Recombinant Human Bone Morphogenetic Protein-2 in Development and Progression of Oral Squamous Cell Carcinoma

  • Zaid, Khaled Waleed (Department of Oral Histology and Pathology, Faculty of Dentistry, Damascus University) ;
  • Chantiri, Mansour (Department of Periodontology, Faculty of Dentistry, Lebanese University) ;
  • Bassit, Ghassan (Department of Oral Surgery and Implantology, IUST University)
  • Published : 2016.04.11


Bone morphogenetic proteins (BMPs), belonging to the transforming growth factor-${\beta}$ superfamily, regulate many cellular activities including cell migration, differentiation, adhesion, proliferation and apoptosis. Use of recombinant human bone morphogenic protein-2 (rhBMP-2) in oral and maxillofacial surgery has seen a tremendous increase. Due to its role in many cellular pathways, the influence of this protein on carcinogenesis in different organs has been intensively studied over the past decade. BMPs also have been detected to have a role in the development and progression of many tumors, particularly disease-specific bone metastasis. In oral squamous cell carcinoma - the tumor type accounting for more than 90% of head and neck malignancies- aberrations of both BMP expression and associated signaling pathways have a certain relation with the development and progression of the disease by regulating a range of biological functions in the altered cells. In the current review, we discuss the influence of BMPs -especially rhBMP-2- in the development and progression of oral squamous cell carcinoma.


  1. Aoki M, Ishigami S, Uenosono Y, et al (2011). Expression of BMP-7 in human gastric cancer and its clinical significance. Br J Cancer, 104, 714-8.
  2. Arnold SF, Tims E, McGrath BE (1999). Identification of bone morphogenetic proteins and their receptors in human breast cancer cell lines: importance of BMP2. Cytokine, 11, 1031-7.
  3. Benezra R (2001). Role of Id proteins in embryonic and tumor angiogenesis. Trends Cardiovasc Med, 11, 237-41.
  4. Bieniasz M, Oszajca K, Eusebio M, et al (2009). The positive correlation between gene expression of the two angiogenic factors: VEGF and BMP-2 in lung cancer patients. Lung Cancer, 66, 319-26.
  5. Campbell I, Polyak K, Haviv I (2009). Clonal mutations in the cancer-associated fibroblasts: the case against genetic coevolution. Cancer Res, 69, 6765-8.
  6. Carragee EJ, Chu G, Rohatgi R, et al (2013). Cancer risk after use of recombinant bone morphogenetic protein-2 for spinal arthrodesis. J Bone Joint Surg Am, 95, 1537-45.
  7. Carragee EJ, Hurwitz EL, Weiner BK (2011). A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J, 11, 471-91.
  8. Chen D, Zhao M, Mundy GR (2004). Bone morphogenetic proteins. Growth Factors, 22, 233-41.
  9. Chen S, Guttridge DC, Tang E, et al (2001). Suppression of tumor necrosis factor-mediated apoptosis by nuclear factor kappaB-independent bone morphogenetic protein/Smad signaling. J Biol Chem, 276, 39259-63.
  10. Chu H, Luo H, Wang H, et al (2014). Silencing BMP-2 expression inhibits A549 and H460 cell proliferation and migration. Diagn Pathol, 9, 123.
  11. Clement JH, Raida M, Sanger J, et al (2005). Bone morphogenetic protein 2 (BMP-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cells. Int J Oncol, 27, 401-7.
  12. Epstein NE (2014). Basic science and spine literature document bone morphogenetic protein increases cancer risk. Surg Neurol Int, 5, S552-60.
  13. Erler JT, Weaver VM (2009). Three-dimensional context regulation of metastasis. Clin Exp Metastasis, 26, 35-49.
  14. Feeley BT, Krenek L, Liu N, et al (2006). Overexpression of noggin inhibits BMP-mediated growth of osteolytic prostate cancer lesions. Bone, 38, 154-66.
  15. Fei ZH, Yao CY, Yang XL, et al (2013). Serum BMP-2 up-regulation as an indicator of poor survival in advanced non-small cell lung cancer patients. Asian Pac J Cancer Prev, 14, 5293-9.
  16. Fessing MY, Atoyan R, Shander B, et al (2010). BMP signaling induces cell-type-specific changes in gene expression programs of human keratinocytes and fibroblasts. J Invest Dermatol, 130, 398-404.
  17. Friedrichs M, Wirsdoerfer F, Flohe SB, et al (2011). BMP signaling balances proliferation and differentiation of muscle satellite cell descendants. BMC Cell Biol, 12, 26.
  18. Gao Q, Tong W, Luria JS, et al (2010). Effects of bone morphogenetic protein-2 on proliferation and angiogenesis in oral squamous cell carcinoma. Int J Oral Maxillofac Surg, 39, 266-71.
  19. Ghosh-Choudhury N, Abboud SL, Nishimura R, et al (2002). Requirement of BMP-2-induced phosphatidylinositol 3-kinase and Akt serine/threonine kinase in osteoblast differentiation and Smad-dependent BMP-2 gene transcription. J Biol Chem, 277, 33361-8.
  20. Ghosh-Choudhury N, Woodruff K, Qi W, et al (2000). Bone morphogenetic protein-2 blocks MDA MB 231 human breast cancer cell proliferation by inhibiting cyclin-dependent kinase-mediated retinoblastoma protein phosphorylation. Biochem Biophys Res Commun, 272, 705-11.
  21. Granjeiro JM, Oliveira RC, Bustos-Valenzuela JC, et al (2005). Bone morphogenetic proteins: from structure to clinical use. Braz J Med Biol Res, 38, 1463-73.
  22. Gunesdogan U, Magnusdottir E, Surani MA (2014). Primordial germ cell specification: a context-dependent cellular differentiation event [corrected]. Philos Trans R Soc Lond B Biol Sci, 369.
  23. Hallahan AR, Pritchard JI, Chandraratna RA, et al (2003). BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect. Nat Med, 9, 1033-8.
  24. Hanahan D, Weinberg RA (2000). The hallmarks of cancer. Cell, 100, 57-70.
  25. Hogan BL (1996). Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev, 10, 1580-94.
  26. Hu F, Meng X, Tong Q, et al (2013). BMP-6 inhibits cell proliferation by targeting microRNA-192 in breast cancer. Biochim Biophys Acta, 1832, 2379-90.
  27. Kang MH, Kang HN, Kim JL, et al (2009). Inhibition of PI3 kinase/Akt pathway is required for BMP2-induced EMT and invasion. Oncol Rep, 22, 525-34.
  28. Kang MH, Kim JS, Seo JE, et al (2010). BMP2 accelerates the motility and invasiveness of gastric cancer cells via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Exp Cell Res, 316, 24-37.
  29. Kawamura C, Kizaki M, Ikeda Y (2002). Bone morphogenetic protein (BMP)-2 induces apoptosis in human myeloma cells. Leuk Lymphoma, 43, 635-9.
  30. Kim BR, Oh SC, Lee DH, et al (2015). BMP-2 induces motility and invasiveness by promoting colon cancer stemness through STAT3 activation. Tumour Biol.
  31. Kim MJ, Kim KM, Kim J, et al (2014). BMP-2 promotes oral squamous carcinoma cell invasion by inducing CCL5 release. PLoS One, 9, 108170.
  32. Kobayashi T, Lyons KM, McMahon AP, et al (2005). BMP signaling stimulates cellular differentiation at multiple steps during cartilage development. Proc Natl Acad Sci U S A, 102, 18023-7.
  33. Koinuma D, Tsutsumi S, Kamimura N, et al (2009). Promoterwide analysis of Smad4 binding sites in human epithelial cells. Cancer Sci, 100, 2133-42.
  34. Kokorina NA, Zakharkin SO, Krebsbach PH, et al (2011). Treatment effects of rhBMP-2 on invasiveness of oral carcinoma cell lines. Laryngoscope, 121, 1876-80.
  35. Krishna A, Singh RK, Singh S, et al (2014). Demographic risk factors, affected anatomical sites and clinicopathological profile for oral squamous cell carcinoma in a north Indian population. Asian Pac J Cancer Prev, 15, 6755-60.
  36. Kwon H, Kim HJ, Rice WL, et al (2010). Development of an in vitro model to study the impact of BMP-2 on metastasis to bone. J Tissue Eng Regen Med, 4, 590-9.
  37. Langenfeld EM, Langenfeld J (2004). Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors. Mol Cancer Res, 2, 141-9.
  38. Le Page C, Puiffe ML, Meunier L, et al (2009). BMP-2 signaling in ovarian cancer and its association with poor prognosis. J Ovarian Res, 2, 4.
  39. Liu S, Yu D, Xu ZP, et al (2001). Angiogenin activates Erk1/2 in human umbilical vein endothelial cells. Biochem Biophys Res Commun, 287, 305-10.
  40. Mancino M, Strizzi L, Wechselberger C, et al (2008). Regulation of human Cripto-1 gene expression by TGF-beta1 and BMP-4 in embryonal and colon cancer cells. J Cell Physiol, 215, 192-203.
  41. Mock K, Preca BT, Brummer T, et al (2015). The EMT-activator ZEB1 induces bone metastasis associated genes including BMP-inhibitors. Oncotarget, 6, 14399-412.
  42. Montesano R, Sarkozi R, Schramek H (2008). Bone morphogenetic protein-4 strongly potentiates growth factor-induced proliferation of mammary epithelial cells. Biochem Biophys Res Commun, 374, 164-8.
  43. Nana AW, Yang PM, Lin HY (2015). Overview of Transforming Growth Factor beta Superfamily Involvement in Glioblastoma Initiation and Progression. Asian Pac J Cancer Prev, 16, 6813-23.
  44. Ocana OH, Corcoles R, Fabra A, et al (2012). Metastatic colonization requires the repression of the epithelialmesenchymal transition inducer Prrx1. Cancer Cell, 22, 709-24.
  45. Owens P, Polikowsky H, Pickup MW, et al (2013). Bone Morphogenetic Proteins stimulate mammary fibroblasts to promote mammary carcinoma cell invasion. PLoS One, 8, e67533.
  46. Peng J, Yoshioka Y, Mandai M, et al (2015). The BMP signaling pathway leads to enhanced proliferation in serous ovarian cancer-a potential therapeutic target. Mol Carcinog.
  47. Perez VA, Ali Z, Alastalo TP, et al (2011). BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways. J Cell Biol, 192, 171-88.
  48. Peterkova R, Peterka M, Vonesch JL, et al (1998). Correlation between apoptosis distribution and BMP-2 and BMP-4 expression in vestigial tooth primordia in mice. Eur J Oral Sci, 106, 667-70.
  49. Petti S (2009). Lifestyle risk factors for oral cancer. Oral Oncol, 45, 340-50.
  50. Pouliot F, Labrie C (2002). Role of Smad1 and Smad4 proteins in the induction of p21WAF1,Cip1 during bone morphogenetic protein-induced growth arrest in human breast cancer cells. J Endocrinol, 172, 187-98.
  51. Qiao B, Johnson NW, Chen X, et al (2011). Disclosure of a stem cell phenotype in an oral squamous cell carcinoma cell line induced by BMP-4 via an epithelial-mesenchymal transition. Oncol Rep, 26, 455-61.
  52. Qiu H, Yang B, Pei ZC, et al (2010). WSS25 inhibits growth of xenografted hepatocellular cancer cells in nude mice by disrupting angiogenesis via blocking bone morphogenetic protein (BMP)/Smad/Id1 signaling. J Biol Chem, 285, 32638-46.
  53. Reddi AH, Reddi A (2009). Bone morphogenetic proteins (BMPs): from morphogens to metabologens. Cytokine Growth Factor Rev, 20, 341-2.
  54. Saitoh M, Shirakihara T, Fukasawa A, et al (2013). Basolateral BMP signaling in polarized epithelial cells. PLoS One, 8, 62659.
  55. Salo T, Vered M, Bello IO, et al (2014). Insights into the role of components of the tumor microenvironment in oral carcinoma call for new therapeutic approaches. Exp Cell Res, 325, 58-64.
  56. Samavarchi-Tehrani P, Golipour A, David L, et al (2010). Functional genomics reveals a BMP-driven mesenchymalto-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell, 7, 64-77.
  57. Sanders AJ, Ye L, Li J, et al (2014). Tumour angiogenesis and repulsive guidance molecule b: a role in HGF- and BMP-7-mediated angiogenesis. Int J Oncol, 45, 1304-12.
  58. Sasaki T, Kishimoto S, Kawabata K, et al (2015). Risk factors for cervical lymph node metastasis in superficial head and neck squamous cell carcinoma. J Med Dent Sci, 62, 19-24.
  59. Secondini C, Wetterwald A, Schwaninger R, et al (2011). The role of the BMP signaling antagonist noggin in the development of prostate cancer osteolytic bone metastasis. PLoS One, 6, 16078.
  60. Soda H, Raymond E, Sharma S, et al (1998). Antiproliferative effects of recombinant human bone morphogenetic protein-2 on human tumor colony-forming units. Anticancer Drugs, 9, 327-31.
  61. Suzawa M, Takeuchi Y, Fukumoto S, et al (1999). Extracellular matrix-associated bone morphogenetic proteins are essential for differentiation of murine osteoblastic cells in vitro. Endocrinol, 140, 2125-33.
  62. Togo N, Ohwada S, Sakurai S, et al (2008). Prognostic significance of BMP and activin membrane-bound inhibitor in colorectal cancer. World J Gastroenterol, 14, 4880-8.
  63. Wang L, Park P, La Marca F, et al (2015). BMP-2 inhibits tumor-initiating ability in human renal cancer stem cells and induces bone formation. J Cancer Res Clin Oncol, 141, 1013-24.
  64. Wang L, Park P, Zhang H, et al (2011). BMP-2 inhibits the tumorigenicity of cancer stem cells in human osteosarcoma OS99-1 cell line. Cancer Biol Ther, 11, 457-63.
  65. Yang S, Pham LK, Liao CP, et al (2008). A novel bone morphogenetic protein signaling in heterotypic cell interactions in prostate cancer. Cancer Res, 68, 198-205.
  66. Yang YL, Ju HZ, Liu SF, et al (2011). BMP-2 suppresses renal interstitial fibrosis by regulating epithelial-mesenchymal transition. J Cell Biochem, 112, 2558-65.
  67. Zaid KW (2014). Immunohistochemical Assessment of E-cadherin and beta-catenin in the Histological Differentiations of Oral Squamous Cell Carcinoma. Asian Pac J Cancer Prev, 15, 8847-53.
  68. Zhou X, Temam S, Oh M, et al (2006). Global expression-based classification of lymph node metastasis and extracapsular spread of oral tongue squamous cell carcinoma. Neoplasia, 8, 925-32.

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