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Beyond TGFβ: roles of other TGFβ superfamily members in cancer

Nature Reviews Cancer volume 13, pages 328–341 (2013)Cite this article

Subjects

Key Points

  • The bone morphogenetic proteins (BMPs), activins, NODAL, and growth and differentiation factors (GDFs) (collectively referred to as BANGs) have essential roles in early embryonic development and in regulating tissue homeostasis in adults, frequently acting in gradients shaped by the activity of ligand antagonists. Their roles in human cancer frequently constitute a redeployment of their activities in embryonic development or a perturbation of their roles in tissue homeostasis.

  • Abberant BMP signalling disrupts stem cell self-renewal and differentiation, and can contribute to tumour formation. This may occur, for example, at the level of genetic or epigenetic changes resulting in the overexpression of BMP antagonists, or the loss of BMP receptors, ligands or SMAD4.

  • NODAL is not expressed in most normal adult tissues, but is expressed, along with the co-receptor CRIPTO, in many different tumours. It promotes phenotypic plasticity, which is important for tumour progression, and can positively regulate cancer stem cell self-renewal.

  • High BMP signalling provides a natural barrier to tumour progression and metastasis. In the primary tumour, BMP signalling inhibits epithelial-to-mesenchymal transition (EMT), which can prevent tumour invasion. At metastatic sites, high BMP signalling prevents tumour cell colonization by enforcing a dormant state. This can be reversed by tumour-expressed BMP antagonists.

  • BANGs sculpt the tumour microenvironment by promoting angiogenesis and suppressing immune responses.

  • Increased expression of BANGs in tumours and as a result of chemotherapy can contribute to severe complications of cancer such as cachexia, anaemia and bone loss.

  • Strategies are under development to target BANG signalling for therapeutic ends. These include inhibiting NODAL–CRIPTO signalling in the tumour cells, reducing tumour angiogenesis by inhibiting activin receptor-like kinase 1 (ALK1), and inhibiting activin receptors and myostatin to treat cachexia, anaemia and bone loss. Therapies that aim to increase BMP activity are also being developed.

Abstract

Much of the focus on the transforming growth factor-β (TGFβ) superfamily in cancer has revolved around the TGFβ ligands themselves. However, it is now becoming apparent that deregulated signalling by many of the other superfamily members also has crucial roles in both the development of tumours and metastasis. Furthermore, these signalling pathways are emerging as plausible therapeutic targets. Their roles in tumorigenesis frequently reflect their function in embryonic development or in adult tissue homeostasis, and their influence extends beyond the tumours themselves, to the tumour microenvironment and more widely to complications of cancer such as cachexia and bone loss.

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Figure 1: Signalling downstream of TGFβ superfamily ligands.
Figure 2: Roles for BMPs in normal tissue homeostasis and tumorigenesis.
Figure 3: Role of NODAL signalling in HESCs and in cancer.
Figure 4: Therapeutic approaches to targeting the BANGs in cancer.

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References

  1. Hardwick, J. C., Kodach, L. L., Offerhaus, G. J. & van den Brink, G. R. Bone morphogenetic protein signalling in colorectal cancer. Nature Rev. Cancer 8, 806–812 (2008).

    Article  CAS  Google Scholar 

  2. Oshimori, N. & Fuchs, E. The Harmonies played by TGF-β in stem cell biology. Cell Stem Cell 11, 751–764 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wu, M. Y. & Hill, C. S. TGF-β superfamily signaling in embryonic development and homeostasis. Dev. Cell 16, 329–343 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Huminiecki, L. et al. Emergence, development and diversification of the TGF-β signalling pathway within the animal kingdom. BMC Evol. Biol. 9, 28 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Pang, K., Ryan, J. F., Baxevanis, A. D. & Martindale, M. Q. Evolution of the TGF-β signaling pathway and its potential role in the ctenophore, Mnemiopsis leidyi. PLoS ONE 6, e24152 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Constam, D. B. & Robertson, E. J. Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases. J. Cell Biol. 144, 139–149 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Constam, D. B. & Robertson, E. J. SPC4/PACE4 regulates a TGFβ signaling network during axis formation. Genes Dev. 14, 1146–1155 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mueller, T. D. & Nickel, J. Promiscuity and specificity in BMP receptor activation. FEBS Lett. 586, 1846–1859 (2012).

    Article  CAS  PubMed  Google Scholar 

  9. Shi, Y. & Massague, J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113, 685–700 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Kang, J. S., Liu, C. & Derynck, R. New regulatory mechanisms of TGF-β receptor function. Trends Cell Biol. 19, 385–394 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Goumans, M. J. et al. Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFβ/ALK5 signaling. Mol. Cell 12, 817–828 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Daly, A. C., Randall, R. A. & Hill, C. S. Transforming growth factor β-induced Smad1/5 phosphorylation in epithelial cells is mediated by novel receptor complexes and is essential for anchorage-independent growth. Mol. Cell. Biol. 28, 6889–6902 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu, I. M. et al. TGFβ-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFβ switch. EMBO J. 28, 88–98 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Wrighton, K. H., Lin, X., Yu, P. B. & Feng, X. H. Transforming growth factor β can stimulate Smad1 phosphorylation independently of bone morphogenic protein receptors. J. Biol. Chem. 284, 9755–9763 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chu, G. C., Dunn, N. R., Anderson, D. C., Oxburgh, L. & Robertson, E. J. Differential requirements for Smad4 in TGFβ-dependent patterning of the early mouse embryo. Development 131, 3501–3512 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Levy, L. & Hill, C. S. Smad4 dependency defines two classes of transforming growth factor β (TGF-β) target genes and distinguishes TGF-β-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Mol. Cell. Biol. 25, 8108–8125 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gronroos, E. et al. Transforming growth factor β inhibits bone morphogenetic protein-induced transcription through novel phosphorylated Smad1/5-Smad3 complexes. Mol. Cell. Biol. 32, 2904–2916 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ross, S. & Hill, C. S. How the Smads regulate transcription. Int. J. Biochem. Cell Biol. 40, 383–408 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Chen, X., Rubock, M. J. & Whitman, M. A transcriptional partner for MAD proteins in TGF-β signalling. Nature 383, 691–696 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Bruce, D. L. & Sapkota, G. P. Phosphatases in SMAD regulation. FEBS Lett. 586, 1897–1905 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Schmierer, B. & Hill, C. S. TGFβ-SMAD signal transduction: molecular specificity and functional flexibility. Nature Rev. Mol. Cell Biol. 8, 970–982 (2007).

    Article  CAS  Google Scholar 

  22. Ramel, M. C. & Hill, C. S. Spatial regulation of BMP activity. FEBS Lett. 586, 1929–1941 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Massague, J. TGFβ signalling in context. Nature Rev. Mol. Cell Biol. 13, 616–630 (2012).

    Article  CAS  Google Scholar 

  24. Singh, A. M. et al. Signaling network crosstalk in human pluripotent cells: a Smad2/3-regulated switch that controls the balance between self-renewal and differentiation. Cell Stem Cell 10, 312–326 (2012). This paper explains the underlying mechanism that dictates whether activin signalling in HESCs induces pluripotency or differentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Levine, A. J., Levine, Z. J. & Brivanlou, A. H. GDF3 is a BMP inhibitor that can activate Nodal signaling only at very high doses. Dev. Biol. 325, 43–48 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Candia, A. F. et al. Cellular interpretation of multiple TGF-β signals: intracellular antagonism between activin/BVg1 and BMP-2/4 signaling mediated by Smads. Development 124, 4467–4480 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Itoh, S. & ten Dijke, P. Negative regulation of TGF-β receptor/Smad signal transduction. Curr. Opin. Cell Biol. 19, 176–184 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Galvin, K. E., Travis, E. D., Yee, D., Magnuson, T. & Vivian, J. L. Nodal signaling regulates the bone morphogenic protein pluripotency pathway in mouse embryonic stem cells. J. Biol. Chem. 285, 19747–19756 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mesnard, D., Guzman-Ayala, M. & Constam, D. B. Nodal specifies embryonic visceral endoderm and sustains pluripotent cells in the epiblast before overt axial patterning. Development 133, 2497–2505 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Arnold, S. J. & Robertson, E. J. Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo. Nature Rev. Mol. Cell Biol. 10, 91–103 (2009).

    Article  CAS  Google Scholar 

  31. Schier, A. F. Nodal signaling in vertebrate development. Annu. Rev. Cell Dev. Biol. 19, 589–621 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Bianco, C. et al. Role of Cripto-1 in stem cell maintenance and malignant progression. Am. J. Pathol. 177, 532–540 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pera, M. F. & Tam, P. P. Extrinsic regulation of pluripotent stem cells. Nature 465, 713–720 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Vallier, L. et al. Activin/Nodal signalling maintains pluripotency by controlling Nanog expression. Development 136, 1339–1349 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Miyazono, K., Kamiya, Y. & Morikawa, M. Bone morphogenetic protein receptors and signal transduction. J. Biochem. 147, 35–51 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Wagner, D. O. et al. BMPs: from bone to body morphogenetic proteins. Sci. Signal. 3, mr1 (2010).

    PubMed  Google Scholar 

  37. Strizzi, L., Hardy, K. M., Kirschmann, D. A., Ahrlund-Richter, L. & Hendrix, M. J. Nodal expression and detection in cancer: experience and challenges. Cancer Res. 72, 1915–1920 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Magee, J. A., Piskounova, E. & Morrison, S. J. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21, 283–296 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Blanpain, C. & Fuchs, E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nature Rev. Mol. Cell Biol. 10, 207–217 (2009).

    Article  CAS  Google Scholar 

  40. Bond, A. M., Bhalala, O. G. & Kessler, J. A. The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation. Dev. Neurobiol. 72, 1068–1084 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. He, X. C. et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-β-catenin signaling. Nature Genet. 36, 1117–1121 (2004). This paper demonstrates that conditional inactivation of ALK3 generates a mouse model of JPS and shows important antagonistic actions of BMP and WNT signalling on stem cell self-renewal.

    Article  CAS  PubMed  Google Scholar 

  42. Kosinski, C. et al. Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc. Natl Acad. Sci. USA 104, 15418–15423 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Waite, K. A. & Eng, C. From developmental disorder to heritable cancer: it's all in the BMP/TGF-β family. Nature Rev. Genet. 4, 763–773 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Jaeger, E. et al. Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nature Genet. 44, 699–703 (2012). This paper demonstrates that a genetic lesion leading to overexpression of the BMP antagonist gremlin 1 underlies hereditary mixed polyposis syndrome.

    Article  CAS  PubMed  Google Scholar 

  45. Haramis, A. P. et al. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science 303, 1684–1686 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Itasaki, N. & Hoppler, S. Crosstalk between Wnt and bone morphogenic protein signaling: a turbulent relationship. Dev. Dyn. 239, 16–33 (2010).

    CAS  PubMed  Google Scholar 

  47. Auclair, B. A., Benoit, Y. D., Rivard, N., Mishina, Y. & Perreault, N. Bone morphogenetic protein signaling is essential for terminal differentiation of the intestinal secretory cell lineage. Gastroenterology 133, 887–896 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Scheel, C. et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 145, 926–940 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Panchision, D. M. & McKay, R. D. The control of neural stem cells by morphogenic signals. Curr. Opin. Genet. Dev. 12, 478–487 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Piccirillo, S. G. et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444, 761–765 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Lee, J. et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 13, 69–80 (2008). This paper shows that ALK6 is epigenetically silenced in some human glioblastomas, causing reversion to an early embryonic BMP signalling pattern and the loss of inhibitory effects on the CSC population.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sneddon, J. B. et al. Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proc. Natl Acad. Sci. USA 103, 14842–14847 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Buijs, J. T. et al. The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation. Oncogene 31, 2164–2174 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Upadhyay, G. et al. Stem cell antigen-1 enhances tumorigenicity by disruption of growth differentiation factor-10 (GDF10)-dependent TGF-β signaling. Proc. Natl Acad. Sci. USA 108, 7820–7825 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhang, L. et al. BMP4 administration induces differentiation of CD133+ hepatic cancer stem cells, blocking their contributions to hepatocellular carcinoma. Cancer Res. 72, 4276–4285 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Gruber, T. A. et al. An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia. Cancer Cell 22, 683–697 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Quail, D. F., Siegers, G. M., Jewer, M. & Postovit, L. M. Nodal signalling in embryogenesis and tumourigenesis. Int. J. Biochem. Cell Biol. 45, 885–898 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Topczewska, J. M. et al. Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness. Nature Med. 12, 925–932 (2006). This was the first demonstration that NODAL is secreted by tumour cells, with the level of NODAL correlating with tumour aggressiveness.

    Article  CAS  PubMed  Google Scholar 

  60. Lawrence, M. G. et al. Reactivation of embryonic nodal signaling is associated with tumor progression and promotes the growth of prostate cancer cells. Prostate 71, 1198–1209 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Strizzi, L. et al. Potential for the embryonic morphogen Nodal as a prognostic and predictive biomarker in breast cancer. Breast Cancer Res. 14, R75 (2011).

    Article  Google Scholar 

  62. Spiller, C. M. et al. Endogenous Nodal signaling regulates germ cell potency during mammalian testis development. Development 139, 4123–4132 (2012).

    Article  CAS  PubMed  Google Scholar 

  63. Bianco, C. & Salomon, D. S. Targeting the embryonic gene Cripto-1 in cancer and beyond. Expert Opin. Ther. Pat. 20, 1739–1749 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lonardo, E. et al. Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. Cell Stem Cell 9, 433–446 (2011). This was the first demonstration that NODAL and activin signalling promotes self-renewal of CSCs.

    Article  CAS  PubMed  Google Scholar 

  65. Postovit, L. M. et al. Human embryonic stem cell microenvironment suppresses the tumorigenic phenotype of aggressive cancer cells. Proc. Natl Acad. Sci. USA 105, 4329–4334 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hardy, K. M. et al. Regulation of the embryonic morphogen Nodal by Notch4 facilitates manifestation of the aggressive melanoma phenotype. Cancer Res. 70, 10340–10350 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Costa, F. F. et al. Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment. Epigenomics 1, 387–398 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Seftor, R. E. et al. Tumor cell vasculogenic mimicry: from controversy to therapeutic promise. Am. J. Pathol. 181, 1115–1125 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Quail, D. F. et al. Embryonic protein nodal promotes breast cancer vascularization. Cancer Res. 72, 3851–3863 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. Lonardo, E., Frias-Aldeguer, J., Hermann, P. C. & Heeschen, C. Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness. Cell Cycle 11, 1282–1290 (2012).

    Article  CAS  PubMed  Google Scholar 

  71. Ocana, O. H. et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer prrx1. Cancer Cell 22, 709–724 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Tsai, J. H., Donaher, J. L., Murphy, D. A., Chau, S. & Yang, J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22, 725–736 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Brabletz, T. To differentiate or not--routes towards metastasis. Nature Rev. Cancer 12, 425–436 (2012).

    Article  CAS  Google Scholar 

  74. Polyak, K. & Weinberg, R. A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nature Rev. Cancer 9, 265–273 (2009).

    Article  CAS  Google Scholar 

  75. Buijs, J. T. et al. BMP7, a putative regulator of epithelial homeostasis in the human prostate, is a potent inhibitor of prostate cancer bone metastasis in vivo. Am. J. Pathol. 171, 1047–1057 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ding, Z. et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature 470, 269–273 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bailey, J. M., Singh, P. K. & Hollingsworth, M. A. Cancer metastasis facilitated by developmental pathways: Sonic hedgehog, Notch, and bone morphogenic proteins. J. Cell Biochem. 102, 829–839 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Gao, H. et al. The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 150, 764–779 (2012). This paper shows that tumour cells can upregulate BANG antagonists to overcome organ-specific BMP barriers to metastatic colonization.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kobayashi, A. et al. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J. Exp. Med. 208, 2641–2655 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Samavarchi-Tehrani, P. et al. Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 7, 64–77 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Tarragona, M. et al. Identification of NOG as a specific breast cancer bone metastasis-supporting gene. J. Biol. Chem. 287, 21346–21355 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Katsuno, Y. et al. Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway. Oncogene 27, 6322–6333 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Nishimori, H., Ehata, S., Suzuki, H. I., Katsuno, Y. & Miyazono, K. Prostate cancer cells and bone stromal cells mutually interact with each other through bone morphogenetic protein-mediated signals. J. Biol. Chem. 287, 20037–20046 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Cunha, S. I. & Pietras, K. ALK1 as an emerging target for antiangiogenic therapy of cancer. Blood 117, 6999–7006 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Cunha, S. I. et al. Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis. J. Exp. Med. 207, 85–100 (2010). This study implicated ALK1 ligands as key players in tumour angiogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hu-Lowe, D. D. et al. Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies. Cancer Res. 71, 1362–1373 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Strizzi, L. et al. Nodal as a biomarker for melanoma progression and a new therapeutic target for clinical intervention. Expert Rev. Dermatol. 4, 67–78 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Hedger, M. P., Winnall, W. R., Phillips, D. J. & de Kretser, D. M. The regulation and functions of activin and follistatin in inflammation and immunity. Vitam. Horm. 85, 255–297 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Antsiferova, M. et al. Activin enhances skin tumourigenesis and malignant progression by inducing a pro-tumourigenic immune cell response. Nature Commun. 2, 576 (2011).

    Article  CAS  Google Scholar 

  90. Roth, P. et al. GDF-15 contributes to proliferation and immune escape of malignant gliomas. Clin. Cancer Res. 16, 3851–3859 (2010).

    Article  CAS  PubMed  Google Scholar 

  91. Corre, J. et al. Bioactivity and prognostic significance of growth differentiation factor GDF15 secreted by bone marrow mesenchymal stem cells in multiple myeloma. Cancer Res. 72, 1395–1406 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Harada, K. et al. Serum immunoreactive activin A levels in normal subjects and patients with various diseases. J. Clin. Endocrinol. Metab. 81, 2125–2130 (1996).

    CAS  PubMed  Google Scholar 

  93. Vallet, S. et al. Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proc. Natl Acad. Sci. USA 107, 5124–5129 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhou, X. et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142, 531–543 (2010). This important preclinical study showed that neutralization of ACTRIIB ligands leads to dramatically prolonged survival in cancer-bearing mice by reversing adverse effects of BANGs on host tissues.

    Article  CAS  PubMed  Google Scholar 

  95. Fields, S. Z. et al. Activin receptor antagonists for cancer-related anemia and bone disease. Expert Opin. Investig. Drugs 22, 87–101 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Pellagatti, A. et al. Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients. Proc. Natl Acad. Sci. USA 104, 11406–11411 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Matzuk, M. M. et al. Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice. Proc. Natl Acad. Sci. USA 91, 8817–8821 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Johnen, H. et al. Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1. Nature Med. 13, 1333–1340 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Zimmers, T. A. et al. Induction of cachexia in mice by systemically administered myostatin. Science 296, 1486–1488 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Saad, F. et al. Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer 110, 1860–1867 (2007).

    Article  PubMed  Google Scholar 

  101. Baud'huin, M. et al. A soluble bone morphogenetic protein type IA receptor increases bone mass and bone strength. Proc. Natl Acad. Sci. USA 109, 12207–12212 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Pearsall, R. S. et al. A soluble activin type IIA receptor induces bone formation and improves skeletal integrity. Proc. Natl Acad. Sci. USA 105, 7082–7087 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Vogt, J., Traynor, R. & Sapkota, G. P. The specificities of small molecule inhibitors of the TGFβ and BMP pathways. Cell. Signal. 23, 1831–1842 (2011).

    Article  CAS  PubMed  Google Scholar 

  104. Rangel, M. C. et al. Role of Cripto-1 during epithelial-to-mesenchymal transition in development and cancer. Am. J. Pathol. 180, 2188–2200 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Akhurst, R. J. & Hata, A. Targeting the TGFβ signalling pathway in disease. Nature Rev. Drug Discov. 11, 790–811 (2012).

    Article  CAS  Google Scholar 

  106. Alison, M. R., Lin, W. R., Lim, S. M. & Nicholson, L. J. Cancer stem cells: in the line of fire. Cancer Treat. Rev. 38, 589–598 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. Lombardo, Y. et al. Bone morphogenetic protein 4 induces differentiation of colorectal cancer stem cells and increases their response to chemotherapy in mice. Gastroenterology 140, 297–309 (2011).

    Article  CAS  PubMed  Google Scholar 

  108. Ivanova, T. et al. Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer. Gut 62, 22–33 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. Antsiferova, M. & Werner, S. The bright and the dark sides of activin in wound healing and cancer. J. Cell Sci. 125, 3929–3937 (2012).

    CAS  PubMed  Google Scholar 

  110. Weigelt, B. & Downward, J. Genomic determinants of PI3K pathway inhibitor response in Cancer. Front. Oncol. 2, 109 (2012).

    PubMed  Google Scholar 

  111. Kodach, L. L. et al. Statins augment the chemosensitivity of colorectal cancer cells inducing epigenetic reprogramming and reducing colorectal cancer cell 'stemness' via the bone morphogenetic protein pathway. Gut 60, 1544–1553 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Kugimiya, F. et al. Mechanism of osteogenic induction by FK506 via BMP/Smad pathways. Biochem. Biophys. Res. Commun. 338, 872–879 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. van der Poel, H. G., Hanrahan, C., Zhong, H. & Simons, J. W. Rapamycin induces Smad activity in prostate cancer cell lines. Urol. Res. 30, 380–386 (2003).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank members of the Hill and Wakefield laboratories, K. Hunter, E. Sahai, M. Sporn, S. Yuspa and Y. Zhang for useful comments on the manuscript. C.S.H. acknowledges Cancer Research UK and the European Commission Network of Excellence EpiGeneSys (HEALTH-F4-2010-257082) for funding. L.M.W. acknowledges the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research for funding.

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Authors and Affiliations

  1. Laboratory of Cancer Biology and Genetics, National Cancer Institute, Building 37, Room 4032A, 37 Convent Drive, MSC 4255, Bethesda, 20892–4255, Maryland, USA

    Lalage M. Wakefield

  2. Developmental Signalling Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3LY, UK

    Caroline S. Hill

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  1. Lalage M. Wakefield
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Correspondence to Lalage M. Wakefield or Caroline S. Hill.

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Glossary

Mesoderm

The middle germ layer of the developing embryo. Gives rise to the musculoskeletal, vascular and urinogenital systems, and to connective tissue (including that of the dermis).

Endoderm

The innermost of the three germ layers of the developing embryo. It differentiates to form the linings of two tubes in the body: the digestive tube, which extends the entire length of the body and the respiratory tube. Buds from the digestive tube form the liver, gall bladder and pancreas.

Cell-sorting behaviour

The process by which a heterogeneous population of cells with different attractive and repellent properties migrate and sort themselves into homogeneous populations.

Epithelial-to-mesenchymal transition

(EMT). Conversion from an epithelial to a mesenchymal phenotype, which is a normal process in embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

Mesendoderm

The term given to an embryonic tissue layer that can differentiate into mesoderm and endoderm.

Ectoderm

The outermost of the three germ layers of the developing embryo. It differentiates to form the nervous system, tooth enamel, the epidermis, hair, nails and the lining of mouth, anus, nostrils and sweat glands.

Hamartomatous polyps

Intestinal polyps in patients with juvenile polyposis syndrome. They are characterized by increased crypt formation and cell proliferation but otherwise normal epithelial cell maturation, and are associated with an abnormally expanded mesenchymal component with a pronounced inflammatory infiltrate. Unlike intestinal adenomas, they do not show epithelial dysplasia.

Mesenchymal-to epithelial transition

(MET). The conversion of non-polarized and motile mesenchymal cells into polarized epithelial cells.

Ligand traps

Chimeric proteins that typically contain the ligand-binding domain of a receptor coupled to the Fc domain of an immunoglobulin. This generates an antibody-like ligand antagonist with the ligand specificity and high affinity of the parent receptor, coupled with the in vivo stability and distribution characteristics of the parent immunoglobulin.

Osteoblast

A cell responsible for bone formation.

Osteoclast

A cell that breaks down mineralized bone and that is responsible for bone resorption.

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Wakefield, L., Hill, C. Beyond TGFβ: roles of other TGFβ superfamily members in cancer. Nat Rev Cancer 13, 328–341 (2013). https://doi.org/10.1038/nrc3500

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