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Inhibition of Transforming Growth Factor-ß Signaling in Human Cancer: Targeting a Tumor Suppressor Network as a Therapeutic Strategy

Authors' Affiliation: Departments of Medicine and Cancer Biology, Breast Cancer Research Program, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee

Requests for reprints: Carlos L. Arteaga, Division of Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 PRB, Nashville, TN 37232-6307. Phone: 615-936-3524; Fax: 615-936-1790; E-mail: carlos.arteaga{at}vanderbilt.edu.

Transforming growth factor-ß (TGFß) is both a tumor suppressor and tumor promoter. The loss or attenuation of TGFß signaling in epithelial cells and stroma is permissive for epithelial cell transformation, whereas the introduction of dominant-negative TGFß receptors into metastatic cancer cells inhibits epithelial-to-mesenchymal transition, motility, invasiveness, survival, and metastases. In addition, excess production and/or activation of TGFß by cancer cells can contribute to tumor progression by paracrine mechanisms involving modulation of the tumor microenvironment. These data provide a rationale in favor of the blockade of autocrine/paracrine TGFß signaling in human cancer with a therapeutic intent.

TGFß Signaling and Developmental Functions

The TGFß family comprises a superfamily of ligands that includes the TGFßs, activins, and bone morphogenetic proteins. TGFß ligands play functional roles in cell proliferation, functional differentiation, extracellular matrix production, cell motility, and apoptosis (1). They are secreted as small latent complexes composed of the active carboxyl-terminal TGFß dimer linked noncovalently to a dimer of the latency-associated peptide. The large latent complex are the small latent complexes linked via disulfide bonds to the latent TGFß-binding protein. The latent TGFß-binding protein glycoproteins localize large latent complexes in the extracellular matrix in which the bulk of the TGFßs are sequestered. The release of active TGFß from matrix-associated latent complexes may require two steps: release of the complex from the extracellular matrix by proteolysis and subsequent activation by disruption of the noncovalent association between TGFß and the latency-associated peptide. This can be achieved by chemical, enzymatic, proteolytic, and hormonal mechanisms (2).

There are three mammalian TGFß isoforms, TGFß1, TGFß2, and TGFß3 exhibit similar functions in vitro (1). However, each seems to have distinct activities in vivo as evidenced by the phenotypes of mice lacking each of these ligands. Targeted inactivation of the Tgfb1 gene leads to hematopoietic and vasculogenic defects resulting in the death of approximately half of the embryos at 10 days of gestation (3). The embryos that survive succumb to a wasting syndrome and multiorgan necrosis due to inflammatory cells (4). TGFß2-null mice die in the perinatal period as a result of developmental abnormalities affecting the cardiopulmonary, urogenital, visual, auditory, neural, and skeletal systems (5). Mice lacking TGFß3 also die perinatally and exhibit abnormal lung and palate development (6, 7).

The TGFßs bind to a heteromeric complex of transmembrane serine/threonine kinases, the type I and type II receptors (TßRI and TßRII). These ligands also bind a large transmembrane proteoglycan referred to as the type III TGFß receptor, or betaglycan, whose role is to present ligand to TßRII (1). Following ligand binding to TßRII, TßRI is recruited to the ligand-receptor complex. This allows the constitutively active TßRII kinase to transphosphorylate and activate the TßRI kinase (8), which, in turn, phosphorylates the receptor-regulated Smad2 and Smad3 (Fig. 1 ). Smad2/3 then associate with Smad4 and translocate to the nucleus where they regulate the transcription of genes involved in cell cycle control and apoptosis (9). The inhibitory Smad7 can interact with TßRI and prevent the phosphorylation of effector Smads (10). In addition to Smads, other signaling pathways have been implicated in TGFß actions. These include the extracellular signal-regulated kinase, c-Jun NH₂-terminal kinase, p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol-3 kinase (PI3K), nuclear factor B, and Rho GTPases (11). The molecular mechanisms by which TGFß receptors engage non–Smad pathways remain to be fully characterized.

View larger version (74K): [in this window] [in a new window]   Fig. 1. Signaling pathways induced by TGFß receptors. The ligand-activated type I and II receptor complex recruits and phosphorylates the receptor-specific Smad2/3 which, in turn, recruit Smad4. Transcriptional responses induced by the Smad complex have been shown to be associated with ligand-induced inhibition of cell proliferation, apoptosis, and genomic stability. The molecular mechanisms by which TGFß activates non–Smad pathways such as PI3K/Akt, Rho/Rac GTPases, and Ras/MAPK are less clear.

Although TGFß was originally reported as an oncogene (12), early studies also showed that it is a potent inhibitor of epithelial cell proliferation (13). Mice with targeted disruption of TGFb1 and Smad genes as well as transgenic mice with tissue-specific expression of dominant-negative TßRII are prone to cancer development (reviewed in ref. 14). Inactivating mutations in the TGFBR2 gene occur in both sporadic and inherited colon cancers with microsatellite instability (15); restoration of TßRII by transfection reverses transformation in certain colon cancer cell lines (16). Inactivating mutations in Smad2 and Smad4 are present in cancers of the gastrointestinal tract and pancreas (17). More recently, conditional inactivation of TßRII in mouse fibroblasts resulted in prostatic intraepithelial neoplasias and carcinomas of the forestomach (18). These data are consistent with the ability of TGFß to maintain tissue architecture, inhibit genomic instability, and induce replicative senescence and apoptosis in nontransformed cells/tissues (14). Despite this evidence supporting a tumor suppressor role for TGFß, exogenous TGFß has never been shown to inhibit an established cancer in vivo nor has the administration of a TGFß inhibitor resulted in spontaneous tumor development or the acceleration of an already established cancer in an animal model or in humans.

On the other hand, an excess production and/or activation of TGFß by established tumor cells can promote cancer progression by mechanisms such as an increase in tumor neoangiogenesis and extracellular matrix production, up-regulation of peritumor proteases, and inhibition of immune surveillance mechanisms in the cancer host among others (reviewed in ref. 19). High TGFß levels in tumors or in patients' serum correlate with markers of a more metastatic phenotype and/or poor patient outcome (20–23). TGFß can also induce an epithelial-to-mesenchymal transition and increase tumor cell invasiveness (24, 25). Re-expression of TßRII in colon cancer cells with low invasive potential restores tumor cells invasiveness (26). Forced expression of dominant-active Smad2 in squamous cancer cells results in enhanced tumor cell motility and metastatic dissemination (27). Finally, expression of dominant-negative TßRII in metastatic cancer cells prevents epithelial-to-mesenchymal transition and inhibits motility, tumorigenicity, and metastases (reviewed in ref. 19).

There is also evidence that the tumor suppressor versus oncogenic effects of TGFß are contextual and/or depend on the temporal stage of cellular transformation. For example, the expression of a kinase-intact type I receptor (TßRI) mutant that is unable to bind Smad2/3 results in larger, more proliferative, less differentiated mammary tumors. However, expression of the same mutant in highly malignant mammary cells suppresses their ability to metastasize to the lungs (28). In a second example, transgenic mice engineered to lack TßRII in the mammary gland developed Polyomavirus middle T (PyVmT) oncogene-induced mammary tumors with shorter latency and with more lung metastases compared with TßRII-expressing tumors (29). In these mice, the floxed TßRII allele was excised upon crossbreeding with mouse mammary tumor virus (MMTV)/Cre mice, where Cre is expressed in the mammary gland at puberty before mammary tumors are established. This report seems to contrast with another study of triple transgenic (MMTV/rtTA x tet-op/TGFß1^S223/225 x MMTV/PyVmT) mice in which active TGFß1 expression at tumor sites was controlled with doxycycline. In their study, 2 weeks of administration of doxycycline to 8-week-old mice with established mammary tumors markedly accelerated metastases and death (30). These data suggest that the net effect of TGFß signaling in tumor progression may diverge as a function of the (early versus late) stage of transformation.

Additional examples support a promoter role for autocrine/paracrine TGFß in late phases of transformation. Mice overexpressing active TGFß1 in suprabasal keratinocytes develop fewer benign papillomas than controls. However, the few transgenic tumors which do develop acquire a spindle cell phenotype, overexpress TGFß3, and metastasize (31). Overexpression of an active mutant of TßRI (Alk5) or active TGFß1 in the mammary gland of transgenic mice accelerates metastases from Neu-induced mammary tumors (32–34). Finally, expression of TßRII in tumors has been associated with shorter patient survival in several tumor types (35–37), suggesting that TGFß signaling in cancer cells may select tumors with high metastatic behavior. Recent reviews have summarized a number of studies in which the inhibition of TGFß by pharmacologic or genetic means inhibited tumor progression in animal models (19, 38, 39).

TGFß and Oncogenic Signaling Pathways

Recent studies have identified oncogenic signaling pathways which are activated by TGFß. For example, secreted TGFß2 induces nuclear factor B activity in cancer cells and RNA interference of TGFß2 in LNCaP cells reduces nuclear factor B activity and survival (40). TGFß stimulates PI3K and Akt activities. Both TßRII and Alk5 associate with p85, the regulatory subunit of PI3K, and expression of constitutively active Alk5^T204D markedly up-regulates PI3K catalytic activity (34, 41, 42). TGFß- or active Alk5-mediated cell motility and protection from apoptosis are blocked by LY294002 (30, 43), dominant-negative Akt (44), dominant-negative c-Jun (45), or TßRI kinase inhibitors (34). Inhibition of PI3K has also been shown to reverse the fibroblastoid phenotype of Ras-transformed hepatocytes to an epithelial phenotype (46), further suggesting that PI3K signaling is an effector of the oncogenic function of TGFß. Transgenic mice expressing an active mutant of Alk5 in the mammary gland exhibit increased PI3K activity in mammary epithelium as well as reduced apoptosis in terminal end buds and during (delayed) postlactational involution (34). Although MMTV/Alk5^T204D mice did not develop mammary tumors, bigenic MMTV/Neu x Alk5^T204D mice developed cancers that were markedly more metastatic than those occurring in MMTV/Neu mice (34).

Oncogenic signaling pathways activated by TGFß can subvert Smad signaling and, thus, antagonize ligand-induced antiproliferative action. For example, PI3K/Akt represses the induction of p21^CIP1 and, in doing so, inhibits the cytostatic action of TGFß (47). Activated Akt can sequester Smad3 and prevent its phosphorylation, association with Smad4, and nuclear translocation, hence blocking TGFß-induced apoptosis (48, 49). These data may explain in part how oncogenes attenuate the tumor suppressive action of TGFß. How essential these non–Smad oncogenic pathways are for the effects of TGFß on tumor progression remains to be determined.

TGFß cooperates with activated Ras on the conversion of noninvasive to metastatic tumors and on the promotion of epithelial-to-mesenchymal transition (27, 50). Oncogenically activated Ras has been shown to inhibit TGFß-mediated nuclear accumulation of Smad2/3, Smad-dependent transcription, and antimitogenesis (51). Ha-Ras abrogates TGFß-mediated inhibition of proliferation by inducing MAPK-dependent proteasomal degradation of Smad4 (52). TGFß can activate Ras/MAPK signaling in transformed cells (53) and expression of a dominant-negative truncated Alk5 blocks the growth of Ras-transformed Jnk^–/– tumors in mice (54), suggesting that autocrine TGFß is at least in part required for Ras-induced transformation in vivo.

TGFß synergizes with other oncogenes that activate Ras/MAPK. For example, overexpression of active TGFß1 or active Alk5 mutants in the mammary gland of bitransgenic mice also expressing neu/erbB2 accelerates metastases from oncogene-induced mammary cancers (32–34). A genetic modifier screen in nontumorigenic mammary epithelial cells identified TGFß1 and TGFß3 as molecules that cooperate with ErbB2 on inducing cell motility and invasion, which were blocked by inhibitors of MAPK (55). Inhibition of ErbB2 (HER2) with the HER2 neutralizing antibody trastuzumab or with MAPK inhibitors blocked the promigratory effect of TGFß in HER2-overexpressing mammary epithelial cells (56), suggesting that oncogene function is required for TGFß action. These data imply that (a) oncogenes that activate Ras/MAPK signaling engage and require TGFß for tumor progression, and (b) tumors with activating Ras mutations or with active Ras/MAPK are attractive targets for the testing of TGFß inhibitors.

Therapeutic Inhibitors of TGFß Signaling

The main strategies for inhibition of TGFß include compounds that interfere with the binding of ligand to TGFß receptors, drugs that block intracellular signaling, and antisense oligonucleotides. These have been summarized in recent reviews (38, 39) and will be only mentioned in brief here. Lerdelimumab (CAT-152) and metelimumab (CAT-192) are recombinant human IgGs generated by phage display technology that blocks TGFß1 and ß2, respectively (57, 58). They are under development by Cambridge Antibody Technology (London, United Kingdom) and Genzyme Corporation (Framingham, MA). Because of the expression of multiple TGFß isoforms in tumors, a panspecific monoclonal antibody GC-1008 (also developed by CAT/Genzyme) is in early phase I testing in patients with cancer. The phase I studies of CAT-152 and GC-1008 have been conducted in patients with fibrotic disorders, however, the final reports for these are not yet available. In two studies, CAT-152 seemed to prevent subconjunctival scarring after glaucoma filtration surgery (57, 59). Recombinant fusion proteins containing the ectodomains of the type II and type III (betaglycan) receptors have also been used to prevent ligand binding to TGFß receptors. Soluble TßRII/Fc has shown potent antimetastatic activity in transgenic mice (60) but its clinical development in cancer is unclear at this time. Human recombinant TßRIII has also shown antimetastatic and antiendothelial cell activity (61) in preclinical models.

A second group of strategies is aimed at directly blocking the catalytic activity of TßRI. These include the small molecules SB-431542 and SB-505124 (GlaxoSmithKline, Collegeville, PA), SD-093 and SD-908 (Scios Inc., Fremont, CA), and LY2157299 (Lilly Research Laboratories, Indianapolis, IN), which are ATP-competitive inhibitors of the Alk5 kinase and whose structural properties have been reviewed recently (39). One difference (and potential advantage) of these compounds from the pharmacologically more stable ligand-specific antibodies is that they cross-react with other Alk5-homologous serine/threonine kinases such as Alk4 and Alk7, suggesting that they could modulate the activin-mediated activation of Smad2/3 (62–64). At the time of this writing, some of these compounds are just entering phase I investigation.

Finally, TGFß antisense approaches are also in development in cancer. In preclinical studies using intracranial gliomas, a TGFß2 antisense-modified allogeneic tumor cell vaccine was shown to inhibit TGFß-mediated immune suppression and promote tumor rejection (65). Antisense Pharma (Regensburg, Germany) is developing two TGFß-specific phosphorothioate antisense oligonucleotides. AP-12009, against TGFß2, has shown remarkable early clinical activity when delivered intratumorally by convection-enhanced delivery to patients with high-grade gliomas (66). AP-11014, against TGFß1, is being developed for the treatment of non–small cell, colorectal, and prostate carcinomas (67).

At this point, therapeutic targeting of TGFß signaling in human cancers has been endorsed by the scientific community. However, many questions remain about this enterprise as it applies to drug tolerability and/or toxicities, molecular and/or biochemical surrogate markers of TGFß activation and drug-induced inactivation in situ, the molecular profile and/or tumor types most appropriate for investigational trials with TGFß inhibitors, and scientifically based combinations that will include inhibitors of TGFß signaling, among others.

Footnotes

Grant support: R01 CA62212 (C.L. Arteaga), Breast Cancer Specialized Program of Research Excellence grant P50 CA98131, and Vanderbilt-Ingram Cancer Center Support grant CA68485. T.L. Criswell is supported by NCI T32 grant CA09592.

Received 4/18/06; revised 5/16/06; accepted 5/23/06.

References

1. Massague J. TGF-ß signal transduction. Annu Rev Biochem 1998;67:753–91.[CrossRef][Medline]
2. Koli K, Saharinen J, Hyytiainen M, Penttinen C, Keski-Oja J. Latency, activation, and binding proteins of TGF-ß. Microsc Res Tech 2001;52:354–62.[CrossRef][Medline]
3. Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ. Defective haematopoiesis and vasculogenesis in transforming growth factor-ß1 knock out mice. Development 1995;121:1845–54.[Abstract]
4. Shull MM, Ormsby I, Kier AB, et al. Targeted disruption of the mouse transforming growth factor-ß1 gene results in multifocal inflammatory disease. Nature 1992;359:693–9.[CrossRef][Medline]
5. Sanford LP, Ormsby I, Gittenberger-de Groot AC, et al. TGFß2 knockout mice have multiple developmental defects that are non-overlapping with other TGFß knockout phenotypes. Development 1997;124:2659–70.[Abstract]
6. Proetzel G, Pawlowski SA, Wiles MV, et al. Transforming growth factor-ß3 is required for secondary palate fusion. Nat Genet 1995;11:409–14.[CrossRef][Medline]
7. Kaartinen V, Voncken JW, Shuler C, et al. Abnormal lung development and cleft palate in mice lacking TGF-ß3 indicates defects of epithelial-mesenchymal interaction. Nat Genet 1995;11:415–21.[CrossRef][Medline]
8. Wrana JL, Attisano L, Wieser R, Ventura F, Massague J. Mechanism of activation of the TGF-ß receptor. Nature 1994;370:341–7.[CrossRef][Medline]
9. Massague J, Seoane J, Wotton D. Smad transcription factors. Genes Dev 2005;19:2783–810.[Abstract/Free Full Text]
10. Hayashi H, Abdollah S, Qiu Y, et al. The MAD-related protein Smad7 associates with the TGFß receptor and functions as an antagonist of TGFß signaling. Cell 1997;89:1165–73.[CrossRef][Medline]
11. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-ß family signalling. Nature 2003;425:577–84.[CrossRef][Medline]
12. Moses HL, Branum EL, Proper JA, Robinson RA. Transforming growth factor production by chemically transformed cells. Cancer Res 1981;41:2842–8.[Abstract/Free Full Text]
13. Tucker RF, Shipley GD, Moses HL, Holley RW. Growth inhibitor from BSC-1 cells closely related to platelet type ß transforming growth factor. Science 1984;226:705–7.[Abstract/Free Full Text]
14. Siegel PM, Massague J. Cytostatic and apoptotic actions of TGF-ß in homeostasis and cancer. Nat Rev Cancer 2003;3:807–20.[CrossRef][Medline]
15. Markowitz S, Wang J, Myeroff L, et al. Inactivation of the type II TGF-ß receptor in colon cancer cells with microsatellite instability. Science 1995;268:1336–8.[Abstract/Free Full Text]
16. Wang J, Sun L, Myeroff L, et al. Demonstration that mutation of the type II transforming growth factor ß receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells. J Biol Chem 1995;270:22044–9.[Abstract/Free Full Text]
17. Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996;271:350–3.[Abstract]
18. Bhowmick NA, Chytil A, Plieth D, et al. TGF-ß signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004;303:848–51.[Abstract/Free Full Text]
19. Dumont N, Arteaga CL. Targeting the TGF ß signaling network in human neoplasia. Cancer Cell 2003;3:531–6.[CrossRef][Medline]
20. Ito N, Kawata S, Tamura S, et al. Positive correlation of plasma transforming growth factor-ß1 levels with tumor vascularity in hepatocellular carcinoma. Cancer Lett 1995;89:45–8.[Medline]
21. Shariat SF, Kim JH, Andrews B, et al. Preoperative plasma levels of transforming growth factor ß(1) strongly predict clinical outcome in patients with bladder carcinoma. Cancer 2001;92:2985–92.[CrossRef][Medline]
22. Shariat SF, Shalev M, Menesses-Diaz A, et al. Preoperative plasma levels of transforming growth factor ß(1) (TGF-ß(1)) strongly predict progression in patients undergoing radical prostatectomy. J Clin Oncol 2001;19:2856–64.[Abstract/Free Full Text]
23. Tsushima H, Ito N, Tamura S, et al. Circulating transforming growth factor ß1 as a predictor of liver metastasis after resection in colorectal cancer. Clin Cancer Res 2001;7:1258–62.[Abstract/Free Full Text]
24. Miettinen PJ, Ebner R, Lopez AR, Derynck R. TGF-ß induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol 1994;127:2021–36.[Abstract/Free Full Text]
25. Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E. TGF-ß1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 1996;10:2462–77.[Abstract/Free Full Text]
26. Oft M, Heider KH, Beug H. TGFß signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 1998;8:1243–52.[CrossRef][Medline]
27. Oft M, Akhurst RJ, Balmain A. Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol 2002;4:487–94.[CrossRef][Medline]
28. Tian F, Byfield SD, Parks WT, et al. Smad-binding defective mutant of transforming growth factor ß type I receptor enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Res 2004;64:4523–30.[Abstract/Free Full Text]
29. Forrester E, Chytil A, Bierie B, et al. Effect of conditional knockout of the type II TGF-ß receptor gene in mammary epithelia on mammary gland development and Polyomavirus middle T antigen induced tumor formation and metastasis. Cancer Res 2005;65:2296–302.[Abstract/Free Full Text]
30. Muraoka-Cook RS, Kurokawa H, Koh Y, et al. Conditional overexpression of active transforming growth factor ß1 in vivo accelerates metastases of transgenic mammary tumors. Cancer Res 2004;64:9002–11.[Abstract/Free Full Text]
31. Cui W, Fowlis DJ, Bryson S, et al. TGFß1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 1996;86:531–42.[CrossRef][Medline]
32. Siegel PM, Shu W, Cardiff RD, Muller WJ, Massague J. Transforming growth factor ß signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci U S A 2003;100:8430–5.[Abstract/Free Full Text]
33. Muraoka RS, Koh Y, Roebuck LR, et al. Increased malignancy of Neu-induced mammary tumors overexpressing active transforming growth factor ß1. Mol Cell Biol 2003;23:8691–703.[Abstract/Free Full Text]
34. Muraoka-Cook RS, Shin I, Yi JY, et al. Activated type I TGFß receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene 2006;24:3408–23.
35. Watanabe T, Wu TT, Catalano PJ, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 2001;344:1196–206.[Abstract/Free Full Text]
36. Wagner M, Kleeff J, Friess H, Buchler MW, Korc M. Enhanced expression of the type II transforming growth factor-ß receptor is associated with decreased survival in human pancreatic cancer. Pancreas 1999;19:370–6.[Medline]
37. Tateishi M, Kusaba I, Masuda H, Tanaka T, Matsumata T, Sugimachi K. The progression of invasiveness regarding the role of transforming growth factor ß receptor type II in gastric cancer. Eur J Surg Oncol 2000;26:377–80.[CrossRef][Medline]
38. Arteaga CL. Inhibition of TGFß signaling in cancer therapy. Curr Opin Genet Dev 2006;16:30–7.[CrossRef][Medline]
39. Yingling JM, Blanchard KL, Sawyer JS. Development of TGF-ß signalling inhibitors for cancer therapy. Nat Rev Drug Discov 2004;3:1011–22.[CrossRef][Medline]
40. Lu T, Burdelya LG, Swiatkowski SM, et al. Secreted transforming growth factor ß2 activates NF-B, blocks apoptosis, and is essential for the survival of some tumor cells. Proc Natl Acad Sci U S A 2004;101:7112–7.[Abstract/Free Full Text]
41. Wilkes MC, Mitchell H, Penheiter SG, et al. Transforming growth factor-ß activation of phosphatidylinositol 3-kinase is independent of Smad2 and Smad3 and regulates fibroblast responses via p21-activated kinase-2. Cancer Res 2005;65:10431–40.[Abstract/Free Full Text]
42. Yi JY, Shin I, Arteaga CL. Type I transforming growth factor ß receptor binds to and activates phosphatidylinositol 3-kinase. J Biol Chem 2005;280:10870–6.[Abstract/Free Full Text]
43. Horowitz JC, Lee DY, Waghray M, et al. Activation of the pro-survival phosphatidylinositol 3-kinase/AKT pathway by transforming growth factor-ß1 in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine growth factor. J Biol Chem 2004;279:1359–67.[Abstract/Free Full Text]
44. Shin I, Bakin AV, Rodeck U, Brunet A, Arteaga CL. Transforming growth factor ß enhances epithelial cell survival via Akt-dependent regulation of FKHRL1. Mol Biol Cell 2001;12:3328–39.[Abstract/Free Full Text]
45. Huang Y, Hutter D, Liu Y, et al. Transforming growth factor-ß1 suppresses serum deprivation-induced death of A549 cells through differential effects on c-Jun and JNK activities. J Biol Chem 2000;275:18234–42.[Abstract/Free Full Text]
46. Gotzmann J, Huber H, Thallinger C, et al. Hepatocytes convert to a fibroblastoid phenotype through the cooperation of TGF-ß1 and Ha-Ras: steps towards invasiveness. J Cell Sci 2002;115:1189–202.[Abstract/Free Full Text]
47. Seoane J, Le HV, Shen L, Anderson SA, Massague J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 2004;117:211–23.[CrossRef][Medline]
48. Conery AR, Cao Y, Thompson EA, Townsend CM, Jr., Ko TC, Luo K. Akt interacts directly with Smad3 to regulate the sensitivity to TGF-ß induced apoptosis. Nat Cell Biol 2004;6:366–72.[CrossRef][Medline]
49. Remy I, Montmarquette A, Michnick SW. PKB/Akt modulates TGF-ß signalling through a direct interaction with Smad3. Nat Cell Biol 2004;6:358–65.[CrossRef][Medline]
50. Janda E, Lehmann K, Killisch I, et al. Ras and TGF[ß] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 2002;156:299–313.[Abstract/Free Full Text]
51. Kretzschmar M, Doody J, Timokhina I, Massague J. A mechanism of repression of TGFß/Smad signaling by oncogenic Ras. Genes Dev 1999;13:804–16.[Abstract/Free Full Text]
52. Saha D, Datta PK, Beauchamp RD. Oncogenic ras represses transforming growth factor-ß/Smad signaling by degrading tumor suppressor Smad4. J Biol Chem 2001;276:29531–7.[Abstract/Free Full Text]
53. Mulder KM. Role of Ras and Mapks in TGFß signaling. Cytokine Growth Factor Rev 2000;11:23–35.[CrossRef][Medline]
54. Ventura JJ, Kennedy NJ, Flavell RA, Davis RJ. JNK regulates autocrine expression of TGF-ß1. Mol Cell 2004;15:269–78.[CrossRef][Medline]
55. Seton-Rogers SE, Lu Y, Hines LM, et al. Cooperation of the ErbB2 receptor and transforming growth factor ß in induction of migration and invasion in mammary epithelial cells. Proc Natl Acad Sci U S A 2004;101:1257–62.[Abstract/Free Full Text]
56. Ueda Y, Wang S, Dumont N, Yi JY, Koh Y, Arteaga CL. Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor ß-induced cell motility. J Biol Chem 2004;279:24505–13.[Abstract/Free Full Text]
57. Mead AL, Wong TT, Cordeiro MF, Anderson IK, Khaw PT. Evaluation of anti-TGF-ß2 antibody as a new postoperative anti-scarring agent in glaucoma surgery. Invest Ophthalmol Vis Sci 2003;44:3394–401.[Abstract/Free Full Text]
58. Benigni A, Zoja C, Corna D, et al. Add-on anti-TGF-ß antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat. J Am Soc Nephrol 2003;14:1816–24.[Abstract/Free Full Text]
59. Siriwardena D, Khaw PT, King AJ, et al. Human antitransforming growth factor ß(2) monoclonal antibody—a new modulator of wound healing in trabeculectomy: a randomized placebo controlled clinical study. Ophthalmology 2002;109:427–31.[CrossRef]
60. Muraoka RS, Dumont N, Ritter CA, et al. Blockade of TGF-ß inhibits mammary tumor cell viability, migration, and metastases. J Clin Invest 2002;109:1551–9.[CrossRef][Medline]
61. Bandyopadhyay A, Lopez-Casillas F, Malik SN, et al. Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft. Cancer Res 2002;62:4690–5.[Abstract/Free Full Text]
62. Peng SB, Yan L, Xia X, et al. Kinetic characterization of novel pyrazole tgf-ß receptor I kinase inhibitors and their blockade of the epithelial-mesenchymal transition. Biochemistry 2005;44:2293–304.[CrossRef][Medline]
63. DaCosta Byfield S, Major C, Laping NJ, Roberts AB. SB-505124 is a selective inhibitor of transforming growth factor-ß type I receptors ALK4, ALK5, and ALK7. Mol Pharmacol 2004;65:744–52.[Abstract/Free Full Text]
64. Inman GJ, Nicolas FJ, Callahan JF, et al. SB-431542 is a potent and specific inhibitor of transforming growth factor-ß superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol 2002;62:65–74.[Abstract/Free Full Text]
65. Liau LM, Fakhrai H, Black KL. Prolonged survival of rats with intracranial C6 gliomas by treatment with TGF-ß antisense gene. Neurol Res 1998;20:742–7.[Medline]
66. Bogdahn U, Hau P, Brawanski A, et al. Specific therapy for high-grade glioma by convection-enhanced delivery of the TGF-ß2 specific antisense oligonucleotide AP12009. Proc Am Soc Clin Oncol 2004;23:110.
67. Schlingensiepen K-H, Bischof A, Egger T, et al. The TGF-ß1 antisense oligonucleotide AP 11014 for the treatment of non-small-cell lung, colorectal and prostate cancer: preclinical studies. Proc Am Soc Clin Oncol 2004;23:227.

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				B. A Teicher, J. M Yingling, and J. M McPherson TGF{beta} Blockade as Anticancer Therapy Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 71 - 81. [Abstract] [Full Text] [PDF]

				B. A. Teicher Transforming Growth Factor-{beta} and the Immune Response to Malignant Disease Clin. Cancer Res., November 1, 2007; 13(21): 6247 - 6251. [Abstract] [Full Text] [PDF]

				Y. S. Kim and J. A. Milner Dietary Modulation of Colon Cancer Risk J. Nutr., November 1, 2007; 137(11): 2576S - 2579S. [Abstract] [Full Text] [PDF]

				M. Mimeault and S. K. Batra Interplay of distinct growth factors during epithelial mesenchymal transition of cancer progenitor cells and molecular targeting as novel cancer therapies Ann. Onc., October 1, 2007; 18(10): 1605 - 1619. [Abstract] [Full Text] [PDF]

				B. Y. Chin, G. Jiang, B. Wegiel, H. J. Wang, T. MacDonald, X. C. Zhang, D. Gallo, E. Cszimadia, F. H. Bach, P. J. Lee, et al. Hypoxia-inducible factor 1{alpha} stabilization by carbon monoxide results in cytoprotective preconditioning PNAS, March 20, 2007; 104(12): 5109 - 5114. [Abstract] [Full Text] [PDF]

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