Skip to main content

Advertisement

SpringerLink
Log in

BMP2 as a promising anticancer approach: functions and molecular mechanisms

  • Review
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Bone morphogenetic protein 2 (BMP2), a pluripotent factor, is a member of the transforming growth factor-beta (TGF-β) superfamily and is implicated in embryonic development and postnatal homeostasis in tissues and organs. Experimental research in the contexts of physiology and pathology has indicated that BMP2 can induce macrophages to differentiate into osteoclasts and accelerate the osteolytic mechanism, aggravating cancer cell bone metastasis. Emerging studies have stressed the potent regulatory effect of BMP2 in cancer cell differentiation, proliferation, survival, and apoptosis. Complicated signaling networks involving multiple regulatory proteins imply the significant biological functions of BMP2 in cancer. In this review, we comprehensively summarized and discussed the current evidence related to the modulation of BMP2 in tumorigenesis and development, including evidence related to the roles and molecular mechanisms of BMP2 in regulating cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), cancer angiogenesis and the tumor microenvironment (TME). All these findings suggest that BMP2 may be an effective therapeutic target for cancer and a new marker for assessing treatment efficacy.

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
Fig. 3

Similar content being viewed by others

References

  1. Huminiecki L, Goldovsky L, Freilich S et al (2009) Emergence, development and diversification of the TGF-beta signalling pathway within the animal kingdom. BMC Evol Biol 9:28

    Article  PubMed  PubMed Central  Google Scholar 

  2. Moustakas A, Heldin CH (2009) The regulation of TGF beta signal transduction. Development 136(22):3699–3714

  3. Wheeler SE, Lee NY (2017) Emerging Roles of Transforming Growth Factor beta Signaling in Diabetic Retinopathy. J Cell Physiol 232(3)486–489

  4. Russow G, Jahn D, Appelt J et al (2018) Anabolic Therapies in Osteoporosis and Bone Regeneration. Int J Mol Sci 20(1)

  5. Begum S (2019) Engineering renal epithelial cells: programming and directed differentiation towards glomerular podocyte's progenitor and mature podocyte. Am J Transl Res 11(2):1102–1115

  6. Shimmi O, Matsuda S, Hatakeyama M (2014) Insights into the molecular mechanisms underlying diversified wing venation among insects. Proc Biol Sci 281(1789):20140264

    PubMed  PubMed Central  Google Scholar 

  7. Wagstaff PE, Heredero BA, Boon C et al (2021) The Role of Small Molecules and Their Effect on the Molecular Mechanisms of Early Retinal Organoid Development. Int J Mol Sci 22(13)

  8. Ihle CL, Straign DM, Provera MD et al (2020) Loss of Myeloid BMPR1a Alters Differentiation and Reduces Mouse Prostate Cancer Growth. Front Oncol 10:357

    Article  PubMed  PubMed Central  Google Scholar 

  9. Lu X, Jin EJ, Cheng X et al (2017) Opposing roles of TGFbeta and BMP signaling in prostate cancer development. Genes Dev 31(23–24):2337–2342

  10. Bonetti J, Corti A, Lerouge L et al (2021) Phenotypic Modulation of Macrophages and Vascular Smooth Muscle Cells in Atherosclerosis-Nitro-Redox Interconnections. Antioxidants (Basel) 10(4)

  11. Han O, Pak B, Jin SW (2021) The Role of BMP Signaling in Endothelial Heterogeneity. Front Cell Dev Biol 9:673396

    Article  PubMed  PubMed Central  Google Scholar 

  12. Nakashima K, Yanagisawa M, Arakawa H et al (1999) Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 284(5413)479–482

  13. Reddi AH (2005) BMPs: from bone morphogenetic proteins to body morphogenetic proteins. Cytokine Growth Factor Rev 16(3):249–250

  14. Wagner DO, Sieber C, Bhushan R et al (2010) BMPs: from bone to body morphogenetic proteins. Sci Signal 3(107):r1

    Google Scholar 

  15. Wang EA, Rosen V, Cordes P et al (1988) Purification and characterization of other distinct bone-inducing factors. Proc Natl Acad Sci USA 85(24):9484–9488

  16. Bessa PC, Casal M, Reis RL (2008) Bone morphogenetic proteins in tissue engineering: the road from the laboratory to the clinic, part I (basic concepts). J Tissue Eng Regen Med 2(1):1–13

  17. Bessa PC, Casal M, Reis RL (2008) Bone morphogenetic proteins in tissue engineering: the road from laboratory to clinic, part II (BMP delivery). J Tissue Eng Regen Med 2(2–3):81–96

  18. Jia Q, Xu B, Zhang Y et al (2021) CCN Family Proteins in Cancer: Insight Into Their Structures and Coordination Role in Tumor Microenvironment. Front Genet 12:649387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Damiati LA, El-Messeiry S (2021) An Overview of RNA-Based Scaffolds for Osteogenesis. Front Mol Biosci 8:682581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Krajewska-Wlodarczyk M, Owczarczyk-Saczonek A, Placek W et al (2017) Role of Stem Cells in Pathophysiology and Therapy of Spondyloarthropathies-New Therapeutic Possibilities. Int J Mol Sci 19(1)

  21. Tsai CL, Tsai CN, Lin CY et al (2012) Secreted stress-induced phosphoprotein 1 activates the ALK2-SMAD signaling pathways and promotes cell proliferation of ovarian cancer cells. Cell Rep 2(2):283–293

  22. Ishay-Ronen D, Diepenbruck M, Kalathur R et al (2019) Gain Fat-Lose Metastasis: Converting Invasive Breast Cancer Cells into Adipocytes Inhibits Cancer Metastasis. Cancer Cell 35(1):17–32

  23. Yu J, Wang Q, Zhang X et al (2021) Mechanisms of Neoantigen-Targeted Induction of Pyroptosis and Ferroptosis: From Basic Research to Clinical Applications. Front Oncol 11:685377

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kim KK, Sheppard D, Chapman HA (2018) TGF-beta1 Signaling and Tissue Fibrosis. Cold Spring Harb Perspect Biol 10(4)

  25. Taylor RA, Chang CF, Goods BA et al (2017) TGF-beta1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage. J Clin Invest 127(1)280–292

  26. Delaney K, Kasprzycka P, Ciemerych MA et al (2017) The role of TGF-beta1 during skeletal muscle regeneration. Cell Biol Int 41(7)706–715

  27. Hadaschik EN, Enk AH (2015) TGF-beta1-induced regulatory T cells. Hum Immunol 76(8)561–564

  28. Yu SN, Miao YY, Zhang BT et al (2021) MicroRNA-1269a promotes the occurrence and progression of osteosarcoma by inhibiting TGF-beta1 expression. Eur Rev Med Pharmacol Sci 25(7):2824

    PubMed  Google Scholar 

  29. Fezza M, Moussa M, Aoun R et al (2019) DKK1 promotes hepatocellular carcinoma inflammation, migration and invasion: Implication of TGF-beta1. PLoS ONE 14(9):e223252

    Article  Google Scholar 

  30. Zhang M, Meng QC, Yang XF et al (2020) TGF-beta1/WISP1/Integrin-alpha interaction mediates human chondrocytes dedifferentiation. Eur Rev Med Pharmacol Sci 24(17):8675–8684

  31. Yu H, Ma S, Sun L et al (2019) TGFbeta1 upregulates the expression of lncRNAATB to promote atherosclerosis. Mol Med Rep 19(5)4222–4228

  32. Gomes FC, Sousa VO, Romao L (2005) Emerging roles for TGF-beta1 in nervous system development. Int J Dev Neurosci 23(5):413–424

  33. Rosenkranz S (2004) TGF-beta1 and angiotensin networking in cardiac remodeling. Cardiovasc Res 63(3):423–432

  34. Caraci F, Spampinato S, Sortino MA et al (2012) Dysfunction of TGF-beta1 signaling in Alzheimer's disease: perspectives for neuroprotection. Cell Tissue Res 347(1):291–301

  35. Sun F, Yu PF, Wang D et al (2019) MicroRNA-488 regulates diabetic nephropathy via TGF-beta1 pathway. Eur Rev Med Pharmacol Sci 23(10):4333–4340

  36. Manuyakorn W, Kamchaisatian W, Atamasirikul K et al (2008) Serum TGF-beta1 in atopic asthma. Asian Pac J Allergy Immunol 26:185–189

  37. Takahashi H, Alves C, Stanford KI et al (2019) TGF-beta2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism. Nat Metab 1(2):291–303

  38. Dropmann A, Dooley S, Dewidar B et al (2020) TGF-beta2 silencing to target biliary-derived liver diseases. Gut 69(9)1677–1690

  39. Futakuchi A, Inoue T, Wei FY et al (2018) YAP/TAZ Are Essential for TGF-beta2-Mediated Conjunctival Fibrosis. Invest Ophthalmol Vis Sci 59(7):3069–3078

  40. Zhang C, Zhang X, Xu R et al (2017) TGF-beta2 initiates autophagy via Smad and non-Smad pathway to promote glioma cells’ invasion. J Exp Clin Cancer Res 36(1):162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hau P, Jachimczak P, Schlaier J et al (2011) TGF-beta2 signaling in high-grade gliomas. Curr Pharm Biotechnol 12(12):2150–2157

  42. Hibino T, Nishiyama T (2004) Role of TGF-beta2 in the human hair cycle. J Dermatol Sci 35(1):9–18

  43. Lv Y, Zhang Z, Xing X et al (2020) lncRNA TGFbeta2-AS1 promotes ECM production via TGF-beta2 in human trabecular meshwork cells. Biochem Biophys Res Commun 527(4):881–888

  44. Balzar S, Chu HW, Silkoff P et al (2005) Increased TGF-beta2 in severe asthma with eosinophilia. J Allergy Clin Immunol 115(1):110–117

  45. Duan M, Wang Q, Liu Y et al (2021) The role of TGF-beta2 in cartilage development and diseases. Bone Joint Res 10(8):474–487

  46. Tian L, Sun S, Li W et al (2020) Down-regulated microRNA-141 facilitates osteoblast activity and inhibits osteoclast activity to ameliorate osteonecrosis of the femoral head via up-regulating TGF-beta2. Cell Cycle 19(7):772–786

  47. Smith P, Mosiello G, Deluca L et al (1999) TGF-beta2 activates proliferative scar fibroblasts. J Surg Res 82(2):319–323

  48. Gottanka J, Chan D, Eichhorn M et al (2004) Effects of TGF-beta2 in perfused human eyes. Invest Ophthalmol Vis Sci 45(1):153–158

  49. Xue L, Xiong C, Li J et al (2020) miR-200–3p suppresses cell proliferation and reduces apoptosis in diabetic retinopathy via blocking the TGF-beta2/Smad pathway. Biosci Rep 40(11)

  50. Okamura T, Morita K, Iwasaki Y et al (2015) Role of TGF-beta3 in the regulation of immune responses. Clin Exp Rheumatol 33(4 Suppl 92):S63-S69

  51. Laverty HG, Wakefield LM, Occleston NL et al (2009) TGF-beta3 and cancer: a review. Cytokine Growth Factor Rev 20(4):305–317

  52. Yang Y, Chen L, Si J et al (2020) TGF-beta3/Smad3 Contributes to Isoflurane Postconditioning Against Cerebral Ischemia-Reperfusion Injury by Upregulating MEF2C. Cell Mol Neurobiol 40(8):1353–1365

  53. Tang QO, Shakib K, Heliotis M et al (2009) TGF-beta3: A potential biological therapy for enhancing chondrogenesis. Expert Opin Biol Ther 9(6):689–701

  54. Li Y, Qiao Z, Yu F et al (2019) Transforming Growth Factor-beta3/Chitosan Sponge (TGF-beta3/CS) Facilitates Osteogenic Differentiation of Human Periodontal Ligament Stem Cells. Int J Mol Sci 20(20)

  55. Herath CB, Yamashita M, Watanabe G et al (2001) Regulation of follicle-stimulating hormone secretion by estradiol and dimeric inhibins in the infantile female rat. Biol Reprod 65(6):1623–1633

  56. Ball EM, Mellor SL, Risbridger GP (2004) Cancer progression: is inhibin alpha from Venus or Mars? Cytokine Growth Factor Rev 15(5):291–296

  57. Kim YI, Park SW, Kwon HS et al (2017) Inhibin-alpha gene mutations and mRNA levels in human lymphoid and myeloid leukemia cells. Int J Oncol 50(4):1403–1412

  58. Schmitt JF, Millar DS, Pedersen JS et al (2002) Hypermethylation of the inhibin alpha-subunit gene in prostate carcinoma. Mol Endocrinol 16(2)213–220

  59. Huang M, Cheng YL, Zeng JT et al (2018) Inhibin alpha-subunit inhibits BMP9-induced osteogenic differentiation through blocking BMP/Smad signal and activating NF-kappaB signal in mesenchymal stem cells. J Cell Biochem 119(10):8271–8281

  60. He Z, Liang J, Wang B (2021) Inhibin, beta A regulates the transforming growth factor-beta pathway to promote malignant biological behaviour in colorectal cancer. Cell Biochem Funct 39(2)258–266

  61. Kleeff J, Ishiwata T, Friess H et al (1998) Concomitant over-expression of activin/inhibin beta subunits and their receptors in human pancreatic cancer. Int J Cancer 77(6)860–868

  62. Sawchenko PE, Plotsky PM, Pfeiffer SW et al (1988) Inhibin beta in central neural pathways involved in the control of oxytocin secretion. Nature 334(6183):615–617

  63. Sjoholm K, Palming J, Lystig TC et al (2006) The expression of inhibin beta B is high in human adipocytes, reduced by weight loss, and correlates to factors implicated in metabolic disease. Biochem Biophys Res Commun 344(4)1308–1314

  64. Cross JC, Baczyk D, Dobric N et al (2003) Genes, development and evolution of the placenta. Placenta 24(2–3):123–130

  65. Luo L, Ye G, Nadeem L et al (2012) MicroRNA-378a-5p promotes trophoblast cell survival, migration and invasion by targeting Nodal. J Cell Sci 125(13)3124–3132

  66. Sharma M, McFarlane C, Kambadur R et al (2015) Myostatin: expanding horizons. IUBMB Life 67(8):589–600

  67. Wei Q, Holle A, Li J et al (2020) BMP-2 Signaling and Mechanotransduction Synergize to Drive Osteogenic Differentiation via YAP/TAZ. Adv Sci (Weinh) 7(15):1902931

  68. Park SY, Kim KH, Kim S et al (2019) BMP-2 Gene Delivery-Based Bone Regeneration in Dentistry. Pharmaceutics 11(8)

  69. Skovrlj B, Koehler SM, Anderson PA et al (2015) Association Between BMP-2 and Carcinogenicity. Spine (Phila Pa 1976) 40(23):1862–1871

  70. Matzelle MM, Shaw AT, Baum R et al (2016) Inflammation in arthritis induces expression of BMP3, an inhibitor of bone formation. Scand J Rheumatol 45(5):379–383

  71. Gamer LW, Cox K, Carlo JM et al (2009) Overexpression of BMP3 in the developing skeleton alters endochondral bone formation resulting in spontaneous rib fractures. Dev Dyn 238(9):2374–2381

  72. Yu X, Gu P, Huang Z et al (2017) Reduced expression of BMP3 contributes to the development of pulmonary fibrosis and predicts the unfavorable prognosis in IIP patients. Oncotarget 8(46):80531–80544

  73. Kisiel JB, Li J, Zou H et al (2013) Methylated Bone Morphogenetic Protein 3 (BMP3) Gene: Evaluation of Tumor Suppressor Function and Biomarker Potential in Biliary Cancer. J Mol Biomark Diagn 4(145):1000145

    PubMed  PubMed Central  Google Scholar 

  74. Kawabata T, Otsuka T, Fujita K et al (2017) Suppression by HSP90 inhibitors of BMP4stimulated osteoprotegerin synthesis in osteoblasts: Attenuation of p70 S6 kinase. Mol Med Rep 16(6)8507–8512

  75. Yokoyama Y, Watanabe T, Tamura Y et al (2017) Autocrine BMP-4 Signaling Is a Therapeutic Target in Colorectal Cancer. Cancer Res 77(15)4026–4038

  76. Son JW, Jang EH, Kim MK et al (2011) Serum BMP-4 levels in relation to arterial stiffness and carotid atherosclerosis in patients with Type 2 diabetes. Biomark Med 5(6)827–835

  77. Mailhot G, Yang M, Mason-Savas A et al (2008) BMP-5 expression increases during chondrocyte differentiation in vivo and in vitro and promotes proliferation and cartilage matrix synthesis in primary chondrocyte cultures. J Cell Physiol 214(1):56–64

  78. Beck HN, Drahushuk K, Jacoby DB et al (2001) Bone morphogenetic protein-5 (BMP-5) promotes dendritic growth in cultured sympathetic neurons. BMC Neurosci 2:12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bramlage CP, Muller GA, Tampe B et al (2011) The role of bone morphogenetic protein-5 (BMP-5) in human nephrosclerosis. J Nephrol 24(5):647–655

  80. Gruber R, Graninger W, Bobacz K et al (2003) BMP-6-induced osteogenic differentiation of mesenchymal cell lines is not modulated by sex steroids and resveratrol. Cytokine 23(4–5):133–137

  81. Verhamme FM, De Smet EG, Van Hooste W et al (2019) Bone morphogenetic protein 6 (BMP-6) modulates lung function, pulmonary iron levels and cigarette smoke-induced inflammation. Mucosal Immunol 12(2):340–351

  82. Hu F, Zhang Y, Li M et al (2016) BMP-6 inhibits the metastasis of MDA-MB-231 breast cancer cells by regulating MMP-1 expression. Oncol Rep 35(3):1823–1830

  83. Toma K, Otsuka F, Oguni K et al (2016) BMP-6 modulates somatostatin effects on luteinizing hormone production by gonadrotrope cells. Peptides 76:96–101

    Article  CAS  PubMed  Google Scholar 

  84. Liu L, Wang Y, Yan R et al (2019) BMP-7 inhibits renal fibrosis in diabetic nephropathy via miR-21 downregulation. Life Sci 238:116957

    Article  CAS  PubMed  Google Scholar 

  85. Aluganti NC, Singla DK (2020) The Role of Bone Morphogenetic Protein 7 (BMP-7) in Inflammation in Heart Diseases. Cells 9(2)

  86. Mathavan N, Raina DB, Tagil M et al (2020) Longitudinal in vivo monitoring of callus remodeling in BMP-7- and Zoledronate-treated fractures. J Orthop Res 38(9):1905–1913

  87. Tasli PN, Aydin S, Yalvac ME et al (2014) Bmp 2 and bmp 7 induce odonto- and osteogenesis of human tooth germ stem cells. Appl Biochem Biotechnol 172(6):3016–3025

  88. 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(4):714–718

  89. Manson SR, Austin PF, Guo Q et al (2015) BMP-7 Signaling and its Critical Roles in Kidney Development, the Responses to Renal Injury, and Chronic Kidney Disease. Vitam Horm 99:91–144

    Article  CAS  PubMed  Google Scholar 

  90. Urisarri A, Gonzalez-Garcia I, Estevez-Salguero A et al (2021) BMP8 and activated brown adipose tissue in human newborns. Nat Commun 12(1):5274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wang XJ, Lian TY, Jiang X et al (2019) Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension. Eur Respir J 53(3)

  92. Tang N, Rao S, Ying Y et al (2020) New insights into BMP9 signaling in organ fibrosis. Eur J Pharmacol 882:173291

    Article  CAS  PubMed  Google Scholar 

  93. Viallard C, Audiger C, Popovic N et al (2020) BMP9 signaling promotes the normalization of tumor blood vessels. Oncogene 39(14):2996–3014

  94. Xiao H, Wang X, Wang C et al (2020) BMP9 exhibits dual and coupled roles in inducing osteogenic and angiogenic differentiation of mesenchymal stem cells. Biosci Rep 40(6)

  95. Neuhaus H, Rosen V, Thies RS (1999) Heart specific expression of mouse BMP-10 a novel member of the TGF-beta superfamily. Mech Dev 80(2):181–184

  96. Ye L, Bokobza S, Li J et al (2010) Bone morphogenetic protein-10 (BMP-10) inhibits aggressiveness of breast cancer cells and correlates with poor prognosis in breast cancer. Cancer Sci 101(10):2137–2144

  97. Karkera JD, Lee JS, Roessler E et al (2007) Loss-of-function mutations in growth differentiation factor-1 (GDF1) are associated with congenital heart defects in humans. Am J Hum Genet 81(5):987–994

  98. Li Q, Ling Y, Yu L (2012) GDF3 inhibits the growth of breast cancer cells and promotes the apoptosis induced by Taxol. J Cancer Res Clin Oncol 138(6):1073–1079

  99. Andersson O, Bertolino P, Ibanez CF (2007) Distinct and cooperative roles of mammalian Vg1 homologs GDF1 and GDF3 during early embryonic development. Dev Biol 311(2):500–511

  100. Mounier R, Chazaud B (2017) [PPARgamma transcription factor controls in anti-inflammatory macrophages the expression of GDF3 that stimulates myogenic cell fusion during skeletal muscle regeneration]. Med Sci (Paris) 33(5):466–469

  101. Li X, Zheng Y, Zheng Y et al (2018) Circular RNA CDR1as regulates osteoblastic differentiation of periodontal ligament stem cells via the miR-7/GDF5/SMAD and p38 MAPK signaling pathway. Stem Cell Res Ther 9(1):232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhang W, Wu X, Pei Z et al (2019) GDF5 Promotes White Adipose Tissue Thermogenesis via p38 MAPK Signaling Pathway. DNA Cell Biol 38(11):1303–1312

  103. Lettre G (2017) The osteoarthritis and height GDF5 locus yields its secrets. Nat Genet 49(8):1165–1166

  104. Sullivan AM, O'Keeffe GW (2005) The role of growth/differentiation factor 5 (GDF5) in the induction and survival of midbrain dopaminergic neurones: relevance to Parkinson's disease treatment. J Anat 207(3):219–226

  105. Clendenning DE, Mortlock DP (2012) The BMP ligand Gdf6 prevents differentiation of coronal suture mesenchyme in early cranial development. PLoS ONE 7(5):e36789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Asai-Coakwell M, French CR, Berry KM et al (2007) GDF6, a novel locus for a spectrum of ocular developmental anomalies. Am J Hum Genet 80(2):306–315

  107. Becker J, May A, Gerges C et al (2016) The Barrett-associated variants at GDF7 and TBX5 also increase esophageal adenocarcinoma risk. Cancer Med 5(5):888–891

  108. Zhou Y, Liu S, Wang W et al (2021) The miR-204-5p/FOXC1/GDF7 axis regulates the osteogenic differentiation of human adipose-derived stem cells via the AKT and p38 signalling pathways. Stem Cell Res Ther 12(1):64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Belli M, Shimasaki S (2018) Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function. Vitam Horm 107:317–348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Li S, Nie EH, Yin Y et al (2015) GDF10 is a signal for axonal sprouting and functional recovery after stroke. Nat Neurosci 18(12):1737–1745

  111. Zhou T, Yu L, Huang J et al (2019) GDF10 inhibits proliferation and epithelial-mesenchymal transition in triple-negative breast cancer via upregulation of Smad7. Aging (Albany NY) 11(10):3298–3314

  112. Rochette L, Mazini L, Meloux A et al (2020) Anti-Aging Effects of GDF11 on Skin. Int J Mol Sci 21(7)

  113. Simoni-Nieves A, Gerardo-Ramirez M, Pedraza-Vazquez G et al (2019) GDF11 Implications in Cancer Biology and Metabolism. Facts and Controversies. Front Oncol 9:1039

  114. Zhang YH, Pan LH, Pang Y et al (2018) GDF11/BMP11 as a novel tumor marker for liver cancer. Exp Ther Med 15(4):3495–3500

  115. Rochette L, Malka G (2019) Neuroprotective Potential of GDF11: Myth or Reality?" Int J Mol Sci 20(14)

  116. Emmerson PJ, Duffin KL, Chintharlapalli S et al (2018) GDF15 and Growth Control. Front Physiol 9:1712

    Article  PubMed  PubMed Central  Google Scholar 

  117. Baek SJ, Eling T (2019) Growth differentiation factor 15 (GDF15): A survival protein with therapeutic potential in metabolic diseases. Pharmacol Ther 198:46–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Zhang Y, Jiang M, Nouraie M et al (2019) GDF15 is an epithelial-derived biomarker of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 317(4):L510-L521

  119. Ahmed DS, Isnard S, Lin J et al (2021) GDF15/GFRAL Pathway as a Metabolic Signature for Cachexia in Patients with Cancer. J Cancer 12(4):1125–1132

  120. Li C, Wang J, Kong J et al (2016) GDF15 promotes EMT and metastasis in colorectal cancer. Oncotarget 7(1):860–872

  121. Liu H, Huang Y, Lyu Y et al (2021) GDF15 as a biomarker of ageing. Exp Gerontol 146:111228

    Article  CAS  PubMed  Google Scholar 

  122. Dewailly D, Laven J (2019) AMH as the primary marker for fertility. Eur J Endocrinol 181(6):D45-D51

  123. Saijoh Y, Adachi H, Mochida K et al (1999) Distinct transcriptional regulatory mechanisms underlie left-right asymmetric expression of lefty-1 and lefty-2. Genes Dev 13(3):259–269

  124. Alowayed N, Salker MS, Zeng N et al (2016) LEFTY2 Controls Migration of Human Endometrial Cancer Cells via Focal Adhesion Kinase Activity (FAK) and miRNA-200a. Cell Physiol Biochem 39(3):815–826

  125. Zabala M, Lobo NA, Antony J et al (2020) LEFTY1 Is a Dual-SMAD Inhibitor that Promotes Mammary Progenitor Growth and Tumorigenesis. Cell Stem Cell 27(2):284–299

  126. Yang S, Zhong C, Frenkel B et al (2005) Diverse biological effect and Smad signaling of bone morphogenetic protein 7 in prostate tumor cells. Cancer Res 65(13):5769–5777

  127. Dzietczenia J, Wrobel T, Jazwiec B et al (2010) Expression of bone morphogenetic proteins (BMPs) receptors in patients with B-cell chronic lymphocytic leukemia (B-CLL). Int J Lab Hematol 32(6 Pt 1):e217-e221

  128. Tang N, Song WX, Luo J et al (2008) Osteosarcoma development and stem cell differentiation. Clin Orthop Relat Res 466(9):2114–2130

  129. Zhou N, Li Q, Lin X et al (2016) BMP2 induces chondrogenic differentiation, osteogenic differentiation and endochondral ossification in stem cells. Cell Tissue Res 366(1):101–111

  130. Qi D, Tian X, Wang Y et al (2019) BMP2 variants in the risk of ankylosing spondylitis. J Cell Biochem

  131. Huang F, Cao Y, Wu G et al (2020) BMP2 signalling activation enhances bone metastases of non-small cell lung cancer. J Cell Mol Med 24(18):10768–10784

  132. Xu F, Liu C, Zhou D et al (2016) TGF-beta/SMAD Pathway and Its Regulation in Hepatic Fibrosis. J Histochem Cytochem 64(3):157–167

  133. Bobik A (2006) Transforming growth factor-betas and vascular disorders. Arterioscler Thromb Vasc Biol 26(8):1712–1720

  134. Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113(6):685–700

  135. Massague J, Seoane J, Wotton D (2005) Smad transcription factors. Genes Dev 19(23):2783–2810

  136. Miyazawa K, Miyazono K (2017) Regulation of TGF-beta Family Signaling by Inhibitory Smads. Cold Spring Harb Perspect Biol 9(3)

  137. Chen G, Deng C, Li YP (2012) TGF-beta and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci 8(2):272–288

  138. Abe E (2006) Function of BMPs and BMP antagonists in adult bone. Ann N Y Acad Sci 1068:41–53

    Article  CAS  PubMed  Google Scholar 

  139. Javed A, Bae JS, Afzal F et al (2008) Structural coupling of Smad and Runx2 for execution of the BMP2 osteogenic signal. J Biol Chem 283(13):8412–8422

  140. Chen X, Xiao F, Wang Y et al (2012) Structure-activity relationship study of WSS25 derivatives with anti-angiogenesis effects. Glycoconj J 29(5–6)389–398

  141. Keller S, Nickel J, Zhang JL et al (2004) Molecular recognition of BMP-2 and BMP receptor IA. Nat Struct Mol Biol 11(5):481–488

  142. Kamiya N, Kobayashi T, Mochida Y et al (2010) Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts. J Bone Miner Res 25(2):200–210

  143. Wang J, Guo J, Liu J et al (2014) BMP-functionalised coatings to promote osteogenesis for orthopaedic implants. Int J Mol Sci 15(6):10150–10168

  144. Kiwanuka E, Junker JP, Eriksson E (2017) Transforming growth factor beta1 regulates the expression of CCN2 in human keratinocytes via Smad-ERK signalling. Int Wound J 14(6):1006–1018

  145. 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(1):24–37

  146. Noth U, Tuli R, Seghatoleslami R et al (2003) Activation of p38 and Smads mediates BMP-2 effects on human trabecular bone-derived osteoblasts. Exp Cell Res 291(1):201–211

  147. Gersbach CA, Guldberg RE, Garcia AJ (2007) In vitro and in vivo osteoblastic differentiation of BMP-2- and Runx2-engineered skeletal myoblasts. J Cell Biochem 100(5):1324–1336

  148. Keyvani-Ghamsari S, Khorsandi K, Rasul A et al (2021) Current understanding of epigenetics mechanism as a novel target in reducing cancer stem cells resistance. Clin Epigenetics 13(1):120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Wang L, Park P, La Marca F et al (2013) Bone formation induced by BMP-2 in human osteosarcoma cells. Int J Oncol 43(4):1095–1102

  150. 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(5):457–463

  151. 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(6):1013–1024

  152. Persano L, Pistollato F, Rampazzo E et al (2012) BMP2 sensitizes glioblastoma stem-like cells to Temozolomide by affecting HIF-1alpha stability and MGMT expression. Cell Death Dis 3:e412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Huang P, Chen A, He W et al (2017) BMP-2 induces EMT and breast cancer stemness through Rb and CD44. Cell Death Discov 3:17039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Zhang G, Huang P, Chen A et al (2018) How BMP-2 induces EMT and breast cancer stemness through Rb and CD44? Cell Death Dis 9(2):20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. 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 36(12):9475–9486

  156. Takada I, Yogiashi Y, Kato S (2012) Signaling Crosstalk between PPARgamma and BMP2 in Mesenchymal Stem Cells. PPAR Res 2012:607141

    Article  PubMed  PubMed Central  Google Scholar 

  157. Abolarinwa BA, Ibrahim RB, Huang YH (2019) Conceptual Development of Immunotherapeutic Approaches to Gastrointestinal Cancer. Int J Mol Sci 20(18)

  158. Saitoh M (2018) Involvement of partial EMT in cancer progression. J Biochem 164(4):257–264

  159. Gabryanczyk A, Klimczak S, Szymczak-Pajor I et al (2021) Is Vitamin D Deficiency Related to Increased Cancer Risk in Patients with Type 2 Diabetes Mellitus? Int J Mol Sci 22(12)

  160. Singh M, Yelle N, Venugopal C et al (2018) EMT: Mechanisms and therapeutic implications. Pharmacol Ther 182:80–94

    Article  CAS  PubMed  Google Scholar 

  161. Aiello NM, Kang Y (2019) Context-dependent EMT programs in cancer metastasis. J Exp Med 216(5):1016–1026

  162. 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(3):525–534

  163. Wang MH, Zhou XM, Zhang MY et al (2017) BMP2 promotes proliferation and invasion of nasopharyngeal carcinoma cells via mTORC1 pathway. Aging (Albany NY) 9(4):1326–1340

  164. Liu J, Ben QW, Yao WY et al (2012) BMP2 induces PANC-1 cell invasion by MMP-2 overexpression through ROS and ERK. Front Biosci (Landmark Ed) 17(7):2541–2549

  165. Wu CJ, Sundararajan V, Sheu BC et al (2019) Activation of STAT3 and STAT5 Signaling in Epithelial Ovarian Cancer Progression: Mechanism and Therapeutic Opportunity. Cancers (Basel) 12(1)

  166. Raida M, Heymann AC, Gunther C et al (2006) Role of bone morphogenetic protein 2 in the crosstalk between endothelial progenitor cells and mesenchymal stem cells. Int J Mol Med 18(4):735–739

  167. Langenfeld EM, Langenfeld J (2004) Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors. Mol Cancer Res 2(3):141–149

  168. 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(3):319–326

  169. Feng PC, Ke XF, Kuang HL et al (2019) BMP2 secretion from hepatocellular carcinoma cell HepG2 enhances angiogenesis and tumor growth in endothelial cells via activation of the MAPK/p38 signaling pathway. Stem Cell Res Ther 10(1):237

    Article  PubMed  PubMed Central  Google Scholar 

  170. Becker V, Hui X, Nalbach L et al (2021) Linalool inhibits the angiogenic activity of endothelial cells by downregulating intracellular ATP levels and activating TRPM8. Angiogenesis 24(3):613–630

  171. Wang P, Zhang L, Yao J et al (2015) An arabinogalactan from flowers of Panax notoginseng inhibits angiogenesis by BMP2/Smad/Id1 signaling. Carbohydr Polym 121:328–335

    Article  CAS  PubMed  Google Scholar 

  172. 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(42):32638–32646

  173. Chen M, Liu H, Li Z et al (2021) Mechanism of PKM2 affecting cancer immunity and metabolism in Tumor Microenvironment. J Cancer 12(12):3566–3574

  174. Smith MG, Hold GL, Tahara E et al (2006) Cellular and molecular aspects of gastric cancer. World J Gastroenterol 12(19):2979–2990

  175. Chapellier M, Bachelard-Cascales E, Schmidt X et al (2015) Disequilibrium of BMP2 levels in the breast stem cell niche launches epithelial transformation by overamplifying BMPR1B cell response. Stem Cell Reports 4(2):239–254

  176. McLean K, Gong Y, Choi Y et al (2011) Human ovarian carcinoma-associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production. J Clin Invest 121(8):3206–3219

  177. Rubio R, Abarrategi A, Garcia-Castro J et al (2014) Bone environment is essential for osteosarcoma development from transformed mesenchymal stem cells. Stem Cells 32(5):1136–1148

  178. Avnet S, Di Pompo G, Chano T et al (2017) Cancer-associated mesenchymal stroma fosters the stemness of osteosarcoma cells in response to intratumoral acidosis via NF-kappaB activation. Int J Cancer 140(6):1331–1345

  179. Engin AB, Nikitovic D, Neagu M et al (2017) Mechanistic understanding of nanoparticles’ interactions with extracellular matrix: the cell and immune system. Part Fibre Toxicol 14(1):22

    Article  PubMed  PubMed Central  Google Scholar 

  180. Chouaib S, Messai Y, Couve S et al (2012) Hypoxia promotes tumor growth in linking angiogenesis to immune escape. Front Immunol 3:21

    Article  PubMed  PubMed Central  Google Scholar 

  181. Zara JN, Siu RK, Zhang X et al (2011) High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo. Tissue Eng Part A 17(9–10):1389–1399

  182. Wu G, Huang F, Chen Y et al (2020) High Levels of BMP2 Promote Liver Cancer Growth via the Activation of Myeloid-Derived Suppressor Cells. Front Oncol 10:194

    Article  PubMed  PubMed Central  Google Scholar 

  183. Chen Z, Wu C, Gu W et al (2014) Osteogenic differentiation of bone marrow MSCs by beta-tricalcium phosphate stimulating macrophages via BMP2 signalling pathway. Biomaterials 35(5):1507–1518

  184. Wang S, Jiang H, Zheng C et al (2022) Secretion of BMP-2 by tumor-associated macrophages (TAM) promotes microcalcifications in breast cancer. BMC Cancer 22(1):34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all participants involved in this research.

Funding

This work was supported by the National Natural Science Foundation of China (No. 21777060), the Horizontal Project of Jiangsu Medical Vocational College (jcyxhxkt2021-01), and the Biology Discipline Team (jdxktd-2019003).

Author information

Author notes

  1. Tong-tong Li and Yong-wei Lai contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, Jiamusi University, Jiamusi, 154007, China

    Tong-tong Li, Yong-wei Lai, Xu Han, Xin Niu & Peng-xia Zhang

  2. Department of Pathology and Pathophysiology, Jiangsu Vocational College of Medicine, Yancheng, 224005, Jiangsu, China

    Tong-tong Li

  3. Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Heilongjiang Province 154000, Jiamusi, People’s Republic of China

    Peng-xia Zhang

Authors
  1. Tong-tong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yong-wei Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xu Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xin Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peng-xia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Tongtong Li, Yongwei Lai and Xu Han wrote the main manuscript. Tongtong Li, Yongwei Lai, Xu Han, and Xin Niu compiled Figs. 1, 2, and 3. Pengxia Zhang was responsible for proofreading.

Corresponding author

Correspondence to Peng-xia Zhang.

Ethics declarations

Ethics approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study, informed consent was not needed.

Conflicts of interest

All authors declare no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Tt., Lai, Yw., Han, X. et al. BMP2 as a promising anticancer approach: functions and molecular mechanisms. Invest New Drugs 40, 1322–1332 (2022). https://doi.org/10.1007/s10637-022-01298-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-022-01298-4

Keywords

Search

Navigation