TGFβ signalling: a complex web in cancer progression (original) (raw)

• Blobe, G. C., Schiemann, W. P. & Lodish, H. F. Role of transforming growth factor β in human disease. N. Engl. J. Med. 342, 1350–1358 (2000).
  Article CAS PubMed Google Scholar
• Levy, L. & Hill, C. S. Alterations in components of the TGF-β superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev. 17, 41–58 (2006).
  Article CAS PubMed Google Scholar
• Markowitz, S. et al. Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338 (1995).
  Article CAS PubMed Google Scholar
• Bornstein, S. et al. Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. J. Clin. Invest. 119, 3408–3419 (2009).
  CAS PubMed PubMed Central Google Scholar
• Tsushima, H. et al. High levels of transforming growth factor β1 in patients with colorectal cancer: association with disease progression. Gastroenterology 110, 375–382 (1996).
  Article CAS PubMed Google Scholar
• Wikström, P., Stattin, P., Franck-Lissbrant, I., Damber, J. E. & Bergh, A. Transforming growth factor β1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer. Prostate 37, 19–29 (1998).
  Article PubMed Google Scholar
• Walker, R. A. & Dearing, S. J. Transforming growth factor β1 in ductal carcinoma in situ and invasive carcinomas of the breast. Eur. J. Cancer 28, 641–644 (1992).
  Article CAS PubMed Google Scholar
• Friedman, E. et al. High levels of transforming growth factor β1 correlate with disease progression in human colon cancer. Cancer Epidemiol. Biomarkers Prev. 4, 549–554 (1995).
  CAS PubMed Google Scholar
• Dalal, B. I., Keown, P. A. & Greenberg, A. H. Immunocytochemical localization of secreted transforming growth factor-β1 to the advancing edges of primary tumors and to lymph node metastases of human mammary carcinoma. Am. J. Pathol. 143, 381–389 (1993).
  CAS PubMed PubMed Central Google Scholar
• Picon, A., Gold, L. I., Wang, J., Cohen, A. & Friedman, E. A subset of metastatic human colon cancers expresses elevated levels of transforming growth factor β1. Cancer Epidemiol. Biomarkers Prev. 7, 497–504 (1998).
  CAS PubMed Google Scholar
• Bierie, B. & Moses, H. L. Tumour microenvironment: TGFβ: the molecular Jekyll and Hyde of cancer. Nature Rev. Cancer 6, 506–520 (2006). This Review covers the roles of TGFβ signalling in the tumour microenvironment and discusses the paradoxical effects of this cytokine in tumour progression: tumour promotion compared with tumour suppression.
  Article CAS PubMed Google Scholar
• Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A. K. & Flavell, R. A. Transforming growth factor-β regulation of immune responses. Annu. Rev. Immunol. 24, 99–146 (2006).
  Article CAS PubMed Google Scholar
• Heldin, C. H., Miyazono, K. & ten Dijke, P. TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 390, 465–471 (1997).
  Article CAS PubMed Google Scholar
• 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
• Feng, X. H. & Derynck, R. Specificity and versatility in TGF-β signaling through Smads. Annu. Rev. Cell Dev. Biol. 21, 659–693 (2005).
  Article CAS PubMed Google Scholar
• Annes, J. P., Munger, J. S. & Rifkin, D. B. Making sense of latent TGFβ activation. J. Cell Sci. 116, 217–224 (2003).
  Article CAS PubMed Google Scholar
• Rifkin, D. B. Latent transforming growth factor-β (TGF-β) binding proteins: orchestrators of TGF-β availability. J. Biol. Chem. 280, 7409–7412 (2005).
  Article CAS PubMed Google Scholar
• 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
• 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
• Derynck, R. & Zhang, Y. E. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 425, 577–584 (2003).
  Article CAS PubMed Google Scholar
• Miyazawa, K., Shinozaki, M., Hara, T., Furuya, T. & Miyazono, K. Two major Smad pathways in TGF-β superfamily signalling. Genes Cells 7, 1191–1204 (2002).
  Article CAS PubMed Google Scholar
• Koinuma, D. et al. Chromatin immunoprecipitation on microarray analysis of Smad2/3 binding sites reveals roles of ETS1 and TFAP2A in transforming growth factor β signaling. Mol. Cell. Biol. 29, 172–186 (2009).
  Article CAS PubMed Google Scholar
• Koinuma, D. et al. Promoter-wide analysis of Smad4 binding sites in human epithelial cells. Cancer Sci. 100, 2133–2142 (2009).
  Article CAS PubMed Google Scholar
• Lin, X. Chen, Y. G. & Feng, X. H. in The TGF-β Family (eds Derynck, R. & Miyazono, K.) 287–332 (Cold Spring Harbor Laboratory Press, New York, 2008).
  Google Scholar
• Ikushima, H. et al. An Id-like molecule, HHM, is a synexpression group-restricted regulator of TGF-β signalling. EMBO J. 27, 2955–2965 (2008). This paper suggests a new mechanism for regulating some of the TGFβ-induced cellular responses. HHM targets some of the Smad-binding transcriptional cofactors and regulates TGFβ signalling in a synexpression group-selective manner.
  Article CAS PubMed PubMed Central Google Scholar
• Massague, J. TGFβ in cancer. Cell 134, 215–230 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Ikushima, H. & Miyazono, K. Cellular context-dependent “colors” of transforming growth factor-β signaling. Cancer Sci. 101, 306–312 (2010).
  Article CAS PubMed Google Scholar
• Janknecht, R., Wells, N. J. & Hunter, T. TGF-β-stimulated cooperation of Smad proteins with the coactivators CBP/p300. Genes Dev. 12, 2114–2119 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Feng, X. H., Zhang, Y., Wu, R. Y. & Derynck, R. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for Smad3 in TGF-β-induced transcriptional activation. Genes Dev. 12, 2153–2163 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, C. R., Kang, Y., Siegel, P. M. & Massague, J. E2F4/5 and p107 as Smad cofactors linking the TGFβ receptor to c-myc repression. Cell 110, 19–32 (2002).
  Article CAS PubMed Google Scholar
• Moustakas, A. & Heldin, C. H. Non-Smad TGF-β signals. J. Cell Sci. 118, 3573–3584 (2005).
  Article CAS PubMed Google Scholar
• Zhang, Y. E. Non-Smad pathways in TGF-β signaling. Cell Res. 19, 128–139 (2009).
  Article CAS PubMed Google Scholar
• Datto, M. B. et al. Transforming growth factor β induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc. Natl Acad. Sci. USA 92, 5545–5549 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Hannon, G. J. & Beach, D. p15INK4B is a potential effector of TGF-β-induced cell cycle arrest. Nature 371, 257–261 (1994).
  Article CAS PubMed Google Scholar
• Yagi, K. et al. c-myc is a downstream target of the Smad pathway. J. Biol. Chem. 277, 854–861 (2002).
  Article CAS PubMed Google Scholar
• Azar, R., Alard, A., Susini, C., Bousquet, C. & Pyronnet, S. 4E-BP1 is a target of Smad4 essential for TGFβ-mediated inhibition of cell proliferation. EMBO J. 28, 3514–3522 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Deheuninck, J. & Luo, K. Ski and SnoN, potent negative regulators of TGF-β signaling. Cell Res. 19, 47–57 (2009). This review discusses recent findings on the biological functions of SKI and SKIL and their mechanisms of action. It also addresses how expression levels of these factors are regulated.
  Article CAS PubMed Google Scholar
• Suzuki, H. et al. c-Ski inhibits the TGF-β signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements. Oncogene 23, 5068–5076 (2004).
  Article CAS PubMed Google Scholar
• Pan, D., Zhu, Q. & Luo, K. SnoN functions as a tumour suppressor by inducing premature senescence. EMBO J. 28, 3500–3513 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Zhu, Q. et al., Dual role of SnoN in mammalian tumorigenesis. Mol. Cell. Biol. 27, 324–339 (2007).
  Article CAS PubMed Google Scholar
• Heider, T. R., Lyman, S., Schoonhoven, R. & Behrns, K. E. Ski promotes tumor growth through abrogation of transforming growth factor-β signaling in pancreatic cancer. Ann. Surg. 246, 61–68 (2007).
  Article PubMed PubMed Central Google Scholar
• Morishita, K. et al. Activation of EVI1 gene expression in human acute myelogenous leukemias by translocations spanning 300–400 kilobases on chromosome band 3q26. Proc. Natl Acad. Sci. USA. 89, 3937–3941 (1992).
  Article CAS PubMed PubMed Central Google Scholar
• Kurokawa, M. et al. The oncoprotein Evi-1 represses TGF-β signalling by inhibiting Smad3. Nature 394, 92–96 (1998).
  Article CAS PubMed Google Scholar
• Mochizuki, N. et al. A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. Blood 96, 3209–3214 (2000).
  Article CAS PubMed Google Scholar
• Takahata, M. et al. SKI and MEL1 cooperate to inhibit transforming growth factor-β signal in gastric cancer cells. J. Biol. Chem. 284, 3334–3344 (2009). This paper reports that MEL1, a novel regulator of SKI, stabilizes an inactive SMAD3–SKI complex on the promoter of TGFβ target genes and inhibits TGFβ signalling in gastric cancer cells.
  Article CAS PubMed Google Scholar
• Ohno, H. Pathogenetic role of BCL6 translocation in B-cell non-Hodgkin's lymphoma. Histol. Histopathol. 19, 637–650 (2004).
  CAS PubMed Google Scholar
• Pasqualucci, L. et al. Molecular pathogenesis of non-Hodgkin's lymphoma: the role of Bcl-6. Leuk. Lymphoma 44, S5–S12 (2003).
  Article CAS PubMed Google Scholar
• Wang, D. et al. BCL6 represses Smad signaling in transforming growth factor-β resistance. Cancer Res. 68, 783–789 (2008). This paper indicates that overexpression of BCL6 contributes to the resistance of B cell lymphoma to TGFβ-mediated growth inhibition.
  Article CAS PubMed Google Scholar
• Mori, N. et al. Human T-cell leukemia virus type I oncoprotein Tax represses Smad-dependent transforming growth factor β signaling through interaction with CREB-binding protein/p300. Blood 97, 2137–2144 (2001).
  Article CAS PubMed Google Scholar
• Lee, D. K., Kim, B. C., Brady, J. N., Jeang, K. T. & Kim, S. J. Human T-cell lymphotropic virus type 1 tax inhibits transforming growth factor-β signaling by blocking the association of Smad proteins with Smad-binding element. J. Biol. Chem. 277, 33766–33775 (2002).
  Article CAS PubMed Google Scholar
• Ito, Y. & Miyazono, K. RUNX transcription factors as key targets of TGF-β superfamily signaling. Curr. Opin. Genet. Dev. 13, 43–47 (2003).
  Article CAS PubMed Google Scholar
• Chi, X. Z. et al. RUNX3 suppresses gastric epithelial cell growth by inducing p21WAF1/Cip1 expression in cooperation with transforming growth factor β-activated SMAD. Mol. Cell. Biol. 25, 8097–8107 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Yano, T. et al. The RUNX3 tumor suppressor upregulates Bim in gastric epithelial cells undergoing transforming growth factor β-induced apoptosis. Mol. Cell. Biol. 26, 4474–4488 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Battegay, E. J., Raines, E. W., Seifert, R. A., Bowen-Pope, D. F. & Ross, R. TGF-β induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop. Cell 63, 515–524 (1990).
  Article CAS PubMed Google Scholar
• Bruna, A. et al. High TGFβ-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cancer Cell 11, 147–160 (2007). This study demonstrates the pathological importance of epigenetic regulation of TGFβ signalling through methylation of Smad-binding elements in CpG islands of TGFβ target genes.
  Article CAS PubMed Google Scholar
• Matsuyama, S. et al. SB-431542 and Gleevec inhibit transforming growth factor-β-induced proliferation of human osteosarcoma cells. Cancer Res. 63, 7791–7798 (2003).
  CAS PubMed Google Scholar
• Lu, Q. R. et al. Oligodendrocyte lineage genes (OLIG) as molecular markers for human glial brain tumors. Proc. Natl Acad. Sci. USA 98, 10851–10856 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Jang, C. W. et al. TGF-β induces apoptosis through Smad-mediated expression of DAP-kinase. Nature Cell Biol. 4, 51–58 (2002).
  Article CAS PubMed Google Scholar
• Takekawa, M. et al. Smad-dependent GADD45β expression mediates delayed activation of p38 MAP kinase by TGF-β. EMBO J. 21, 6473–6482 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Ohgushi, M. et al. Transforming growth factor β-dependent sequential activation of Smad, Bim, and caspase-9 mediates physiological apoptosis in gastric epithelial cells. Mol. Cell. Biol. 25, 10017–10028 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Egle, A., Harris, A. W., Bouillet, P. & Cory, S. Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc. Natl Acad. Sci. USA 101, 6164–6169 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Ehata, S. et al., Transforming growth factor-β promotes survival of mammary carcinoma cells through induction of antiapoptotic transcription factor DEC1. Cancer Res. 67, 9694–9703 (2007).
  Article CAS PubMed Google Scholar
• Currie, M. J. et al. Expression of vascular endothelial growth factor D is associated with hypoxia inducible factor (HIF-1α) and the HIF-1α target gene DEC1, but not lymph node metastasis in primary human breast carcinomas. J. Clin. Pathol. 57, 829–834 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Chakrabarti, J. et al. The transcription factor DEC1 (stra13, SHARP2) is associated with the hypoxic response and high tumour grade in human breast cancers. Br. J. Cancer 91, 954–958 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Kiyono, K. et al. Autophagy is activated by TGF-β and potentiates TGF-β-mediated growth inhibition in human hepatocellular carcinoma cells. Cancer Res. 69, 8844–8852 (2009).
  Article CAS PubMed Google Scholar
• Eisenberg-Lerner, A. & Kimchi, A. The paradox of autophagy and its implication in cancer etiology and therapy. Apoptosis 14, 376–391 (2009).
  Article PubMed Google Scholar
• Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).
  Article CAS PubMed Google Scholar
• Iwasaki, H. & Suda, T. Cancer stem cells and their niche. Cancer Sci. 100, 1166–1172 (2009).
  Article CAS PubMed Google Scholar
• Yamazaki, S. et al. TGF-β as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation. Blood 113, 1250–1256 (2009).
  Article CAS PubMed Google Scholar
• Tang, B. et al. Transforming growth factor-β can suppress tumorigenesis through effects on the putative cancer stem or early progenitor cell and committed progeny in a breast cancer xenograft model. Cancer Res. 67, 8643–8652 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008). This paper is the first to report a link between EMT and stem cell characteristics.
  Article CAS PubMed PubMed Central Google Scholar
• Watabe, T. & Miyazono, K. Roles of TGF-β family signaling in stem cell renewal and differentiation. Cell Res. 19, 103–115 (2009).
  Article CAS PubMed Google Scholar
• Golestaneh, N. & Mishra, B. TGF-β, neuronal stem cells and glioblastoma. Oncogene 24, 5722–5730 (2005).
  Article CAS PubMed Google Scholar
• Peñuelas, S. et al. TGF-β increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 15, 315–327 (2009).
  Article PubMed CAS Google Scholar
• Ikushima, H. et al. Autocrine TGF-β signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell 5, 504–514 (2009). References 74 and 75 provide evidence that TGFβ signalling has crucial roles in the maintenance of self-renewal and tumorigenicity of glioma-initiating cells.
  Article CAS PubMed Google Scholar
• Kamachi, Y., Uchikawa, M. & Kondoh, H. Pairing SOX off: with partners in the regulation of embryonic development. Trends Genet. 16, 182–187 (2000).
  Article CAS PubMed Google Scholar
• Graham, V., Khudyakov, J., Ellis, P. & Pevny, L. SOX2 functions to maintain neural progenitor identity. Neuron 39, 749–765 (2003).
  Article CAS PubMed Google Scholar
• Ferri, A. L. et al. Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. Development 131, 3805–3819 (2004).
  Article CAS PubMed Google Scholar
• Bao, S. et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006).
  Article CAS PubMed Google Scholar
• Liu, G. et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol. Cancer 5, 67 (2006).
  Article PubMed PubMed Central CAS Google Scholar
• Hau, P. et al. Inhibition of TGF-β2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies. Oligonucleotides 17, 201–212 (2007).
  Article CAS PubMed Google Scholar
• Lim, D. A. et al. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28, 713–726 (2000).
  Article CAS PubMed Google Scholar
• 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
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Naka, K. et al. TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463, 676–680 (2010). This study shows that TGFβ signalling has a crucial role in the maintenance of leukaemia-initiating cells. It suggests that inhibition of the TGFβ pathway might represent a new therapeutic approach for patients with CML.
  Article CAS PubMed Google Scholar
• Hasegawa, Y. et al. Transforming growth factor-β1 level correlates with angiogenesis, tumor progression, and prognosis in patients with nonsmall cell lung carcinoma. Cancer 91, 964–971 (2001).
  Article CAS PubMed Google Scholar
• Tuxhorn, J. A., McAlhany, S. J., Yang, F., Dang, T. D. & Rowley, D. R. Inhibition of transforming growth factor-β activity decreases angiogenesis in a human prostate cancer-reactive stroma xenograft model. Cancer Res. 62, 6021–6025 (2002).
  CAS PubMed Google Scholar
• Stearns, M. E., Garcia, F. U., Fudge, K., Rhim, J. & Wang, M. Role of interleukin 10 and transforming growth factor β1 in the angiogenesis and metastasis of human prostate primary tumor lines from orthotopic implants in severe combined immunodeficiency mice. Clin. Cancer Res. 5, 711–720 (1999).
  CAS PubMed Google Scholar
• Ueki, N. et al. Excessive production of transforming growth-factor β 1 can play an important role in the development of tumorigenesis by its action for angiogenesis: validity of neutralizing antibodies to block tumor growth. Biochim. Biophys. Acta. 1137, 189–196 (1992).
  Article CAS PubMed Google Scholar
• Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).
  Article CAS PubMed Google Scholar
• Sánchez-Elsner, T. et al. Synergistic cooperation between hypoxia and transforming growth factor-β pathways on human vascular endothelial growth factor gene expression. J. Biol. Chem. 276, 38527–38535 (2001).
  Article PubMed Google Scholar
• Derynck, R., Akhurst, R. J. & Balmain, A. TGF-β signaling in tumor suppression and cancer progression. Nature Genet. 29, 117–129 (2001).
  Article CAS PubMed Google Scholar
• Schwarte-Waldhoff, I. et al. Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc. Natl Acad. Sci. USA 97, 9624–9629 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Komuro, A. et al. Diffuse-type gastric carcinoma: progression, angiogenesis, and transforming growth factor β signaling. J. Natl. Cancer Inst. 101, 592–604 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Kiyono, K. et al. c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-β signaling in diffuse-type gastric carcinoma. Cancer Sci. 100, 1809–1816 (2009).
  Article CAS PubMed Google Scholar
• Thiery, J. P. Epithelial-mesenchymal transitions in tumour progression. Nature Rev. Cancer 2, 442–454 (2002).
  Article CAS Google Scholar
• Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).
  Article CAS PubMed Google Scholar
• Moustakas, A. & Heldin, C. H. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci. 98, 1512–1520 (2007). References 96, 97 and 98 cover in detail mechanisms of EMT and discuss the physiological and pathological roles of EMT.
  Article CAS PubMed Google Scholar
• Hurd, T. W., Gao, L., Roh, M. H., Macara, I. G. & Margolis, B. Direct interaction of two polarity complexes implicated in epithelial tight junction assembly. Nature Cell Biol. 5, 137–142 (2003).
  Article CAS PubMed Google Scholar
• Ozdamar, B. et al. Regulation of the polarity protein Par6 by TGFβ receptors controls epithelial cell plasticity. Science 307, 1603–1609 (2005).
  Article CAS PubMed Google Scholar
• Xu, J., Lamouille, S. & Derynck, R. TGF-β-induced epithelial to mesenchymal transition. Cell Res. 19, 156–172 (2009).
  Article CAS PubMed Google Scholar
• Oft, M. et al. TGF-β1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev. 10, 2462–2477 (1996).
  Article CAS PubMed Google Scholar
• Janda, E. et al. Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J. Cell Biol. 156, 299–313 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Vogelmann, R. et al. TGFβ-induced downregulation of E-cadherin-based cell-cell adhesion depends on PI3-kinase and PTEN. J. Cell Sci. 118, 4901–4912 (2005).
  Article CAS PubMed Google Scholar
• Horiguchi, K. et al. Role of Ras signaling in the induction of snail by transforming growth factor-β. J. Biol. Chem. 284, 245–253 (2009).
  Article CAS PubMed Google Scholar
• Araki, S. et al. TGF-β1-induced expression of human Mdm2 correlates with late-stage metastatic breast cancer. J. Clin. Invest. 120, 290–302 (2010).
  Article CAS PubMed Google Scholar
• Adorno, M. et al. A Mutant-p53/Smad complex opposes p63 to empower TGFβ-induced metastasis. Cell 137, 87–98 (2009).
  Article CAS PubMed Google Scholar
• Papageorgis, P. et al. Smad signaling is required to maintain epigenetic silencing during breast cancer progression. Cancer Res. 70, 968–978 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Zeisberg, M. et al. BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nature Med. 9, 964–968 (2003).
  Article CAS PubMed Google Scholar
• Buijs, J. T. et al. Bone morphogenetic protein 7 in the development and treatment of bone metastases from breast cancer. Cancer Res. 67, 8742–8751 (2007).
  Article CAS PubMed Google Scholar
• 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
• Saito, R. A. et al. Thyroid transcription factor-1 inhibits transforming growth factor-β-mediated epithelial-to-mesenchymal transition in lung adenocarcinoma cells. Cancer Res. 69, 2783–2791 (2009).
  Article CAS PubMed Google Scholar
• Li, C. et al. Transforming growth factor-β inhibits pulmonary surfactant protein B gene transcription through SMAD3 interactions with NKX2.1 and HNF-3 transcription factors. J. Biol. Chem. 277, 38399–38408 (2002).
  Article CAS PubMed Google Scholar
• Minoo, P. et al. SMAD3 prevents binding of NKX2.1 and FOXA1 to the SpB promoter through its MH1 and MH2 domains. Nucleic Acids Res. 36, 179–188 (2008).
  Article CAS PubMed Google Scholar
• Tan, D. et al. Thyroid transcription factor-1 expression prevalence and its clinical implications in non-small cell lung cancer: a high-throughput tissue microarray and immunohistochemistry study. Hum. Pathol. 34, 597–604 (2003).
  Article CAS PubMed Google Scholar
• Padua, D. et al. TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133, 66–77 (2008). This paper demonstrates the role of TGFβ signalling in enabling the pulmonary metastasis of breast cancer cells.
  Article CAS PubMed PubMed Central Google Scholar
• Guise, T. A. et al. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J. Clin. Invest. 98, 1544–1549 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Yin, J. J. et al. TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J. Clin. Invest. 103, 197–206 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Kondo, H., Guo, J. & Bringhurst, F. R. Cyclic adenosine monophosphate/protein kinase A mediates parathyroid hormone/parathyroid hormone-related protein receptor regulation of osteoclastogenesis and expression of RANKL and osteoprotegerin mRNAs by marrow stromal cells. J. Bone Miner. Res. 17, 1667–1679 (2002).
  Article CAS PubMed Google Scholar
• Kang, Y., Chen, C. R. & Massague, J. A self-enabling TGFβ response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol. Cell 11, 915–926 (2003).
  Article CAS PubMed Google Scholar
• Kingsley, L. A., Fournier, P. G., Chirgwin, J. M. & Guise, T. A. Molecular biology of bone metastasis. Mol. Cancer Ther. 6, 2609–2617 (2007).
  Article CAS PubMed Google Scholar
• Ehata, S. et al. Ki26894, a novel transforming growth factor-b type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Cancer Sci. 98, 127–133 (2007).
  Article CAS PubMed Google Scholar
• Bandyopadhyay, A. et al. Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-β type I receptor kinase inhibitor. Cancer Res. 66, 6714–6721 (2006).
  Article CAS PubMed Google Scholar
• Ge, R. et al. Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-β type I receptor kinase in vivo. Clin. Cancer Res. 12, 4315–4330 (2006).
  Article CAS PubMed Google Scholar
• Roberts, A. B. & Wakefield, L. M. The two faces of transforming growth factor β in carcinogenesis. Proc. Natl Acad. Sci. USA 100, 8621–8623 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Yingling, J. M., Blanchard, K. L. & Sawyer, J. S. Development of TGF-β signalling inhibitors for cancer therapy. Nature Rev. Drug Discov. 3, 1011–1022 (2004). This review covers various TGFβ inhibitors and discusses the rationale for evaluating them as cancer therapeutics.
  Article CAS Google Scholar
• Schlingensiepen, K. H. et al. Targeted tumor therapy with the TGF-β2 antisense compound AP 12009. Cytokine Growth Factor Rev. 17, 129–139 (2006).
  Article CAS PubMed Google Scholar
• Santamaria-Martínez, A. et al. Identification of multipotent mesenchymal stromal cells in the reactive stroma of a prostate cancer xenograft by side population analysis. Exp. Cell Res. 315, 3004–3013 (2009).
  Article PubMed CAS Google Scholar
• Kabashima, A. et al. Side population of pancreatic cancer cells predominates in TGF-b-mediated epithelial to mesenchymal transition and invasion. Int. J. Cancer. 124, 2771–2779 (2009).
  Article CAS PubMed Google Scholar