS  PubMed  Google Scholar 

  19. Autzen P, Robson CN, Bjartell A, Malcolm AJ, Johnson MI, Neal DE, et al. Bone morphogenetic protein 6 in skeletal metastases from prostate cancer and other common human malignancies. Br J Cancer. 1998;78(9):1219–23.

    CAS  PubMed  Google Scholar 

  20. Masuda H, Fukabori Y, Nakano K, Takezawa Y, CS T, Yamanaka H. Increased expression of bone morphogenetic protein-7 in bone metastatic prostate cancer. Prostate. 2003;54(4):268–74.

    Article  CAS  PubMed  Google Scholar 

  21. Wen XZ, Miyake S, Akiyama Y, Yuasa Y. BMP-2 modulates the proliferation and differentiation of normal and cancerous gastric cells. Biochem Biophys Res Commun. 2004;316(1):100–6.

    Article  CAS  PubMed  Google Scholar 

  22. Young A Yoo MHK, Jun Suk Kim, Sang Cheul Oh. Invasion in BMP2-induced EMT is mediated through down-regulation of PI-3 Kinase/Akt pathway. AACR2007;Abstract C38.

  23. Yoo YA, Kang MH, Kim JS, Oh SC. Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Carcinogenesis. 2008;29(3):480–90.

    Article  CAS  PubMed  Google Scholar 

  24. Park Y, Kim JW, Kim DS, Kim EB, Park SJ, Park JY, et al. The bone morphogenesis protein-2 (BMP-2) is associated with progression to metastatic disease in gastric cancer. Cancer Res Treat. 2008;40(3):127–32.

    Article  PubMed  Google Scholar 

  25. Greene FL. American Joint Committee on Cancer. AJCC cancer staging atlas. 1st ed. New York: Springer; 2006.

    Book  Google Scholar 

  26. Bailey JM, Singh PK, Hollingsworth MA. Cancer metastasis facilitated by developmental pathways: sonic hedgehog, notch, and bone morphogenic proteins. J Cell Biochem. 2007;102(4):829–39.

    Article  CAS  PubMed  Google Scholar 

  27. Hardwick JC, Van Den Brink GR, Bleuming SA, Ballester I, Van Den Brande JM, Keller JJ, et al. Bone morphogenetic protein 2 is expressed by, and acts upon, mature epithelial cells in the colon. Gastroenterology. 2004;126(1):111–21.

    Article  CAS  PubMed  Google Scholar 

  28. Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 2006;444(7120):761–5.

    Article  CAS  PubMed  Google Scholar 

  29. Hallahan AR, Pritchard JI, Chandraratna RA, Ellenbogen RG, Geyer JR, Overland RP, et al. BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect. Nat Med. 2003;9(8):1033–8.

    Article  CAS  PubMed  Google Scholar 

  30. Kawamura C, Kizaki M, Ikeda Y. Bone morphogenetic protein (BMP)-2 induces apoptosis in human myeloma cells. Leuk Lymphoma. 2002;43(3):635–9.

    Article  CAS  PubMed  Google Scholar 

  31. Kim IY, Lee DH, Lee DK, Kim BC, Kim HT, Leach FS, et al. Decreased expression of bone morphogenetic protein (BMP) receptor type II correlates with insensitivity to BMP-6 in human renal cell carcinoma cells. Clin Cancer Res. 2003;9(16 Pt 1):6046–51.

    CAS  PubMed  Google Scholar 

  32. Langenfeld EM, Kong Y, Langenfeld J. Bone morphogenetic protein 2 stimulation of tumor growth involves the activation of Smad-1/5. Oncogene. 2006;25(5):685–92.

    Article  CAS  PubMed  Google Scholar 

  33. Clement JH, Raida M, Sanger J, Bicknell R, Liu J, Naumann A, et al. Bone morphogenetic protein 2 (BMP-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cells. Int J Oncol. 2005;27(2):401–7.

    CAS  PubMed  Google Scholar 

  34. Montesano R. Bone morphogenetic protein-4 abrogates lumen formation by mammary epithelial cells and promotes invasive growth. Biochem Biophys Res Commun. 2007;353(3):817–22.

    Article  CAS  PubMed  Google Scholar 

  35. Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17(5):548–58.

    Article  CAS  PubMed  Google Scholar 

  36. Katoh M. Epithelial-mesenchymal transition in gastric cancer (Review). Int J Oncol. 2005;27(6):1677–83.

    CAS  PubMed  Google Scholar 

  37. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev. 2006;7(2):131–42.

    Article  CAS  Google Scholar 

  38. Greenburg G, Hay ED. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol. 1982;95(1):333–9.

    Article  CAS  PubMed  Google Scholar 

  39. Trelstad RL, Hay ED, Revel JD. Cell contact during early morphogenesis in the chick embryo. Dev Biol. 1967;16(1):78–106.

    Article  CAS  PubMed  Google Scholar 

  40. Ma L, Lu MF, Schwartz RJ, Martin JF. Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning. Development. 2005;132(24):5601–11. Cambridge, England.

    Article  CAS  PubMed  Google Scholar 

  41. Theriault BL, Shepherd TG, Mujoomdar ML, Nachtigal MW. BMP4 induces EMT and Rho GTPase activation in human ovarian cancer cells. Carcinogenesis. 2007;28(6):1153–62.

    Article  CAS  PubMed  Google Scholar 

  42. Kang MH, Kang HN, Kim JL, Kim JS, Oh SC, Yoo YA. Inhibition of PI3 kinase/Akt pathway is required for BMP2-induced EMT and invasion. Oncol Rep. 2009;22(3):525–34.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by the Korea Research Foundation Grant funded by the Korean Government (KRF-2008-331-E00470) and the Korea University Grant. All authors reported that there was no conflict of interests in this study.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sang Cheul Oh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, Y., Kang, M.H., Seo, H.Y. et al. Bone morphogenetic protein-2 levels are elevated in the patients with gastric cancer and correlate with disease progression. Med Oncol 27, 1192–1199 (2010). https://doi.org/10.1007/s12032-009-9358-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-009-9358-x

Keywords

Navigation