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The TGF-β paradox in human cancer: an update

    Maozhen Tian

    Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA

    &
    William P Schiemann

    † Author for correspondence

    Department of Pharmacology, MS-8303, University of Colorado Denver, Anschutz Medical Campus, RC1 South Tower, Room L18-6110, 12801 East 17 Avenue, PO Box 6511, Aurora, CO 80045, USA.

    Published Online:https://doi.org/10.2217/14796694.5.2.259

    TGF-β plays an essential role in maintaining tissue homeostasis through its ability to induce cell cycle arrest, differentiation and apoptosis, and to preserve genomic stability. Thus, TGF-β is a potent anticancer agent that prohibits the uncontrolled proliferation of epithelial, endothelial and hematopoietic cells. Interestingly, tumorigenesis typically elicits aberrations in the TGF-β signaling pathway that engenders resistance to the cytostatic activities of TGF-β, thereby enhancing the development and progression of human malignancies. Moreover, these genetic and epigenetic events conspire to convert TGF-β from a suppressor of tumor formation to a promoter of their growth, invasion and metastasis. The dichotomous nature of TGF-β during tumorigenesis is known as the ‘TGF-β paradox’, which remains the most critical and mysterious question concerning the physiopathological role of this multifunctional cytokine. Here we review recent findings that directly impact our understanding of the TGF-β paradox and discuss their importance to targeting the oncogenic activities of TGF-β in developing and progressing neoplasms.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    Bibliography

    • Bierie B, Moses HL: Tumour microenvironment: TGF-β: the molecular Jekyll and Hyde of cancer. Nat. Rev. Cancer6,506–520 (2006).
    • Mueller MM, Fusenig NE: Friends or foes – bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer4,839–849 (2004).
    • Bhowmick NA, Chytil A, Plieth D et al.: TGF-β signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science303,848–851 (2004).▪▪ Demonstrated that inactivation of TGF-β signaling by fibroblast-specific knockout of TGF-β type II receptor (TbR-II) in mouse fibroblasts results in intraepithelial neoplasia in the prostate, and in invasive squamous cell carcinoma of the forestomach characterized by increased infiltration of stromal cells. Study implicates altered paracrine hepatocyte growth factor (HGF) signaling in mediating aberrant epithelial proliferation that arises from loss of TGF-β signaling in fibroblasts.
    • Bhowmick NA, Moses HL: Tumor-stroma interactions. Curr. Opin. Genet. Dev.15,97–101 (2005).
    • Bhowmick NA, Neilson EG, Moses HL: Stromal fibroblasts in cancer initiation and progression. Nature432,332–337 (2004).▪ Good review detailing the ability of the microenvironment and stromal cells to influence normal and malignant epithelial cell behaviors via altered paracrine signaling during carcinogenesis and tumor progression.
    • Fidler IJ: Critical determinants of metastasis. Semin. Cancer Biol.12,89–96 (2002).
    • Fidler IJ: The organ microenvironment and cancer metastasis. Differentiation70,498–505 (2002).
    • Cheng N, Bhowmick NA, Chytil A et al.: Loss of TGF-β type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-α-, MSP- and HGF-mediated signaling networks. Oncogene24,5053–5068 (2005).▪ Conditional TbR-II-deficiency in mouse mammary fibroblasts was demonstrated to upregulate paracrine TGF-a, macrophage-stimulating protein (MSP), and HGF signaling, which promoted the proliferation and invasion of adjacent epithelial cells.
    • Yang L, Huang J, Ren X et al.: Abrogation of TGF-β signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell13,23–35 (2008).▪▪ Demonstrates that TbR-II-deficiency in breast carcinoma cells increases the infiltration of Gr1+CD11+ myeloid cells into developing mammary tumors, which promotes breast cancer invasion and metastasis in part via increased MMP and TGF-b1 expression. Moreover, elevated chemokine signaling elicited by SDF-1:CXCR4 and CXCL5:CXCR2 signaling axes were identified in mediating recruitment of Gr1+CD11+ myeloid cells into TbR-II-deficient mammary tumors.
    • 10  Bruna A, Darken RS, Rojo F et al.: High TGF-β-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cancer Cell11,147–160 (2007).▪ Demonstrated that high TGF-b:Smad activity correlates with poor clinical prognoses and outcomes in patients with advanced gliomas. Also demonstrated that TGF-β mediates cytostasis in cells having the PDGF-B gene silenced by methylation, while demethylation and expression of PDGF-B enabled TGF-β to induce cell cycle progression.
    • 11  Paszek MJ, Weaver VM: The tension mounts: mechanics meets morphogenesis and malignancy. J. Mammary Gland Biol. Neoplasia9,325–342 (2004).
    • 12  Anderson AR, Weaver AM, Cummings PT, Quaranta V: Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment. Cell127,905–915 (2006).
    • 13  Lucero HA, Kagan HM: Lysyl oxidase: an oxidative enzyme and effector of cell function. Cell. Mol. Life Sci.63,2304–2316 (2006).
    • 14  Payne SL, Hendrix MJ, Kirschmann DA: Paradoxical roles for lysyl oxidases in cancer – a prospect. J. Cell. Biochem.101,1338–1354 (2007).
    • 15  Erler JT, Giaccia AJ: Lysyl oxidase mediates hypoxic control of metastasis. Cancer Res.66,10238–10241 (2006).
    • 16  Kagan HM, Li W: Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J. Cell. Biochem.88,660–672 (2003).
    • 17  Atsawasuwan P, Mochida Y, Katafuchi M et al.: Lysyl oxidase binds TGF-β and regulates its signaling via amine oxidase activity. J. Biol. Chem.283,34229–34240 (2008).
    • 18  Kim DJ, Lee DC, Yang SJ et al.: Lysyl oxidase like 4, a novel target gene of TGF-β1 signaling, can negatively regulate TGF-β1-induced cell motility in PLC/PRF/5 hepatoma cells. Biochem. Biophys. Res. Commun.373,521–527 (2008).
    • 19  Erler JT, Bennewith KL, Nicolau M et al.: Lysyl oxidase is essential for hypoxia-induced metastasis. Nature440,1222–1226 (2006).▪▪ Demonstrates that lysyl oxidase (LOX) expression is essential for hypoxia-induced metastasis of human breast cancer cells, as well as predicting the development of high-grade, poorly differentiated breast cancers that increase disease recurrence.
    • 20  Kirschmann DA, Seftor EA, Fong SF et al.: A molecular role for lysyl oxidase in breast cancer invasion. Cancer Res.62,4478–4483 (2002).
    • 21  Payne SL, Fogelgren B, Hess AR et al.: Lysyl oxidase regulates breast cancer cell migration and adhesion through a hydrogen peroxide-mediated mechanism. Cancer Res.65,11429–11436 (2005).
    • 22  Payne SL, Hendrix MJ, Kirschmann DA: Lysyl oxidase regulates actin filament formation through the p130(Cas)/Crk/DOCK180 signaling complex. J. Cell. Biochem.98,827–837 (2006).
    • 23  Galliher AJ, Schiemann WP: β3 integrin and Src facilitate TGF-β mediated induction of epithelial-mesenchymal transition in mammary epithelial cells. Breast Cancer Res.8,R42 (2006).
    • 24  Galliher AJ, Schiemann WP: Src phosphorylates Tyr284 in TGF-β type II receptor and regulates TGF-β stimulation of p38 MAPK during breast cancer cell proliferation and invasion. Cancer Res.67,3752–3758 (2007).
    • 25  Galliher-Beckley AJ, Schiemann WP: Grb2 Binding to Tyr284 in TβR-II is essential for mammary tumor growth and metastasis stimulated by TGF-β. Carcinogenesis29,244–251 (2008).▪ TGF-β stimulation of mammary tumor growth and pulmonary metastasis requires the activation of a avb3 integrin:Src:Y284-TbR-II:Grb2:p38 MAPK signaling axis.
    • 26  Andarawewa KL, Paupert J, Pal A, Barcellos-Hoff MH: New rationales for using TGF-β inhibitors in radiotherapy. Int. J. Radiat. Biol.83,803–811 (2007).
    • 27  Barcellos-Hoff MH, Medina D: New highlights on stroma-epithelial interactions in breast cancer. Breast Cancer Res.7,33–36 (2005).
    • 28  Biswas S, Guix M, Rinehart C et al.: Inhibition of TGF-β with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J. Clin. Invest.117,1305–1313 (2007).
    • 29  Lin WW, Karin M: A cytokine-mediated link between innate immunity, inflammation, and cancer. J. Clin. Invest.117,1175–1183 (2007).
    • 30  Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA: TGF-β regulation of immune responses. Annu. Rev. Immunol.24,99–146 (2006).
    • 31  Gorelik L, Flavell RA: Abrogation of TGF-β signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity12,171–181 (2000).
    • 32  Kulkarni AB, Huh CG, Becker D et al.: TGF-β1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl. Acad. Sci. USA90,770–774 (1993).
    • 33  Yang X, Letterio JJ, Lechleider RJ et al.: Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-β. EMBO J.18,1280–1291 (1999).
    • 34  Kim BG, Li C, Qiao W et al.: Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature441,1015–1019 (2006).▪▪ Deletion of Smad4 specifically in T cells skews their differentiation towards a Th2 phenotype and elevated interleukin secretion that elicits gastrointestinal carcinomas via disruption of normal paracrine signaling networks.
    • 35  Dalal BI, Keown PA, Greenberg AH: Immunohistochemical localization of secreted TGF-β1 to the advancing edges of primary tumors and to lymph node metastases of human mammary carcinoma. Am. J. Pathol.143,381–389 (1993).
    • 36  Gorsch SM, Memoli VA, Stukel TA, Gold LI, Arrick BA: Immunohistochemical staining for TGF-β1 associates with disease progression in human breast cancer. Cancer Res.52,6949–6952 (1992).
    • 37  Ivanovic V, Todorovic-Rakovic N, Demajo M et al.: Elevated plasma levels of TGF-β1 in patients with advanced breast cancer: Association with disease progression. Eur. J. Cancer39,454–461 (2003).
    • 38  Lin SJ, Chang C, Ng AK, Wang SH, Li JJ, Hu CP: Prevention of TGF-β-induced apoptosis by interlukin-4 through Akt activation and p70S6K survival signaling pathways. Apoptosis12,1659–1670 (2007).
    • 39  Teicher BA: TGF-β and the immune response to malignant disease. Clin. Cancer Res.13,6247–6251 (2007).
    • 40  Wrzesinski SH, Wan YY, Flavell RA: TGF-β and the immune response: implications for anticancer therapy. Clin. Cancer Res.13,5262–5270 (2007).
    • 41  Chen Ml, Pittet MJ, Gorelik L et al.: Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-β signals in vivo. Proc. Natl Acad. Sci. USA102,419–424 (2005).▪▪ Investigators found antigen-specific Tregs suppressed the ability of CD8+ T cells to eradicate tumor formation. Interestingly, expression of an inactive TbR-II mutant in CD8+ T cells rendered these cells resistant to the actions of Tregs and, consequently, restored their immunosurveillance activities.
    • 42  Gorelik L, Flavell RA: TGF-β in T-cell biology. Nat. Rev. Immunol.2,46–53 (2002).
    • 43  Gorelik L, Flavell RA: Immune-mediated eradication of tumors through the blockade of TGF-β signaling in T cells. Nat. Med.7,1118–1122 (2001).
    • 44  Zhang Q, Yang X, Pins M et al.: Adoptive transfer of tumor-reactive TGF-β-insensitive CD8+ T cells: Eradication of autologous mouse prostate cancer. Cancer Res.65,1761–1769 (2005).▪▪ Together with [43], demonstrated that inactivating TGF-β signaling in CD4+ and CD8+ T cells inhibits tumor formation by elevating host immunosurveillance.
    • 45  Nam JS, Terabe M, Kang MJ et al.: TGF-β subverts the immune system into directly promoting tumor growth through interleukin-17. Cancer Res.68,3915–3923 (2008).
    • 46  Neil JR, Schiemann WP: Altered TAB1:IκB kinase interaction promotes TGF-β-mediated NF-κB activation during breast cancer progression. Cancer Res.68,1462–1470 (2008).
    • 47  Lu T, Tian L, Han Y, Vogelbaum M, Stark GR: Dose-dependent cross-talk between the TGF-β and interleukin-1 signaling pathways. Proc. Natl Acad. Sci. USA104,4365–4370 (2007).
    • 48  Fries G, Perneczky A, Kempski O: Enhanced interleukin-1β release and longevity of glioma-associated peripheral blood monocytes in vitro. Neurosurgery35,264–270 (1994).
    • 49  Griffin BDMoynagh PN: Persistent interleukin-1β signaling causes long term activation of NF-κB in a promoter-specific manner in human glial cells. J. Biol. Chem.281,10316–10326 (2006).
    • 50  Tu S, Bhagat G, Cui G et al.: Overexpression of interleukin-1β induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell14,408–419 (2008).
    • 51  Larmonier N, Cathelin D, Larmonier C et al.: The inhibition of TNF-α anti-tumoral properties by blocking antibodies promotes tumor growth in a rat model. Exp. Cell Res.313,2345–2355 (2007).
    • 52  Conti P, Castellani MI, Kempuraj D et al.: Role of mast cells in tumor growth. Ann. Clin. Lab. Sci.37,315–321 (2007).
    • 53  Lin EY, Li JF, Gnatovskiy L et al.: Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res.66,11238–11246 (2006).
    • 54  Pollard JW: Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer4,71–78 (2004).
    • 55  Carmeliet P: Mechanisms of angiogenesis and arteriogenesis. Nat. Med.6,389–395 (2000).
    • 56  Carmeliet P, Jain RK: Angiogenesis in cancer and other diseases. Nature407,249–257 (2000).
    • 57  Carmeliet P: Angiogenesis in health and disease. Nat. Med.9,653–660 (2003).
    • 58  Erler JT, Weaver VM: Three-dimensional context regulation of metastasis. Clin. Exp. Metastasis26(1),35–49 (2009).
    • 59  Bertolino P, Deckers M, Lebrin F, ten Dijke P: TGF-β signal transduction in angiogenesis and vascular disorders. Chest128,585S–590S (2005).
    • 60  Lebrin F, Deckers M, Bertolino P, Ten Dijke P: TGF-β receptor function in the endothelium. Cardiovasc. Res.65,599–608 (2005).
    • 61  Pepper MS: TGF-β: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev.8,21–43 (1997).
    • 62  Pepper MS, Vassalli JD, Orci L, Montesano R: Biphasic effect of TGF-β1 on in vitro angiogenesis. Exp. Cell Res.204,356–363 (1993).
    • 63  Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ: Defective haematopoiesis and vasculogenesis in TGF-β1 knock out mice. Development121,1845–1854 (1995).
    • 64  Larsson J, Goumans MJ, Sjostrand LJ et al.: Abnormal angiogenesis but intact hematopoietic potential in TGF-β type I receptor-deficient mice. EMBO J.20,1663–1673 (2001).
    • 65  Goumans MJ, Zwijsen A, van Rooijen MA, Huylebroeck D, Roelen BA, Mummery CL: TGF-β signalling in extraembryonic mesoderm is required for yolk sac vasculogenesis in mice. Development126,3473–3483 (1999).
    • 66  Oshima M, Oshima H, Taketo MM: TGF-β receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev. Biol.179,297–302 (1996).
    • 67  Compton LA, Potash DA, Brown CB, Barnett JV: Coronary vessel development is dependent on the type III TGF-β receptor. Circ. Res.101,784–791 (2007).
    • 68  Brown CB, Boyer AS, Runyan RB, Barnett JV: Requirement of type III TGF-β receptor for endocardial cell transformation in the heart. Science283,2080–2082 (1999).
    • 69  Lechleider RJ, Ryan JL, Garrett L et al.: Targeted mutagenesis of Smad1 reveals an essential role in chorioallantoic fusion. Dev. Biol.240,157–167 (2001).
    • 70  Chang H, Huylebroeck D, Verschueren K, Guo Q, Matzuk MM, Zwijsen A: Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects. Development126,1631–1642 (1999).
    • 71  McAllister KA, Grogg KM, Johnson DW et al.: Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat. Genet.8,345–351 (1994).
    • 72  Shovlin CL, Hughes JM, Scott J, Seidman CE, Seidman JG: Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia. Am. J. Hum. Genet.61,68–79 (1997).▪ Identified loss or inaction of endoglin as a mediator of HHT1 in humans.
    • 73  Berg JN, Gallione CJ, Stenzel TT et al.: The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am. J. Hum. Genet.61,60–67 (1997).
    • 74  Johnson DW, Berg JN, Baldwin MA et al.: Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat. Genet.13,189–195 (1996).▪ Identified loss or inaction of ALK-1 as a mediator of HHT2 in humans.
    • 75  Arthur HM, Ure J, Smith AJ et al.: Endoglin, an ancillary TGF-β receptor, is required for extraembryonic angiogenesis and plays a key role in heart development. Dev. Biol.217,42–53 (2000).
    • 76  Bourdeau A, Dumont DJ, Letarte M: A murine model of hereditary hemorrhagic telangiectasia. J. Clin. Invest.104,1343–1351 (1999).
    • 77  Srinivasan S, Hanes MA, Dickens T et al.: A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2. Hum. Mol. Genet.12,473–482 (2003).
    • 78  Goumans MJ, Valdimarsdottir G, Itoh S et al.: Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGF-β/ALK5 signaling. Mol. Cell12,817–828 (2003).
    • 79  Oh SP, Seki T, Goss KA et al.: Activin receptor-like kinase 1 modulates TGF-β1 signaling in the regulation of angiogenesis. Proc. Natl Acad. Sci. USA97,2626–2631 (2000).
    • 80  Goumans MJ, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke P: Balancing the activation state of the endothelium via two distinct TGF-β type I receptors. EMBO J.21,1743–1753 (2002).
    • 81  Wu X, Ma J, Han JD, Wang N, Chen YG: Distinct regulation of gene expression in human endothelial cells by TGF-β and its receptors. Microvasc. Res.71,12–19 (2006).
    • 82  Ota T, Fujii M, Sugizaki T et al.: Targets of transcriptional regulation by two distinct type I receptors for TGF-β in human umbilical vein endothelial cells. J. Cell Physiol.193,299–318 (2002).
    • 83  Fajardo LF, Prionas SD, Kwan HH, Kowalski J, Allison AC: TGF-β1 induces angiogenesis in vivo with a threshold pattern. Lab. Invest.74,600–608 (1996).
    • 84  Goumans MJ, Lebrin F, Valdimarsdottir G: Controlling the angiogenic switch: a balance between two distinct TGF-β receptor signaling pathways. Trends Cardiovasc. Med.13,301–307 (2003).
    • 85  Savagner P: Leaving the neighborhood: Molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays23,912–923 (2001).
    • 86  Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer2,442–454 (2002).
    • 87  Thiery JP: Epithelial-mesenchymal transitions in development and pathologies. Curr. Opin. Cell Biol.15,740–746 (2003).
    • 88  Zavadil J, Bottinger EP: TGF-β and epithelial-to-mesenchymal transitions. Oncogene24,5764–5774 (2005).
    • 89  Gupta GP, Perk J, Acharyya S et al.: ID genes mediate tumor reinitiation during breast cancer lung metastasis. Proc. Natl Acad. Sci. USA104,19506–19511 (2007).▪ IDs 1 and 3 are required not only for tumor formation, but also for pulmonary metastasis, particularly carcinoma cell extravasation and metastatic colonization.
    • 90  Padua D, Zhang XH, Wang Q et al.: TGF-β primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell133,66–77 (2008).▪▪ Interesting study describing the ability of TGF-β to induce ANGPTL4 expression, thus promoting breast cancer cell metastasis by inducing their retention, extravasation and colonization, specifically to the lungs, not the bone.
    • 91  Moustakas A, Heldin CH: Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci.98,1512–1520 (2007).
    • 92  Willis BC, Borok Z: TGF-β-induced EMT: Mechanisms and implications for fibrotic lung disease. Am. J. Physiol. Lung Cell. Mol. Physiol.293,L525–L534 (2007).
    • 93  Tian F, DaCosta Byfield S, Parks WT et al.: Reduction in Smad2/3 signaling enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Res.63,8284–8292 (2003).
    • 94  Tian F, Byfield SD, Parks WT et al.: Smad-binding defective mutant of TGF-β type I receptor enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Res.64,4523–4530 (2004).
    • 95  Kang Y, He W, Tulley S et al.: Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc. Natl Acad. Sci. USA102,13909–13914 (2005).
    • 96  Kang Y, Siegel PM, Shu W et al.: A multigenic program mediating breast cancer metastasis to bone. Cancer Cell3,537–549 (2003).
    • 97  Yin JJ, Selander K, Chirgwin JM et al.: TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J. Clin. Invest.103,197–206 (1999).
    • 98  Deckers M, van Dinther M, Buijs J et al.: The tumor suppressor Smad4 is required for TGF-β-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res.66,2202–2209 (2006).
    • 99  Bardeesy N, Cheng KH, Berger JH et al.: Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev.20,3130–3146 (2006).
    • 100  Hayashi H, Abdollah S, Qiu Y et al.: The MAD-related protein Smad7 associates with the TGF-β receptor and functions as an antagonist of TGF-β signaling. Cell89,1165–1173 (1997).
    • 101  Souchelnytskyi S, Nakayama T, Nakao A et al.: Physical and functional interaction of murine and Xenopus Smad7 with bone morphogenetic protein receptors and TGF-β receptors. J. Biol. Chem.273,25364–25370 (1998).
    • 102  Azuma H, Ehata S, Miyazaki H et al.: Effect of Smad7 expression on metastasis of mouse mammary carcinoma JygMC(A) cells. J. Natl. Cancer Inst.97,1734–1746 (2005).
    • 103  Leivonen SK, Ala-Aho R, Koli K, Grenman R, Peltonen J, Kahari VM: Activation of Smad signaling enhances collagenase-3 (MMP-13) expression and invasion of head and neck squamous carcinoma cells. Oncogene25,2588–2600 (2006).
    • 104  Leivonen SK, Kahari VM: TGF-β signaling in cancer invasion and metastasis. Int. J. Cancer121,2119–2124 (2007).
    • 105  Javelaud D, Mohammad KS, McKenna CR et al.: Stable overexpression of Smad7 in human melanoma cells impairs bone metastasis. Cancer Res.67,2317–2324 (2007).
    • 106  Moustakas A, Heldin CH: Non-Smad TGF-β signals. J. Cell Sci.118,3573–3584 (2005).
    • 107  Bakin AV, Rinehart C, Tomlinson AK, Arteaga CL: p38 mitogen-activated protein kinase is required for TGF-β-mediated fibroblastic transdifferentiation and cell migration. J. Cell Sci.115,3193–3206 (2002).
    • 108  Bhowmick NA, Zent R, Ghiassi M, McDonnell M, Moses HL: Integrin β1 signaling is necessary for TGF-β activation of p38MAPK and epithelial plasticity. J. Biol. Chem.276,46707–46713 (2001).
    • 109  Cui W, Fowlis DJ, Bryson S et al.: TGF-β1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell86,531–542 (1996).
    • 110  Davies M, Robinson M, Smith E, Huntley S, Prime S, Paterson I: Induction of an epithelial to mesenchymal transition in human immortal and malignant keratinocytes by TGF-β1 involves MAPK, Smad and AP-1 signalling pathways. J. Cell. Biochem.95,918–931 (2005).
    • 111  Ellenrieder V, Hendler SF, Boeck W et al.: TGF-β1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res.61,4222–4228 (2001).
    • 112  Fowlis DJ, Cui W, Johnson SA, Balmain A, Akhurst RJ: Altered epidermal cell growth control in vivo by inducible expression of TGF-β1 in the skin of transgenic mice. Cell Growth Differ.7,679–687 (1996).
    • 113  Janda E, Lehmann K, Killisch I et al.: Ras and TGF-β cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J. Cell Biol.156,299–313 (2002).
    • 114  Lehmann K, Janda E, Pierreux CE et al.: Raf induces TGF-β production while blocking its apoptotic but not invasive responses: A mechanism leading to increased malignancy in epithelial cells. Genes Dev.14,2610–2622 (2000).
    • 115  Oft M, Akhurst RJ, Balmain A: Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat. Cell Biol.4,487–494. (2002).
    • 116  Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL: Phosphatidylinositol 3-kinase function is required for TGF-β-mediated epithelial to mesenchymal transition and cell migration. J. Biol. Chem.275,36803–36810 (2000).
    • 117  Bhowmick NA, Ghiassi M, Bakin A et al.: TGF-β1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol. Biol. Cell12,27–36 (2001).
    • 118  Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP: Integration of TGF-β/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J.23,1155–1165 (2004).
    • 119  Lamouille S, Derynck R: Cell size and invasion in TGF-β-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J. Cell Biol.178,437–451 (2007).
    • 120  Kim K, Lu Z, Hay ED: Direct evidence for a role of β-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol. Int.26,463–476 (2002).
    • 121  Huber MA, Azoitei N, Baumann B et al.: NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J. Clin. Invest.114,569–581 (2004).
    • 122  Neil JR, Johnson KM, Nemenoff RA, Schiemann WP: Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-β through a PGE2-dependent mechanism. Carcinogenesis29,2227–2235 (2008).
    • 123  Hocevar BA, Smine A, Xu XX, Howe PH: The adaptor molecule Disabled-2 links the TGF-β receptors to the Smad pathway. EMBO J.20,2789–2801 (2001).
    • 124  Prunier C, Howe PH: Disabled-2 (Dab2) is required for TGF-β-induced epithelial to mesenchymal transition (EMT). J. Biol. Chem.280,17540–17548 (2005).
    • 125  Bandyopadhyay A, Agyin JK, Wang L et al.: Inhibition of pulmonary and skeletal metastasis by a TGF-β type I receptor kinase inhibitor. Cancer Res.66,6714–6721 (2006).
    • 126  Sloan EK, Pouliot N, Stanley KL et al.: Tumor-specific expression of αvβ3 integrin promotes spontaneous metastasis of breast cancer to bone. Breast Cancer Res.8,R20 (2006).
    • 127  Muraoka-Cook RS, Kurokawa H, Koh Y et al.: Conditional overexpression of active TGF-β1 in vivo accelerates metastases of transgenic mammary tumors. Cancer Res.64,9002–9011 (2004).
    • 128  Bharathy S, Xie W, Yingling JM, Reiss M: Cancer-associated TGF-β type II receptor gene mutant causes activation of bone morphogenic protein-Smads and invasive phenotype. Cancer Res.68,1656–1666 (2008).
    • 129  Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL: Regulation of the polarity protein Par6 by TGF-β receptors controls epithelial cell plasticity. Science307,1603–1609 (2005).▪ Identified Par6 as a substrate of TbR-II. Once phosphorylated, Par6 associates with TbR-I and coordinates Smurf1-mediated ubiquitination and degradation of RhoA, leading to EMT.
    • 130  Ben-Porath I, Thomson MW, Carey VJ et al.: An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat. Genet.40,499–507 (2008).▪ Authors showed that poorly differentiated, high-grade tumors preferentially express genes normally associated with those observed in embryonic stem cells. Included in this gene list were NANOG, Oct4, Sox2 and c-Myc, whose expression also are upregulated frequently in these aggressive tumors.
    • 131  Mani SA, Guo W, Liao MJ et al.: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell133,704–715 (2008).▪▪ Suggests a direct link between epithelial–mesenchymal transition (EMT) and the acquisition of ‘stemness’ by transitioning epithelial cells.
    • 132  Tang B, Yoo N, Vu M et al.: TGF-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).
    • 133  Shipitsin M, Campbell LL, Argani P et al.: Molecular definition of breast tumor heterogeneity. Cancer Cell11,259–273 (2007).▪▪ Demonstrates that breast cancer stem cells possess an EMT-like phenotype that is governed by TGF-β signaling. Moreover, treating these cells with TGF-b-receptor antagonists suppressed their tumorigenicity by inducing their acquisition more epithelial-like morphologies.
    • 134  Qian B, Katsaros D, Lu L et al.: High miR-21 expression in breast cancer associated with poor disease-free survival in early stage disease and high TGF-β1. Breast Cancer Res. Treat. DOI 10.1007/s10549-008-0219-7 (2008) (Epub ahead of print).
    • 135  Papagiannakopoulos T, Shapiro AKosik KS: MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res.68,8164–8172 (2008).
    • 136  Davis BN, Hilyard AC, Lagna G, Hata A: SMAD proteins control DROSHA-mediated microRNA maturation. Nature454,56–61 (2008).▪▪ Demonstrates that Smad2/3 associate with DROSHA, leading to increased processing of miR-21 and its targeting of PDCD4, which ultimately enhances vascular smooth muscle contractility.
    • 137  Zavadil J, Narasimhan M, Blumenberg M, Schneider RJ: TGF-β and microRNA:mRNA regulatory networks in epithelial plasticity. Cells Tissues Organs185,157–161 (2007).
    • 138  Gregory PA, Bert AG, Paterson EL et al.: The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol.10,593–601 (2008).▪▪ Shows that TGF-β stimulation of EMT requires this cytokine to suppress the expression of miR-205 and miR-200 family members, which enable cellular expression of ZEB1.
    • 139  Hanahan D, Weinberg RA: The hallmarks of cancer. Cell100(1),57–70 (2000).
    • 140  Rizki A, Bissell MJ: Homeostasis in the breast: It takes a village. Cancer Cell6,1–2 (2004).