|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 23, No 9 (March 20), 2005: pp. 2078-2093 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.047
Role of Transforming Growth Factor Beta in Human CancerFrom the Duke University Medical Center, Departments of Medicine and Pharmacology and Cancer Biology, Durham, NC Address reprint requests to e-mail: Gerard C. Blobe, MD, PhD, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, 221 BMSRB Research Drive, Box 2631 DUMC, Durham, NC 27710; e-mail: blobe001{at}mc.duke.edu
Transforming growth factor beta (TGF-ß) is a ubiquitous and essential regulator of cellular and physiologic processes including proliferation, differentiation, migration, cell survival, angiogenesis, and immunosurveillance. Alterations in the TGF-ß signaling pathway, including mutation or deletion of members of the signaling pathway and resistance to TGF-ß-mediated inhibition of proliferation are frequently observed in human cancers. Although these alterations define a tumor suppressor role for the TGF-ß pathway in human cancer, TGF-ß also mediates tumor-promoting effects, either through differential effects on tumor and stromal cells or through a fundamental alteration in the TGF-ß responsiveness of the tumor cells themselves. TGF-ß and members of the TGF-ß signaling pathway are being evaluated as prognostic or predictive markers for cancer patients. Ongoing advances in understanding the TGF-ß signaling pathway will enable targeting of this pathway for the chemoprevention and treatment of human cancers.
The complex process of tumor formation in humans has been distilled to a series of stochastic events that occur in virtually all human cancers.1 These hallmarks include seven functions that cancer cells acquire: the ability to become resistant to growth inhibitory factors, proliferate in the absence of exogenous growth factors, invade and metastasize, achieve limitless replication potential, evade apoptosis, recruit a blood supply through angiogenesis, and evade destruction by the immune system. Acquisition of these functions is facilitated by a general property of human cancer cells: their genomic instability. Each of these functions is regulated through signal transduction pathways that normally control cellular homeostasis. Thus, human tumorigenesis can be viewed as a disruption of these pathways, through genetic, epigenetic, or somatic alterations. One of these signal transduction pathways, the transforming growth factor beta (TGF-ß) pathway, has a defined yet complex role in mediating or regulating each of these hallmarks (Table 1). Despite the prominent role of this pathway in tumorigenesis, targeting of the TGF-ß pathway has been hampered by insufficient understanding of the mechanisms regulating the pathway in vivo and by the heterogeneity of alterations that occur in the pathway in human cancers. This review highlights the role of the TGF-ß pathway in these hallmarks of human cancer and the specific role of the pathway in the four most common human cancers (cancers of the breast, colon, lung, and prostate). The review concludes with a discussion of the utility of assessing the pathway for diagnostic, prognostic, or predictive purposes, and potential strategies for targeting the pathway for the chemoprevention or treatment of human cancers.
The TGF-ß signaling pathway has been the focus of several recent reviews.9–11 Three TGF-ß isoforms are expressed in mammals (TGF-ß1, TGF-ß2, and TGF-ß3) and each is encoded by a unique gene and expressed in both a tissue-specific and developmentally regulated fashion. TGF-ß1 is the most abundant and universally expressed isoform; most studies have either examined or been performed with exogenous TGF-ß1. TGF-ß is secreted into the extracellular matrix as a latent protein complex bound to a latency-associated protein and one of the four isoforms of latent TGF-ß binding protein. Activation of TGF-ß, which is required for biologic activity, occurs through poorly understood mechanisms likely involving proteolytic processing of the associated proteins and release of the TGF-ß ligand. Once activated, the TGF-ß ligands regulate cellular processes by binding to three high-affinity cell surface receptors: the type I TGF-ß receptor (TßRI), type II TGF-ß receptor (TßRII), and type III TGF-ß receptor (TßRIII, also referred to as betaglycan). Where expressed, TßRIII is the most abundant TGF-ß receptor and classically functions by binding the TGF-ß ligand and transferring it to its signaling receptors, TßRI and TßRII.12 TßRI and TßRII contain serine/threonine protein kinases in their intracellular domains. TßRI initiates intracellular signaling by phosphorylating a family of transcription factors, the Smads. Smad2 and Smad3 are the receptor-activated Smads for TGF-ß because they are phosphorylated by TßRI. Smad4 is a common partner for all of the receptor-activated Smads. Smad6 and Smad7 are inhibitory Smads that block the phosphorylation of Smad2 or Smad3, thus inhibiting TGF-ß signaling. A general mechanism for TGF-ß signaling has been elucidated (Fig 1).13,14 The TGF-ß ligand either binds to TßRIII, which presents TGF-ß to TßRII, or binds to TßRII directly. Once bound to TGF-ß, TßRII recruits, binds, and transphosphorylates TßRI, thereby stimulating its protein kinase activity. The activated TßRI phosphorylates Smad2 or Smad3, which binds to Smad4. The resulting Smad complex translocates into the nucleus and interacts in a cell-specific manner with transcription factors to regulate specifically the transcription of a multitude of TGF-ß-responsive genes. TGF-ß signaling is regulated by the level and duration of TGF-ß receptor activation, with continuous nucleocytoplasmic shuttling of Smads permitting them to monitor the levels of activated receptors continuously.15 In addition, TGF-ß signaling may be regulated by internalization of the receptors, with some studies suggesting that receptor internalization is required for signaling,16–18 and others suggesting a role for internalization in downregulation of signaling.18,19
Although TßRI, TßRII, Smad2, Smad3, and Smad4 comprise the core Smad-dependent TGF-ß signaling pathway, Smad-independent signaling through mitogen-activated protein kinase (MAPK) signaling pathways,20–22 Rho guanosine triphosphatases,23 PI-3 kinase/Akt,24 and protein phosphatase 2A25 has been reported; precise molecular mechanisms by which the TGF-ß signaling pathway signals to these pathways have not been established.
Resistance to Antiproliferative Signals and Independence From Exogenous Growth Signals Cellular proliferation is normally regulated by the concerted action of both mitogenic growth signals and antiproliferative signals that converge on regulators of the cell cycle. To proliferate in a dysregulated manner, cancer cells become resistant to these antiproliferative signals and proliferate in the absence of exogenous mitogenic growth signals. TGF-ß is an important regulator of cellular proliferation. Although first identified and named for its ability to stimulate the proliferation and transformation of mesenchymal cells,26 TGF-ß potently inhibits epithelial, endothelial, and hematopoietic cell proliferation. Although the precise mechanism for this growth-inhibitory effect remains elusive, TGF-ß is able to prevent progression through the cell cycle first by inducing expression of the cyclin kinase inhibitors p15INK4b,27 p21CIP1,28 and p27KIP1,29 which block cyclin and cyclin-dependent kinases from phosphorylating the retinoblastoma protein (Rb), thus allowing the hypophosphorylated form of Rb to bind and sequester the E2F transcription factor, and second by directly suppressing c-myc expression.30 Although the growth-inhibitory effect of TGF-ß is believed to be mediated by the Smad-dependent TGF-ß signaling pathway, there have been reports of TGF-ß-mediated inhibition of proliferation in Smad4 null cells.22 Furthermore, the growth-inhibitory effect of TGF-ß can be mediated by Smad-independent pathways, including the MAPK pathways31 and the PP2A/p70S6 kinase pathway.25 Virtually all epithelial-derived tumors (> 85% of all human cancers) become resistant to the growth-inhibitory effects of TGF-ß. In some cancers, including colon and pancreatic cancers, mechanisms for resistance are well defined,32,33 with defects in the Smad proteins (predominately Smad4, originally cloned as deleted in pancreatic cancer 4 [DPC4]) or in TGF-ß receptors, (predominately TßRII, which is a target for mismatch repair errors in hereditary nonpolyposis colon cancer). However, in most human cancers, including cancers of the breast, lung, and prostate, mechanisms for resistance to TGF-ß-mediated inhibition of proliferation remain poorly defined. Proposed alternative mechanisms for resistance to TGF-ß include decreased expression of TßRI,34 TßRII,35 or TßRIII36 on the cell surface; increased expression of the inhibitory Smad, Smad737; repression of TGF-ß signaling by a variety of oncoproteins including p53,38 Myc,39 E1A,40 Ras,41 Ski/SnoN,42,43 and Evi-144; reduced expression or inactivation of tumor suppressors that directly regulate the TGF-ß signaling pathway including Menin,45 Disabled-2,46 and RUNX347; and activation of other signaling pathways including protein kinase C (PKC).48
Cancer cells become independent of exogenous mitogenic growth signals either through overexpression of the mitogenic growth factors themselves or constitutive activation of the signaling pathway downstream of these growth factors. Similar to its effect on mesenchymal cells, TGF-ß is able to stimulate the proliferation of a number of epithelial-derived cancer cell lines, including colon, pancreatic, and prostate cancer cells.3,49,50 Although the precise mechanism by which this is accomplished has not been defined, TGF-ß is able to increase the production of mitogenic growth factors, including platelet-derived growth factor,51 fibroblast growth factor,52 TGF-
Tissue Invasion and Metastasis TGF-ß normally stimulates the production of the extracellular matrix by directly increasing the production of extracellular matrix proteins, including collagen and fibronectin; decreasing the production of enzymes that degrade the extracellular matrix, including collagenase, heparinase, and stromelysin; and increasing the production of proteins that inhibit enzymes that degrade the extracellular matrix, including plasminogen activator inhibitor-1 and tissue inhibitor of metalloprotease.64 However, during tumorigenesis, TGF-ß frequently stimulates the proteolytic activity of cancer cells by increasing the expression of matrix-degrading enzymes.4 Taken together, by decreasing the adhesiveness and increasing the motility and proteolytic activity of cancer cells, increased levels of TGF-ß result in more invasive cancer cells, which may represent one of the tumor-promoting activities of TGF-ß.65 Indeed, exogenous TGF-ß1 increases the invasiveness and metastatic behavior of breast cancer cells in vivo, even while inhibiting their proliferation in vitro.66
Limitless Replication Potential Cancer cells upregulate telomerase through activating transcription of the catalytic component of human telomerase, hTERT.67 Somatic cells have numerous mechanisms to suppress telomerase expression and mechanisms that relieve this suppression during tumorigenesis are not fully understood. Both autocrine and exogenous TGF-ß potently suppress hTERT expression at the transcriptional level.5 A recent screen for negative regulators of telomerase identified three genes in known tumor suppressor/oncogene pathways: Mad1, Menin, and SIP1/ZEB-2.68 Mad1, Menin, and Sip1 are all direct transcriptional targets of the TGF-ß signaling pathway.45,69,70 Mad1 and Menin are both transcriptional repressors and function by directly binding the hTERT promoter, whereas Sip1 is necessary for TGF-ß-induced hTERT repression.68 Thus, the TGF-ß signaling pathway downregulates hTERT expression through at least three distinct mechanisms, suggesting that TGF-ß may mediate its tumor suppressor effects, in part, through suppressing telomerase expression. hTERT expression has also been demonstrated to directly induce resistance to the growth inhibitory effects of TGF-ß in human mammary epithelial cells lacking p16INK4, suggesting that there is significant coregulation between the TGF-ß signaling pathway and the pathways regulating telomerase function.71
Evasion of Apoptosis The mechanisms by which TGF-ß induces and regulates apoptosis are cell and context specific. TGF-ß-induced apoptosis is frequently mediated by the Smad-dependent pathway.83,84 However, the inhibitor Smad, Smad7, has been shown to promote TGF-ß-induced apoptosis in prostate carcinoma cells and lung epithelial cells,82,85 and Smad-independent pathways, including Daxx-mediated JNK activation,86 may also be involved. TGF-ß-induced apoptosis may occur through both p53-dependent87 and p53-independent mechanisms,75 and involves caspase activation,88 upregulation of proapoptotic factors (ie, Bax), and/or downregulation of antiapoptotic factors (ie, Bcl-2 and Bcl-xL).87 The TGF-ß signaling pathway also interacts with other pathways that regulate apoptosis. For example, TGF-ß is able to enhance Fas-induced apoptosis under conditions in which TGF-ß alone does not induce apoptosis,89 whereas activation of the PI-3 kinase/Akt pathway is able to inhibit TGF-ß-mediated apoptosis.90 Recent studies have identified a direct interaction of Akt with Smad3 that prevents Smad3 phosphorylation and Smad3 nuclear translocation, and inhibits both Smad3-mediated transcriptional events and apoptosis.91,92 Furthermore, the ratio of Smad3 to Akt correlates with the sensitivity of cells to TGF-ß-mediated apoptosis, providing a potential explanation for the variable apoptotic response of cells to TGF-ß.91,92 Resistance to TGF-ß-induced apoptosis may be an essential component of tumorigenesis, particularly for cancers arising from tissues in which TGF-ß is a prominent regulator of apoptosis, including hepatocellular carcinoma and prostate cancer. In addition, the ability of TGF-ß to induce apoptosis in lymphocytes may be a critical component for the immunosuppressive effect of TGF-ß during tumorigenesis.
Induction of Angiogenesis TGF-ß signaling in endothelial cells is unique in that TGF-ß can activate two distinct pathways: the classical Smad-dependent pathway through TßRII and TßRI (also known as ALK-5) to activate Smads 2 and 3, and the pathway through TßRII and ALK-1 to activate Smads 1, 5, and 8, which are usually activated by the TGF-ß superfamily members, the bone morphogenetic proteins.102 These two pathways have opposing effects on endothelial cell proliferation and migration. The balance of signaling between these pathways regulates endothelial cell biology through the activation (increased endothelial cell proliferation and migration) and maturation (decreased endothelial cell proliferation and migration) phases of angiogenesis.103,104 These opposing pathways likely explain the ability of TGF-ß to mediate proangiogenic or antiangiogenic effects in vitro. Endoglin is a likely candidate to regulate the balance of TGF-ß signaling through these pathways in endothelial cells, inhibiting the ALK-5 pathway105 while activating the ALK-1 pathway.106
Evasion of the Immune System The immunosuppressive effects of TGF-ß have been demonstrated both in vitro and in vivo,112 and are mediated predominantly through effects on T cells and antigen presenting cells (APCs). TGF-ß is produced by T cells and blocks production of interleukin 2 (IL-2) to inhibit IL-2-dependent proliferation of T cells.113 TGF-ß also inhibits the differentiation of T cells, and prevents naïve T cells from acquiring effector (cytotoxic or helper) functions.114 TGF-ß may also mediate some of its immunosuppressive effects on T cells through CD4+CD25+ regulatory T cells, which both secrete TGF-ß1 and express cell surface-bound TGF-ß1.115 These in vitro effects of TGF-ß on T cells have been validated in murine models. TGF-ß1-deficient mice develop a severe autoimmune phenotype leading to death by 3 weeks, in part, from overactive T cells,116 and T-cell-specific abrogation of TGF-ß signaling in mice results in spontaneous T-cell activation and the development of an autoimmune disease of the lung and colon.117 TGF-ß also has potent effects on APCs. Macrophages secrete TGF-ß, which inhibits tissue macrophage activation.118 TGF-ß also is required for differentiation of dendritic cells from precursors, primarily by protecting their viability.119 In vivo, TGF-ß1-deficient mice have a complete absence of Langerhans cells in the epidermis, although they express functional precursors, suggesting that TGF-ß is required for normal Langerhans cell development and/or migration to the epidermis.120
Genome Instability
In addition to the role the TGF-ß signaling pathway has in directly mediating and regulating these hallmarks of cancer, the TGF-ß signaling pathway and other prominent signaling pathways cross-talk to regulate tumor biology. For example, the Wnt and TGF-ß pathways cooperate to suppress colon125 and pancreatic126 tumorigenesis through several direct interactions between these pathways: Axin, a negative regulator of the Wnt pathway, activates TGF-ß signaling through binding Smad3,127 whereas the HMG box transcription factor, lymphoid enhancer binding factor 1/T-cell-specific factor (LEF1/TCF), a mediator of Wnt effects, interacts directly with Smad3 to coordinately regulate LEF1/TCF target genes,128 and ß-catenin and LEF1/TCF both interact directly with Smad4 to regulate target genes during development.129 The PKC pathway has also been shown to interact with the TGF-ß pathway to regulate tumorigenesis. In murine colon cancer models, elevated expression of PKCßII elevates cyclooxygenase-2 expression and represses TßRII expression to increase susceptibility to colon cancer.130
TGF-ß has the potential to function as a tumor suppressor (via its effects on proliferation, replication potential, and apoptosis) and as a tumor promoter (via its effects on migration, invasion, angiogenesis, and the immune system; Fig 2). Indeed, in animal models, evidence for TGF-ß in mediating each of these roles has been established. The tumor suppressor role is evident in that hemizygous Tgfb1-null animals, which express 10% to 30% of wild-type TGF-ß1 levels, develop an increased number of chemically induced tumors,131 and hemizygous Smad4-null animals when mated with hemizygous adenomatous polyposis coli-null animals develop more invasive colonic tumors.125 The tumor-promoting effects of TGF-ß have been demonstrated by the ability of agents that block TGF-ß signaling (dominant negative TßRII or neutralizing TGF-ß antibodies) to inhibit the invasiveness of cancer cell lines in vitro and their metastatic ability in vivo,132 and by the ability of TGF-ß to directly stimulate the motility of cancer cells.63
TGF-ß has also been demonstrated to have this dichotomous function in humans cancers. The tumor suppressor role is supported by the loss or mutation of members of the TGF-ß signaling pathway in human cancers, particularly colon and pancreatic cancers,32,33 with resulting resistance to TGF-ß-mediated effects correlating to malignant progression.133 The tumor-promoting effect is supported by the elevated levels of TGF-ß found in patients in the latter stages of cancers, with this increased production associated with increased invasiveness and a poorer prognosis for these patients.65,134,135 How can this dichotomy of function be resolved? The prevailing theory suggests that during tumorigenesis TGF-ß functions as both a tumor suppressor and as a tumor promoter, mediating tumor suppressor functions early on, and tumor promoting functions later in the course of disease (Fig 2). Several studies using animal models support both a tumor-suppressor and a tumor-promoter role for TGF-ß during tumorigenesis. When TGF-ß1 overexpression is targeted to the keratinocytes of mice and their skin is exposed to chemical carcinogens, TGF-ß initially inhibits the formation of benign skin tumors, consistent with its tumor-suppressor action. However, in the benign tumors that form, progression to invasive spindle carcinomas is increased, consistent with its tumor-promoting action.136 In addition, introduction of a dominant negative TßRII (to block TGF-ß signaling) into a series of human breast-derived cell lines representing different stages in breast cancer progression cooperates with other oncogenic stimuli to make premalignant cells tumorigenic and low-grade tumorigenic cells more aggressive, while decreasing the metastatic potential of high-grade tumorigenic cells.137 Finally, transgenic mice expressing activated TßRI under control of the mouse mammary tumor virus promoter crossed with mice expressing activated Neu receptor have an increased primary tumor latency but enhanced frequency of lung metastases, whereas transgenic mice expressing dominant negative TßRII crossed with mice expressing activated Neu receptor have decreased primary tumor latency, but significantly fewer lung metastases.138 The precise mechanism for the dichotomous function of TGF-ß in human cancers remains poorly defined. In one proposed scenario, TGF-ß mediates tumor suppressor functions on precancerous epithelial cells by inhibiting proliferation and telomerase, and stimulating differentiation and apoptosis as appropriate (Fig 2). During carcinogenesis, the epithelial-derived cancer cells, through mechanisms defined here and others yet to be discerned, become resistant to these tumor-suppressor effects of TGF-ß. The cancer cells then increase their production of TGF-ß, which promotes tumorigenesis, predominately through effects on the stroma (altering the extracellular matrix and adhesion molecules to increase metastasis; increasing angiogenesis; and inducing immunosuppression). However, another potential scenario is that the tumor-suppressor and tumor-promotor effects are both mediated by effects on the epithelial-derived cancer cells themselves, which undergo a fundamental alteration in their TGF-ß responsiveness whereby they become resistant to the tumor-suppressor effects of TGF-ß (growth inhibition, differentiation, antiapoptotic, suppression of telomerase) but remain responsive to the tumor-promotor effects (enhanced motility, migration, and invasion; Fig 2).132,139 This fundamental alteration in TGF-ß responsiveness may occur as the cancer cells undergo an epithelial to mesenchymal transition (EMT). During EMT, epithelial cells lose their epithelial phenotype (strong cell-cell contact, nonmotility) and adopt a mesenchymal cell phenotype (reduced cell-cell contact, increased motility, and invasion of surrounding tissues).140 EMT is a well-established process during development and, when examined, has been documented to occur in 24% to 45% of human breast cancers,132 39% to 60% of gastric cancers,141 and 74% of renal cell cancers.132 TGF-ß is able to induce EMT in a number of cancer models either by itself or in cooperation with oncogenic Ras (Ha-Ras), and an intact TGF-ß signaling pathway is necessary for cancer cell invasion and metastasis in at least one model of breast EMT.132 EMT is an attractive model for the fundamental alteration in TGF-ß responsiveness because TGF-ß is known to have strikingly disparate effects on epithelial cells and mesenchymal cells. The mechanism by which TGF-ß induces EMT in vivo has been not been established, but studies in vitro have indicated that this proceeds through both Smad-dependent and Smad-independent pathways.24,142 Recent studies have implicated TßRIII in EMT and as a potential mediator of the differential effects of TGF-ß on epithelial and mesenchymal cells. Specifically, TßRIII has been shown to have an essential nonredundant role in TGF-ß signaling, mediating the effects of TGF-ß on EMT in chick embryonic heart development,143 and TßRIII is downregulated during EMT in a human breast epithelial cell model.144 In addition, TßRIII has been demonstrated to enhance TGF-ß signaling in mesenchymal cells,145 but to inhibit TGF-ß signaling in epithelial cells.146 TßRIII also has an emerging role in regulating tumorigenesis, with decreased expression of TßRIII reported in human breast cancer cell lines147 and renal cell cancer cell lines.148 In concordance with this, re-expression of TßRIII in breast cancer cell lines and renal cell cancer cell lines that lack TßRIII expression suppresses their tumorigenicity in vivo.147,148 Taken together with recent reports supporting a substantial role for TßRIII in regulating TGF-ß signaling,19 these observations suggest an emerging role for TßRIII in mediating and/or regulating the effects of TGF-ß, including the dichotomous effects during tumorigenesis.
Because TGF-ß has a prominent role in epithelial cell function and epithelial-derived tumors represent the vast majority of human cancers, we focus on the four most prevalent human cancers: cancers of the breast, colon, lung, and prostate, which together comprise more than 50% of the new occurrences and cancer deaths in the United States each year (Table 2).
Breast Cancer TGF-ß has an important role in normal mammary biology as a potent regulator of mammary epithelial proliferation, mammary ductal and alveolar development, and postlactation involution of the mammary gland.159 The TGF-ß signaling pathway also has an important role in human mammary carcinogenesis. Data to support this include: evidence that TGF-ß can act directly on breast epithelial cells to potently inhibit their growth160; mutation in or loss of expression of members of the TGF-ß signaling pathway including TßRII and TßRI in some human breast cancers149; demonstration that most human breast cancers develop resistance to the antiproliferative effects of TGF-ß despite expression of Smad3, Smad4, TßRI, and TßRII150; decreased breast cancer formation in human patients with elevated levels of TGF-ß161; evidence that the chemopreventive and therapeutics effects of the antiestrogen agent, tamoxifen, may be mediated through potent induction of TGF-ß1162; demonstration of increased TGF-ß levels in human breast cancers, with production increasing with advancing stages of tumor progression,163 decreasing after surgical resection,164 and persistently elevated levels after surgical resection correlating with lymph node metastasis or residual tumor164; and elevated TGF-ß levels conferring a poorer prognosis for human breast cancer patients.165 These results suggest that although resistance to the growth-inhibitory effects of TGF-ß is a key cellular event during mammary carcinogenesis, mechanisms for this resistance remain to be defined. In addition, TGF-ß clearly has a dichotomous function in human breast cancer, and this dichotomous function has been demonstrated in animal models as discussed previously.
Colon Cancer The Smad4 gene is mutated or deleted in 20% of invasive colorectal carcinomas, whereas it is altered in only 5% of adenomas and noninvasive carcinomas,152 consistent with loss of TGF-ß sensitivity occurring in the later stages of colorectal carcinogenesis. Inactivating mutations in the Smad2 gene are less common, but have been detected in 6% of colorectal carcinomas.153 A critical role for the TGF-ß signaling pathway in colon cancer is further supported by the finding of Smad4 mutations in a subset of patients with familial juvenile polyposis, an autosomal dominant disease characterized by a predisposition to hamartomatous polyps and cancers of the GI tract.171 Although these mutations in colon cancers and colon cancer syndromes define a tumor-suppressor role for the TGF-ß signaling pathway, there is evidence that TGF-ß can also have a tumor-promoting role in colon cancer. In some colon cancer models, TGF-ß increases tumor invasion and metastasis to increase tumorigenicity.132 In addition, the fact that RER-positive tumors (the majority of which have TßRII mutations) are less aggressive clinically despite being more poorly differentiated172 is consistent with the importance of TGF-ß sensitivity for invasiveness and metastatic potential of colon cancers.
Lung Cancer
Prostate Cancer Consistent with an essential role in prostate cancer tumorigenesis, loss of TGF-ß receptor expression correlates with advanced Gleason score and tumor stage, and thus predicts a poor prognosis for these patients.179 In addition, elevated urinary or plasma TGF-ß levels have been consistently associated with a worse prognosis for patients with prostate cancer.135 Because bone is a rich source of TGF-ß, TGF-ß may also regulate the blastic bone metastases characteristic of prostate cancer by mediating the ability of prostate cancer cells to migrate and invade into the bone.180
Given that TGF-ß has important roles in tumor suppression and tumor progression, measurements of TGF-ß ligand (in serum, urine, and tissue), TGF-ß mRNA (in tissue), or TGF-ß receptor levels may serve as diagnostic, prognostic, or predictive tools. Although increased TGF-ß1 protein levels are found in the serum of patients with invasive breast cancer,163 colorectal cancer,181 hepatocellular carcinoma,182 lung cancer,183 metastatic melanoma,184 and prostate cancer,185 and urinary excretion of TGF-ß1 is increased in patients with hepatocellular carcinoma,186 a diagnostic role for elevated TGF-ß levels has not yet been established. However, a recent study demonstrated that elevated serum levels of TGF-ß1 were a more sensitive indicator of small hepatocellular carcinomas than alpha-fetoprotein levels, suggesting that measuring serum TGF-ß1 levels may be clinically useful for diagnosing these tumors.182 In addition, elevated expression of the endothelial-specific TGF-ß receptor endoglin on tumor-associated vasculature does have the potential to enhance detection of solid tumors that may not be identified by other means.187 Several studies have revealed the potential clinical prognostic or predictive utility of TGF-ß or TGF-ß receptor levels. For example, increased TGF-ß1 serum protein levels are predictive of liver metastasis after surgery for colon cancer,188 prostate cancer progression after radical prostatectomy,189 bladder cancer recurrence after radical cystectomy,190 and lymph node metastases and peritoneal recurrence after gastric cancer surgery.191 High serum TGF-ß1 concentrations also correlate with the development of fibrosis in postradiation therapy breast cancer patients,192 and with the development of chronic graft-versus-host disease, idiopathic interstitial pneumonitis, and veno-occlusive disease in hematopoietic stem-cell transplantation patients.193,194 Early increases in serum TGF-ß2 concentrations also predict a clinical response to tamoxifen in breast cancer patients.161 In non-small-cell lung cancer patients, plasma TGF-ß1 levels may be useful to select patients for radiation therapy dose escalation, thus increasing response rates without increasing toxicity.195 TßRII mutations in colon cancers with microsatellite instability196 and SMAD4 diploidy197 are predictive of a significantly better prognosis after adjuvant chemotherapy, whereas loss of TßRII expression in renal cell cancers198 and tumor microvessel density of breast,199 colon,200 and lung201 cancer specimens quantified using a antibody to endoglin predicts a worse prognosis. Finally, a TGF-ß1 polymorphism (T29-C), has been associated with a higher level of serum TGF-ß1 and with a decreased risk of breast cancer.202
In human cancers, TGF-ß promotes tumorigenesis through both decreased TGF-ß signaling during early tumorigenesis and increased TGF-ß signaling in advanced, progressive disease. In addition, TGF-ß has complex and often opposing context-specific effects on its cellular targets, mediating these cellular effects through several TGF-ß-specific pathways and through cross-talk with other signaling pathways. Finally, the TGF-ß signaling pathway has a complex role in other human diseases including cardiovascular disease and fibrotic disease.64 Although each of these factors represents a fundamental challenge to targeting the TGF-ß pathway, numerous preclinical strategies have been tried with an encouraging degree of success. In clinical scenarios involving decreased TGF-ß activity, attempts to restore or increase TGF-ß signaling could be used as a chemoprevention strategy, as a postsurgical adjuvant therapy, or as a therapy for early-stage disease. Indeed, the effects of the chemopreventive agents tamoxifen and retinoids may be mediated through their ability to increase serum TGF-ß concentrations.203,204 Increased understanding of TGF-ß ligand activation and the generation of agents that could increase activation may also lead to potential chemoprevention agents. Many human cancers become resistant to the antiproliferative effects of TGF-ß through decreased receptor expression (as opposed to mutation or deletion of the receptor). In these cases, increasing expression of the receptors may be a reasonable therapeutic target. Indeed, increasing expression of TßRII through use of the histone deacetylase inhibitor MS-275,205 the angiotensin-converting enzyme inhibitor captopril,206 the farnesyltransferase inhibitor FTI-277,207 and indirectly, through induction of Sp1 by DNA methyl transferase inhibitor 5-aza-2'-deoxycytidine,208 are all able to restore sensitivity to TGF-ß. Given that the ubiquitin/proteasome pathway has a role in regulating TGF-ß receptor expression,209 the use of proteasome inhibitors such as bortezomib (Velcade; Millennium Pharmaceuticals, Cambridge, MA), could also have a potential role in increasing TGF-ß receptor expression. These agents potentially could be used in conjunction with standard adjuvant therapy for colon cancer and SCLCs, both of which frequently have decreased TßRII levels. In clinical scenarios involving increased TGF-ß activity, attempts to decrease or abrogate TGF-ß signaling could be used as a therapy for advanced or metastatic disease. Attempts to block the effects of excessive TGF-ß activity have involved agents that inhibit TGF-ß binding to its receptors including natural TGF-ß inhibitors (eg, decorin),210 neutralizing TGF-ß antibodies,7 and soluble extracellular domains of TßRII (sTßRII)211 or TßRIII (sTßRIII).212 Several neutralizing TGF-ß antibodies are currently being developed, including humanized monoclonal TGF-ß1- and TGF-ß2-specific antibodies,213 as well as antibodies that recognize all three isoforms of TGF-ß (pan-TGF-ß antibodies).7 Although isoform-specific antibodies may be better tolerated, the contribution of the individual isoforms to the effects of TGF-ß on tumorigenesis in vivo has not been firmly established, making selection of a specific isoform target difficult. With regard to agents using the soluble extracellular domains of receptors, sTßRIII has several advantages over sTßRII. First, sTßRIII is a naturally occurring protein generated by ectodomain shedding of TßRIII,214 and as such, an immune response should not be generated. Second, sTßRIII binds to all three TGF-ß isoforms with high affinity, whereas sTßRII binds to only TGF-ß1 and TGF-ß3. Third, sTßRIII has two TGF-ß binding sites as opposed to one TGF-ß binding site in sTßRII. Attempts to block the effects of excessive TGF-ß activity for the treatment of cancer have also included agents that directly inhibit TGF-ß signaling, including overexpression of the inhibitory Smad or Smad7,82 or of dominant-negative TßRII (truncation mutant lacking the kinase domain),137 and most recently, small molecule inhibitors of TßRI kinase activity.215,216 These small molecule inhibitors of TßRI exhibit a significant degree of specificity for type I TGF-ß superfamily receptors over other cellular serine and threonine kinases (ie, PKC, ERK, JNK, or p38 MAPK).215,216 However, the inhibitor for TßRI (ALK-5) also inhibits other type I TGF-ß superfamily receptors including ALK-4 (a type I receptor for the TGF-ß superfamily member, activin) and ALK-7,215 increasing the likelihood of nonspecific adverse effects. Although global blockade of TGF-ß signaling might be expected to have an undesirable adverse effect profile, expression of a soluble chimeric protein of the extracellular domain of TßRII and the Fc portion of the murine or human immunoglobulin G1 heavy chain (Fc: TßRII) has been shown to inhibit mammary tumor viability and block metastasis in murine models, without significant adverse effects such as autoimmune disease or tumor promotion, even with lifelong exposure.217,218 Application of targeted therapies to block elevated TGF-ß signaling in advanced and metastatic cancers may initially be used in humans to block specific tumor-promoting effects of TGF-ß including proangiogenic and immunosuppressive functions in vivo. With regard to the proangiogenic effects of TGF-ß, because the expression of the endothelial-specific TGF-ß receptor endoglin is upregulated during tumor-induced angiogenesis, antiendoglin antibodies coupled to toxins and radionuclides have been used to selectively target the tumor vasculature in animal models with marked success.219 Given that the TGF-ß signaling pathway has a defined role in tumor-induced immunosuppression,107 inhibitors of this pathway may be used to improve natural immunosurveillance of tumor cells or to enhance the effectiveness of active or passive immunotherapy strategies. Indeed, many of the aforementioned strategies to block the TGF-ß signaling pathway have been demonstrated to improve the ability of the immune system to destroy tumors in animal models. For example, neutralizing antibodies to TGF-ß combined with IL-2 therapy to stimulate the immune system were able to decrease the number of metastases in a murine B16 melanoma model,220 whereas vaccinating with resected cancer cells containing antisense to TGF-ß1 ligand (to decrease TGF-ß1 production) successfully increased the ability of these vaccines to eradicate cancer cells.221 More recently, blockade of the TGF-ß signaling pathway specifically in CD4+ and CD8+ T cells through expression of dominant negative TßRII has been shown to increase the ability of these T cells to produce specific anticancer cell (thymoma and melanoma) cytotoxic responses and to eradicate these cancer cells in vivo.222 Taken together, these studies provide proof of principle that targeting the TGF-ß signaling pathway represents a viable method for improving immunotherapy strategies for human cancers. Another potential strategy for blocking the TGF-ß signaling pathway would be to specifically target defined pathways mediating the immunosuppressive effects of TGF-ß using RNA-mediated interference (RNAi) technology. RNAi is an evolutionarily conserved process that produces small (21 to 23 nucleotide) interfering RNA molecules, which then result in specific degradation of homologous RNA, downregulating the mRNA and subsequently the resulting protein expression. RNAi is able to specifically and potently abrogate expression of targeted proteins in mammalian cells.223 Such an approach could be used to engineer T cells for use in immunotherapy that are specifically resistant to the immunosuppressive effects of TGF-ß through stable expression of RNAi constructs. This approach could initially be used to target members of the TGF-ß pathway known to be necessary for T-cell function—TßRII and Smad3. This approach has the advantages that it could be applied to any component of the TGF-ß signaling pathway or other pathways involved in immunosuppression, it could target specific arms of these pathways (ie, the immunosuppressive arm), it could be used to target more than one pathway simultaneously, and it could be expressed in various components of the immune system (T cells and APC) to modulate the TGF-ß signaling pathway in numerous immunotherapy or vaccine approaches.
Given that TGF-ß has numerous and often opposing cellular effects, as a tumor promoter and a tumor suppressor, and as an inhibitor and stimulator of cellular proliferation, apoptosis, and angiogenesis, a major challenge remains in more precisely defining TGF-ß signaling pathways, including specific pathways involved in mediating the specific and context-dependent effects of TGF-ß. Although Smad-mediated signaling is well established as the predominant TGF-ß signaling pathway, the significance of contributions by other signaling pathways (ie, MAP kinase, Rho, and PI-3 kinase/Akt pathways) and mechanisms for this signaling remain to be established. Once these pathways and other potential signaling pathways downstream of TGF-ß are defined, and the contributions of these pathways to the specific cellular and context-dependent effects of TGF-ß are established, more specific targeting of this pathway will be possible. Concurrently, the ability to define the alterations occurring in the TGF-ß signaling pathways at a molecular level in an individual's tumor will allow the matching of targeted therapies developed with these alterations to make individualized cancer treatment a less toxic and more effective reality.
The authors indicated no potential conflicts of interest.
Supported by the National Institutes of Health/National Cancer Institute (grant Nos. CA91816, CA100065 and CA105255), the American Heart Association, the American Cancer Society, the Elsa U. Pardee Foundation, and a V Scholar Award from The V Foundation for Cancer Research (to G.C.B.). R.L.E. is supported by the Medical Scientist Training Program. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100:57-70, 2000[CrossRef][Medline] 2. Hahn SA, Schutte M, Hoque AT, et al: DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271:350-353, 1996[Abstract]
3. Yan Z, Deng X, Friedman E: Oncogenic Ki-ras confers a more aggressive colon cancer phenotype through modification of transforming growth factor-beta receptor III. J Biol Chem 276:1555-1563, 2001 4. Desruisseau S, Ghazarossian-Ragni E, Chinot O, et al: Divergent effect of TGFbeta1 on growth and proteolytic modulation of human prostatic-cancer cell lines. Int J Cancer 66:796-801, 1996[CrossRef][Medline] 5. Katakura Y, Nakata E, Miura T, et al: Transforming growth factor beta triggers two independent-senescence programs in cancer cells. Biochem Biophys Res Commun 255:110-115, 1999[CrossRef][Medline] 6. Perry RR, Kang Y, Greaves BR: Relationship between tamoxifen-induced transforming growth factor beta 1 expression, cytostasis and apoptosis in human breast cancer cells. Br J Cancer 72:1441-1446, 1995[Medline]
7. Ananth S, Knebelmann B, Gruning W, et al: Transforming growth factor beta1 is a target for the von Hippel-Lindau tumor suppressor and a critical growth factor for clear cell renal carcinoma. Cancer Res 59:2210-2216, 1999
8. Torre-Amione G, Beauchamp RD, Koeppen H, et al: A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance. Proc Natl Acad Sci U S A 87:1486-1490, 1990
9. Attisano L, Wrana JL: Signal transduction by the TGF-beta superfamily. Science 296:1646-1647, 2002 10. Shi Y, Massague J: Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685-700, 2003[CrossRef][Medline] 11. Derynck R, Zhang YE: Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577-584, 2003[CrossRef][Medline] 12. Lopez-Casillas F, Wrana JL, Massague J: Betaglycan presents ligand to the TGF beta signaling receptor. Cell 73:1435-1444, 1993[CrossRef][Medline] 13. Wrana JL, Attisano L, Wieser R, et al: Mechanism of activation of the TGF-beta receptor. Nature 370:341-347, 1994[CrossRef][Medline] 14. Nakao A, Imamura T, Souchelnytskyi S, et al: TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. Embo J 16:5353-5362, 1997[CrossRef][Medline] 15. Inman GJ, Nicolas FJ, Hill CS: Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. Mol Cell 10:283-294, 2002[CrossRef][Medline]
16. Penheiter SG, Mitchell H, Garamszegi N, et al: Internalization-dependent and -independent requirements for transforming growth factor beta receptor signaling via the Smad pathway. Mol Cell Biol 22:4750-4759, 2002
17. Hayes S, Chawla A, Corvera S: TGF beta receptor internalization into EEA1-enriched early endosomes: Role in signaling to Smad2. J Cell Biol 158:1239-1249, 2002 18. Di Guglielmo GM, Le Roy C, Goodfellow AF, et al: Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat Cell Biol 5:410-421, 2003[CrossRef][Medline]
19. Chen W, Kirkbride KC, How T, et al: Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling. Science 301:1394-1397, 2003
20. Engel ME, McDonnell MA, Law BK, et al: Interdependent SMAD and JNK signaling in transforming growth factor- beta-mediated transcription. J Biol Chem 274:37413-37420, 1999 21. Hocevar BA, Brown TL, Howe PH: TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. Embo J 18:1345-1356, 1999[CrossRef][Medline]
22. Fink SP, Swinler SE, Lutterbaugh JD, et al: Transforming growth factor-beta-induced growth inhibition in a Smad4 mutant colon adenoma cell line. Cancer Res 61:256-260, 2001
23. Bhowmick NA, Ghiassi M, Bakin A, et al: Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell 12:27-36, 2001
24. Bakin AV, Tomlinson AK, Bhowmick NA, et al: Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem 275:36803-36810, 2000
25. Petritsch C, Beug H, Balmain A, et al: TGF-beta inhibits p70 S6 kinase via protein phosphatase 2A to induce G(1) arrest. Genes Dev 14:3093-3101, 2000
26. Frolik CA, Dart LL, Meyers CA, et al: Purification and initial characterization of a type beta transforming growth factor from human placenta. Proc Natl Acad Sci U S A 80:3676-3680, 1983 27. Hannon GJ, Beach D: P15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371:257-261, 1994[CrossRef][Medline]
28. Datto MB, Li Y, Panus JF, et al: Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci U S A 92:5545-5549, 1995
29. Polyak K, Kato JY, Solomon MJ, et al: P27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev 8:9-22, 1994 30. Pietenpol JA, Stein RW, Moran E, et al: TGF-beta 1 inhibition of c-myc transcription and growth in keratinocytes is abrogated by viral transforming proteins with pRB binding domains. Cell 61:777-785, 1990[CrossRef][Medline]
31. Hu PP, Shen X, Huang D, et al: The MEK pathway is required for stimulation of p21(WAF1/CIP1) by transforming growth factor-beta. J Biol Chem 274:35381-35387, 1999 32. Villanueva A, Garcia C, Paules AB, et al: Disruption of the antiproliferative TGF-beta signaling pathways in human pancreatic cancer cells. Oncogene 17:1969-1978, 1998[CrossRef][Medline]
33. Grady WM, Myeroff LL, Swinler SE, et al: Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers. Cancer Res 59:320-324, 1999 34. Nicolas FJ, Hill CS: Attenuation of the TGF-beta-Smad signaling pathway in pancreatic tumor cells confers resistance to TGF-beta-induced growth arrest. Oncogene 22:3698-3711, 2003[CrossRef][Medline] 35. Kim WS, Park C, Jung YS, et al: Reduced transforming growth factor-beta type II receptor (TGF-beta RII) expression in adenocarcinoma of the lung. Anticancer Res 19:301-306, 1999[Medline]
36. Chen C, Wang XF, Sun L: Expression of transforming growth factor beta (TGFbeta) type III receptor restores autocrine TGFbeta1 activity in human breast cancer MCF-7 cells. J Biol Chem 272:12862-12867, 1997 37. Kleeff J, Ishiwata T, Maruyama H, et al: The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene 18:5363-5372, 1999[CrossRef][Medline]
38. Ewen ME, Oliver CJ, Sluss HK, et al: p53-dependent repression of CDK4 translation in TGF-beta-induced G1 cell-cycle arrest. Genes Dev 9:204-217, 1995
39. Alexandrow MG, Kawabata M, Aakre M, et al: Overexpression of the c-Myc oncoprotein blocks the growth-inhibitory response but is required for the mitogenic effects of transforming growth factor beta 1. Proc Natl Acad Sci U S A 92:3239-3243, 1995 40. Datto MB, Hu PP, Kowalik TF, et al: The viral oncoprotein E1A blocks transforming growth factor beta-mediated induction of p21/WAF1/Cip1 and p15/INK4B. Mol Cell Biol 17:2030-2037, 1997[Abstract]
41. Kretzschmar M, Doody J, Timokhina I, et al: A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev 13:804-816, 1999 42. Sun Y, Liu X, Eaton EN, et al: Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signaling. Mol Cell 4:499-509, 1999[CrossRef][Medline]
43. Stroschein SL, Wang W, Zhou S, et al: Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science 286:771-774, 1999 44. Kurokawa M, Mitani K, Irie K, et al: The oncoprotein Evi-1 represses TGF-beta signalling by inhibiting Smad3. Nature 394:92-96, 1998[CrossRef][Medline]
45. Kaji H, Canaff L, Lebrun JJ, et al: Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling. Proc Natl Acad Sci U S A 98:3837-3842, 2001 46. Hocevar BA, Smine A, Xu XX, et al: The adaptor molecule Disabled-2 links the transforming growth factor beta receptors to the Smad pathway. Embo J 20:2789-2801, 2001[CrossRef][Medline] 47. Li QL, Ito K, Sakakura C, et al: Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 109:113-124, 2002[CrossRef][Medline]
48. Yakymovych I, Ten Dijke P, Heldin CH, et al: Regulation of Smad signaling by protein kinase C. Faseb J 15:553-555, 2001
49. Park BJ, Park JI, Byun DS, et al: Mitogenic conversion of transforming growth factor-beta1 effect by oncogenic Ha-Ras-induced activation of the mitogen-activated protein kinase signaling pathway in human prostate cancer. Cancer Res 60:3031-3038, 2000 50. Jonson T, Albrechtsson E, Axelson J, et al: Altered expression of TGFB receptors and mitogenic effects of TGFB in pancreatic carcinomas. Int J Oncol 19:71-81, 2001[Medline]
51. Seifert RA, Coats SA, Raines EW, et al: Platelet-derived growth factor (PDGF) receptor alpha-subunit mutant and reconstituted cell lines demonstrate that transforming growth factor-beta can be mitogenic through PDGF A-chain-dependent and -independent pathways. J Biol Chem 269:13951-13955, 1994 52. Strutz F, Zeisberg M, Renziehausen A, et al: TGF-beta 1 induces proliferation in human renal fibroblasts via induction of basic fibroblast growth factor (FGF-2). Kidney Int 59:579-592, 2001[CrossRef][Medline] 53. Chantry D, Turner M, Abney E, et al: Modulation of cytokine production by transforming growth factor-beta. J Immunol 142:4295-4300, 1989[Abstract] 54. Igarashi A, Okochi H, Bradham DM, et al: Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair. Mol Biol Cell 4:637-645, 1993[Abstract] 55. Ishikawa O, LeRoy EC, Trojanowska M: Mitogenic effect of transforming growth factor beta 1 on human fibroblasts involves the induction of platelet-derived growth factor alpha receptors. J Cell Physiol 145:181-186, 1990[CrossRef][Medline]
56. Feng P, Catt KJ, Knecht M: Transforming growth factor beta regulates the inhibitory actions of epidermal growth factor during granulosa cell differentiation. J Biol Chem 261:14167-14170, 1986
57. Piek E, Heldin CH, Ten Dijke P: Specificity, diversity, and regulation in TGF-beta superfamily signaling. FASEB J 13:2105-2124, 1999
58. Hanafusa H, Ninomiya-Tsuji J, Masuyama N, et al: Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expression. J Biol Chem 274:27161-27167, 1999
59. Miettinen PJ, Ebner R, Lopez AR, et al: TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: Involvement of type I receptors. J Cell Biol 127:2021-2036, 1994
60. Giannelli G, Fransvea E, Marinosci F, et al: Transforming growth factor-beta1 triggers hepatocellular carcinoma invasiveness via alpha3beta1 integrin. Am J Pathol 161:183-193, 2002
61. Schiemann WP, Blobe GC, Kalume DE, et al: Context-specific effects of fibulin-5 (DANCE/EVEC) on cell proliferation, motility, and invasion. Fibulin-5 is induced by transforming growth factor-beta and affects protein kinase cascades. J Biol Chem 277:27367-27377, 2002 62. Zicha D, Genot E, Dunn GA, et al: TGFbeta1 induces a cell-cycle-dependent increase in motility of epithelial cells. J Cell Sci 112:447-454, 1999 (pt 4)[Abstract]
63. Dumont N, Bakin AV, Arteaga CL: Autocrine transforming growth factor-beta signaling mediates Smad-independent motility in human cancer cells. J Biol Chem 278:3275-3285, 2003
64. Blobe GC, Schiemann WP, Lodish HF: Role of transforming growth factor beta in human disease. N Engl J Med 342:1350-1358, 2000
65. Maehara Y, Kakeji Y, Kabashima A, et al: Role of transforming growth factor-beta 1 in invasion and metastasis in gastric carcinoma. J Clin Oncol 17:607-614, 1999 66. Tobin SW, Douville K, Benbow U, et al: Consequences of altered TGF-beta expression and responsiveness in breast cancer: Evidence for autocrine and paracrine effects. Oncogene 21:108-118, 2002[CrossRef][Medline]
67. Hahn WC: Role of telomeres and telomerase in the pathogenesis of human cancer. J Clin Oncol 21:2034-2043, 2003 68. Lin SY, Elledge SJ: Multiple tumor suppressor pathways negatively regulate telomerase. Cell 113:881-889, 2003[CrossRef][Medline] 69. Werner S, Beer HD, Mauch C, et al: The Mad1 transcription factor is a novel target of activin and TGF-beta action in keratinocytes: Possible role of Mad1 in wound repair and psoriasis. Oncogene 20:7494-7504, 2001[CrossRef][Medline] 70. Comijn J, Berx G, Vermassen P, et al: The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 7:1267-1278, 2001[CrossRef][Medline]
71. Stampfer MR, Garbe J, Levine G, et al: Expression of the telomerase catalytic subunit, hTERT, induces resistance to transforming growth factor beta growth inhibition in p16INK4A(-) human mammary epithelial cells. Proc Natl Acad Sci U S A 98:4498-4503, 2001 72. Schuster N, Krieglstein K: Mechanisms of TGF-beta-mediated apoptosis. Cell Tissue Res 307:1-14, 2002[CrossRef][Medline]
73. Hsing AY, Kadomatsu K, Bonham MJ, et al: Regulation of apoptosis induced by transforming growth factor-beta1 in nontumorigenic rat prostatic epithelial cell lines. Cancer Res 56:5146-5149, 1996 74. Hyman KM, Seghezzi G, Pintucci G, et al: Transforming growth factor-beta1 induces apoptosis in vascular endothelial cells by activation of mitogen-activated protein kinase. Surgery 132:173-179, 2002[CrossRef][Medline]
75. Francis JM, Heyworth CM, Spooncer E, et al: Transforming growth factor-beta 1 induces apoptosis independently of p53 and selectively reduces expression of Bcl-2 in multipotent hematopoietic cells. J Biol Chem 275:39137-39145, 2000 76. Arsura M, Wu M, Sonenshein GE: TGF beta 1 inhibits NF-kappa B/Rel activity inducing apoptosis of B cells: Transcriptional activation of I kappa B alpha. Immunity 5:31-40, 1996[CrossRef][Medline] 77. Arsura M, FitzGerald MJ, Fausto N, et al: Nuclear factor-kappaB/Rel blocks transforming growth factor beta1-induced apoptosis of murine hepatocyte cell lines. Cell Growth Differ 8:1049-1059, 1997[Abstract] 78. Krieglstein K, Richter S, Farkas L, et al: Reduction of endogenous transforming growth factors beta prevents ontogenetic neuron death. Nat Neurosci 3:1085-1090, 2000[CrossRef][Medline]
79. Kim BC, Mamura M, Choi KS, et al: Transforming growth factor beta 1 induces apoptosis through cleavage of BAD in a Smad3-dependent mechanism in FaO hepatoma cells. Mol Cell Biol 22:1369-1378, 2002 80. Barna G, Sebestyen A, Chinopoulos CC, et al: TGF beta 1 kills lymphoma cells using mitochondrial apoptotic pathway with the help of caspase-8. Anticancer Res 22:3867-3872, 2002[Medline] 81. Lafon C, Mathieu C, Guerrin M, et al: Transforming growth factor beta 1-induced apoptosis in human ovarian carcinoma cells: Protection by the antioxidant N-acetylcysteine and bcl-2. Cell Growth Differ 7:1095-1104, 1996[Abstract] 82. Landstrom M, Heldin NE, Bu S, et al: Smad7 mediates apoptosis induced by transforming growth factor beta in prostatic carcinoma cells. Curr Biol 10:535-538, 2000[CrossRef][Medline]
83. Atfi A, Buisine M, Mazars A, et al: Induction of apoptosis by DPC4, a transcriptional factor regulated by transforming growth factor-beta through stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) signaling pathway. J Biol Chem 272:24731-24734, 1997
84. Yamamura Y, Hua X, Bergelson S, et al: Critical role of smads and AP-1 complex in TGF-beta-dependent apoptosis. J Biol Chem 275:36295-36302, 2000 85. Lallemand F, Mazars A, Prunier C, et al: Smad7 inhibits the survival nuclear factor kappaB and potentiates apoptosis in epithelial cells. Oncogene 20:879-884, 2001[CrossRef][Medline] 86. Perlman R, Schiemann WP, Brooks MW, et al: TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat Cell Biol 3:708-714, 2001[CrossRef][Medline] 87. Motyl T, Grzelkowska K, Zimowska W, et al: Expression of bcl-2 and bax in TGF-beta 1-induced apoptosis of L1210 leukemic cells. Eur J Cell Biol 75:367-374, 1998[Medline]
88. Inman GJ, Allday MJ: Apoptosis induced by TGF-beta 1 in Burkitt's lymphoma cells is caspase 8 dependent but is death receptor independent. J Immunol 165:2500-2510, 2000
89. Hagimoto N, Kuwano K, Inoshima I, et al: TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells. J Immunol 168:6470-6478, 2002 90. Chen RH, Su YH, Chuang RL, et al: Suppression of transforming growth factor-beta-induced apoptosis through a phosphatidylinositol 3-kinase/Akt-dependent pathway. Oncogene 17:1959-1968, 1998[CrossRef][Medline] 91. Conery AR, Cao Y, Thompson EA, et al: Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol 6:366-372, 2004[CrossRef][Medline] 92. Remy I, Montmarquette A, Michnick SW: PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. Nat Cell Biol 6:358-365, 2004[CrossRef][Medline] 93. Pepper MS: Transforming growth factor-beta: Vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev 8:21-43, 1997[CrossRef][Medline] 94. Dickson MC, Martin JS, Cousins FM, et al: Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development 121:1845-1854, 1995[Abstract] 95. Oshima M, Oshima H, Taketo MM: TGF-beta receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev Biol 179:297-302, 1996[CrossRef][Medline] 96. Larsson J, Goumans MJ, Sjostrand LJ, et al: Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice. Embo J 20:1663-1673, 2001[CrossRef][Medline] 97. McAllister KA, Grogg KM, Johnson DW, et al: Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8:345-351, 1994[CrossRef][Medline] 98. 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[CrossRef][Medline]
99. Li DY, Sorensen LK, Brooke BS, et al: Defective angiogenesis in mice lacking endoglin. Science 284:1534-1537, 1999
100. Oh SP, Seki T, Goss KA, et al: Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A 97:2626-2631, 2000 101. Burrows FJ, Derbyshire EJ, Tazzari PL, et al: Up-regulation of endoglin on vascular endothelial cells in human solid tumors: Implications for diagnosis and therapy. Clin Cancer Res 1:1623-1634, 1995[Abstract] 102. Yamamoto T, Kozawa O, Tanabe K, et al: Involvement of p38 MAP kinase in TGF-beta-stimulated VEGF synthesis in aortic smooth muscle cells. J Cell Biochem 82:591-598, 2001[CrossRef][Medline] 103. Goumans MJ, Valdimarsdottir G, Itoh S, et al: Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. Embo J 21:1743-1753, 2002[CrossRef][Medline]
104. Lamouille S, Mallet C, Feige JJ, et al: Activin receptor-like kinase 1 is implicated in the maturation phase of angiogenesis. Blood 100:4495-4501, 2002
105. Lastres P, Letamendia A, Zhang H, et al: Endoglin modulates cellular responses to TGF-beta 1. J Cell Biol 133:1109-1121, 1996 106. Goumans MJ, Valdimarsdottir G, Itoh S, et al: Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. Mol Cell 12:817-828, 2003[CrossRef][Medline] 107. Kirkbride KC, Blobe GC: Inhibiting the TGF-beta signalling pathway as a means of cancer immunotherapy. Expert Opin Biol Ther 3:251-261, 2003[Medline] 108. Bodmer S, Strommer K, Frei K, et al: Immunosuppression and transforming growth factor-beta in glioblastoma: Preferential production of transforming growth factor-beta 2. J Immunol 143:3222-3229, 1989[Abstract] 109. von Bernstorff W, Voss M, Freichel S, et al: Systemic and local immunosuppression in pancreatic cancer patients. Clin Cancer Res 7:925s-932s, 2001 110. Hersey P: Impediments to successful immunotherapy. Pharmacol Ther 81:111-119, 1999[CrossRef][Medline] 111. Leach DR, Krummel MF, Allison JP: Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734-1736, 1996[Abstract]
112. Brandes ME, Wakefield LM, Wahl SM: Modulation of monocyte type I transforming growth factor-beta receptors by inflammatory stimuli. J Biol Chem 266:19697-19703, 1991
113. Kehrl JH, Wakefield LM, Roberts AB, et al: Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med 163:1037-1050, 1986 114. Gorelik L, Flavell RA: Transforming growth factor-beta in T-cell biology. Nat Rev Immunol 2:46-53, 2002[CrossRef][Medline]
115. Nakamura K, Kitani A, Strober W: Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 194:629-644, 2001 116. Shull MM, Ormsby I, Kier AB, et al: Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359:693-699, 1992[CrossRef][Medline] 117. Gorelik L, Flavell RA: Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12:171-181, 2000[CrossRef][Medline]
118. Bogdan C, Paik J, Vodovotz Y, et al: Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J Biol Chem 267:23301-23308, 1992 119. Riedl E, Strobl H, Majdic O, et al: TGF-beta 1 promotes in vitro generation of dendritic cells by protecting progenitor cells from apoptosis. J Immunol 158:1591-1597, 1997[Abstract] 120. Borkowski TA, Letterio JJ, Mackall CL, et al: Langerhans cells in the TGF beta 1 null mouse. Adv Exp Med Biol 417:307-310, 1997[Medline] 121. Kinzler KW, Vogelstein B: Cancer-susceptibility genes: Gatekeepers and caretakers. Nature 386:761-763, 1997[CrossRef][Medline] 122. Kanamoto T, Hellman U, Heldin CH, et al: Functional proteomics of transforming growth factor-beta1-stimulated Mv1Lu epithelial cells: Rad51 as a target of TGFbeta1-dependent regulation of DNA repair. Embo J 21:1219-1230, 2002[CrossRef][Medline]
123. Ewan KB, Henshall-Powell RL, Ravani SA, et al: Transforming growth factor-beta1 mediates cellular response to DNA damage in situ. Cancer Res 62:5627-5631, 2002
124. Glick A, Popescu N, Alexander V, et al: Defects in transforming growth factor-beta signaling cooperate with a Ras oncogene to cause rapid aneuploidy and malignant transformation of mouse keratinocytes. Proc Natl Acad Sci U S A 96:14949-14954, 1999 125. Takaku K, Oshima M, Miyoshi H, et al: Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Cell 92:645-656, 1998[CrossRef][Medline] 126. Cullingworth J, Hooper ML, Harrison DJ, et al: Carcinogen-induced pancreatic lesions in the mouse: Effect of Smad4 and Apc genotypes. Oncogene 21:4696-4701, 2002[CrossRef][Medline]
127. Furuhashi M, Yagi K, Yamamoto H, et al: Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway. Mol Cell Biol 21:5132-5141, 2001
128. Labbe E, Letamendia A, Attisano L: Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-beta and wnt pathways. Proc Natl Acad Sci U S A 97:8358-8363, 2000 129. Nishita M, Hashimoto MK, Ogata S, et al: Interaction between Wnt and TGF-beta signalling pathways during formation of Spemann's organizer. Nature 403:781-785, 2000[CrossRef][Medline]
130. Murray NR, Weems C, Chen L, et al: Protein kinase C betaII and TGFbetaRII in omega-3 fatty acid-mediated inhibition of colon carcinogenesis. J Cell Biol 157:915-920, 2002 131. Tang B, Bottinger EP, Jakowlew SB, et al: Transforming growth factor-beta1 is a new form of tumor suppressor with true haploid insufficiency. Nat Med 4:802-807, 1998[CrossRef][Medline] 132. Oft M, Heider KH, Beug H: TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 8:1243-1252, 1998[CrossRef][Medline] 133. Knaus PI, Lindemann D, DeCoteau JF, et al: A dominant inhibitory mutant of the type II transforming growth factor beta receptor in the malignant progression of a cutaneous T-cell lymphoma. Mol Cell Biol 16:3480-3489, 1996[Abstract]
134. Picon A, Gold LI, Wang J, et al: A subset of metastatic human colon cancers expresses elevated levels of transforming growth factor beta1. Cancer Epidemiol Biomarkers Prev 7:497-504, 1998 135. Wikstrom P, Stattin P, Franck-Lissbrant I, et al: Transforming growth factor beta1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer. Prostate 37:19-29, 1998[CrossRef][Medline] 136. Cui W, Fowlis DJ, Bryson S, et al: TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86:531-542, 1996[CrossRef][Medline] 137. Tang B, Vu M, Booker T, et al: TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression. J Clin Invest 112:1116-1124, 2003[CrossRef][Medline]
138. Siegel PM, Shu W, Cardiff RD, et al: Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci U S A 100:8430-8435, 2003 139. McEarchern JA, Kobie JJ, Mack V, et al: Invasion and metastasis of a mammary tumor involves TGF-beta signaling. Int J Cancer 91:76-82, 2001[CrossRef][Medline] 140. Thiery JP, Chopin D: Epithelial cell plasticity in development and tumor progression. Cancer Metastasis Rev 18:31-42, 1999[CrossRef][Medline]
141. Rosivatz E, Becker I, Specht K, et al: Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol 161:1881-1891, 2002 142. Piek E, Moustakas A, Kurisaki A, et al: TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. J Cell Sci 112:4557-4568, 1999 (pt 24)[Abstract]
143. Brown CB, Boyer AS, Runyan RB, et al: Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. Science 283:2080-2082, 1999
144. Reeves R, Edberg DD, Li Y: Architectural transcription factor HMGI(Y) promotes tumor progression and mesenchymal transition of human epithelial cells. Mol Cell Biol 21:575-594, 2001
145. Blobe GC, Schiemann WP, Pepin MC, et al: Functional roles for the cytoplasmic domain of the type III transforming growth factor beta receptor in regulating transforming growth factor beta signaling. J Biol Chem 276:24627-24637, 2001
146. Eickelberg O, Centrella M, Reiss M, et al: Betaglycan inhibits TGF-beta signaling by preventing type I-type II receptor complex formation: Glycosaminoglycan modifications alter betaglycan function. J Biol Chem 277:823-829, 2002
147. Sun L, Chen C: Expression of transforming growth factor beta type III receptor suppresses tumorigenicity of human breast cancer MDA-MB-231 cells. J Biol Chem 272:25367-25372, 1997 148. Copland JA, Luxon BA, Ajani L, et al: Genomic profiling identifies alterations in TGFbeta signaling through loss of TGFbeta receptor expression in human renal cell carcinogenesis and progression. Oncogene 22:6109-6118, 2003
149. Lucke CD, Philpott A, Metcalfe JC, et al: Inhibiting mutations in the transforming growth factor beta type 2 receptor in recurrent human breast cancer. Cancer Res 61:482-485, 2001
150. Xie W, Mertens JC, Reiss DJ, et al: Alterations of Smad signaling in human breast carcinoma are associated with poor outcome: A tissue microarray study. Cancer Res 62:497-505, 2002
151. Parsons R, Myeroff LL, Liu B, et al: Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res 55:5548-5550, 1995 152. Miyaki M, Iijima T, Konishi M, et al: Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene 18:3098-3103, 1999[CrossRef][Medline] 153. Eppert K, Scherer SW, Ozcelik H, et al: MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 86:543-552, 1996[CrossRef][Medline]
154. Nagatake M, Takagi Y, Osada H, et al: Somatic in vivo alterations of the DPC4 gene at 18q21 in human lung cancers. Cancer Res 56:2718-2720, 1996
155. Uchida K, Nagatake M, Osada H, et al: Somatic in vivo alterations of the JV18-1 gene at 18q21 in human lung cancers. Cancer Res 56:5583-5585, 1996
156. Goggins M, Shekher M, Turnacioglu K, et al: Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res 58:5329-5332, 1998 157. Latil A, Pesche S, Valeri A, et al: Expression and mutational analysis of the MADR2/smad2 gene in human prostate cancer. Prostate 40:225-231, 1999[CrossRef][Medline] 158. MacGrogan D, Pegram M, Slamon D, et al: Comparative mutational analysis of DPC4 (Smad4) in prostatic and colorectal carcinomas. Oncogene 15:1111-1114, 1997[CrossRef][Medline] 159. Jhappan C, Geiser AG, Kordon EC, et al: Targeting expression of a transforming growth factor beta 1 transgene to the pregnant mammary gland inhibits alveolar development and lactation. Embo J 12:1835-1845, 1993[Medline] 160. Knabbe C, Lippman ME, Wakefield LM, et al: Evidence that transforming growth factor-beta is a hormonally regulated negative growth factor in human breast cancer cells. Cell 48:417-428, 1987[CrossRef][Medline] 161. Decensi A, Torrisi R, Fontana V, et al: Correlation between plasma transforming growth factor-beta 1 and second primary breast cancer in a chemoprevention trial. Eur J Cancer 34:999-1003, 1998
162. Kopp A, Jonat W, Schmahl M, et al: Transforming growth factor beta 2 (TGF-beta 2) levels in plasma of patients with metastatic breast cancer treated with tamoxifen. Cancer Res 55:4512-4515, 1995
163. Gorsch SM, Memoli VA, Stukel TA, et al: Immunohistochemical staining for transforming growth factor beta 1 associates with disease progression in human breast cancer. Cancer Res 52:6949-6952, 1992 164. Kong FM, Anscher MS, Murase T, et al: Elevated plasma transforming growth factor-beta 1 levels in breast cancer patients decrease after surgical removal of the tumor. Ann Surg 222:155-162, 1995[Medline] 165. Ghellal A, Li C, Hayes M, et al: Prognostic significance of TGF beta 1 and TGF beta 3 in human breast carcinoma. Anticancer Res 20:4413-4418, 2000[Medline] 166. Kurokowa M, Lynch K, Podolsky DK: Effects of growth factors on an intestinal epithelial cell line: Transforming growth factor beta inhibits proliferation and stimulates differentiation. Biochem Biophys Res Commun 142:775-782, 1987[CrossRef][Medline] 167. Avery A, Paraskeva C, Hall P, et al: TGF-beta expression in the human colon: Differential immunostaining along crypt epithelium. Br J Cancer 68:137-139, 1993[Medline] 168. Hoosein NM, McKnight MK, Levine AE, et al: Differential sensitivity of subclasses of human colon carcinoma cell lines to the growth inhibitory effects of transforming growth factor-beta 1. Exp Cell Res 181:442-453, 1989[CrossRef][Medline] 169. Ionov Y, Peinado MA, Malkhosyan S, et al: Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558-561, 1993[CrossRef][Medline]
170. Wang J, Sun L, Myeroff L, et al: Demonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells. J Biol Chem 270:22044-22049, 1995
171. Howe JR, Roth S, Ringold JC, et al: Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280:1086-1088, 1998
172. Lothe RA, Peltomaki P, Meling GI, et al: Genomic instability in colorectal cancer: Relationship to clinicopathological variables and family history. Cancer Res 53:5849-5852, 1993
173. Masui T, Wakefield LM, Lechner JF, et al: Type beta transforming growth factor is the primary differentiation-inducing serum factor for normal human bronchial epithelial cells. Proc Natl Acad Sci U S A 83:2438-2442, 1986
174. Osada H, Tatematsu Y, Masuda A, et al: Heterogeneous transforming growth factor (TGF)-beta unresponsiveness and loss of TGF-beta receptor type II expression caused by histone deacetylation in lung cancer cell lines. Cancer Res 61:8331-8339, 2001 175. de Jonge RR, Garrigue-Antar L, Vellucci VF, et al: Frequent inactivation of the transforming growth factor beta type II receptor in small-cell lung carcinoma cells. Oncol Res 9:89-98, 1997[Medline] 176. Kong F, Jirtle RL, Huang DH, et al: Plasma transforming growth factor-beta1 level before radiotherapy correlates with long term outcome of patients with lung carcinoma. Cancer 86:1712-1719, 1999[CrossRef][Medline] 177. Danielpour D: Transdifferentiation of NRP-152 rat prostatic basal epithelial cells toward a luminal phenotype: Regulation by glucocorticoid, insulin-like growth factor-I and transforming growth factor-beta. J Cell Sci 112:169-179, 1999 (pt 2)[Abstract]
178. Morton DM, Barrack ER: Modulation of transforming growth factor beta 1 effects on prostate cancer cell proliferation by growth factors and extracellular matrix. Cancer Res 55:2596-2602, 1995 179. Kim IY, Ahn HJ, Lang S, et al: Loss of expression of transforming growth factor-beta receptors is associated with poor prognosis in prostate cancer patients. Clin Cancer Res 4:1625-1630, 1998[Abstract] 180. Festuccia C, Bologna M, Gravina GL, et al: Osteoblast conditioned media contain TGF-beta1 and modulate the migration of prostate tumor cells and their interactions with extracellular matrix components. Int J Cancer 81:395-403, 1999[CrossRef][Medline] 181. Shim KS, Kim KH, Han WS, et al: Elevated serum levels of transforming growth factor-beta1 in patients with colorectal carcinoma: Its association with tumor progression and its significant decrease after curative surgical resection. Cancer 85:554-561, 1999[CrossRef][Medline] 182. Song BC, Chung YH, Kim JA, et al: Transforming growth factor-beta1 as a useful serologic marker of small hepatocellular carcinoma. Cancer 94:175-180, 2002[CrossRef][Medline] 183. Barthelemy-Brichant N, David JL, Bosquee L, et al: Increased TGFbeta1 plasma level in patients with lung cancer: Potential mechanisms. Eur J Clin Invest 32:193-198, 2002[CrossRef][Medline] 184. Krasagakis K, Tholke D, Farthmann B, et al: Elevated plasma levels of transforming growth factor (TGF)-beta1 and TGF-beta2 in patients with disseminated malignant melanoma. Br J Cancer 77:1492-1494, 1998[Medline] 185. Ivanovic V, Melman A, Davis-Joseph B, et al: Elevated plasma levels of TGF-beta 1 in patients with invasive prostate cancer. Nat Med 1:282-284, 1995[CrossRef][Medline] 186. Tsai JF, Jeng JE, Chuang LY, et al: Elevated urinary transforming growth factor-beta1 level as a tumour marker and predictor of poor survival in cirrhotic hepatocellular carcinoma. Br J Cancer 76:244-250, 1997[Medline]
187. Fonsatti E, Jekunen AP, Kairemo KJ, et al: Endoglin is a suitable target for efficient imaging of solid tumors: In vivo evidence in a canine mammary carcinoma model. Clin Cancer Res 6:2037-2043, 2000
188. Tsushima H, Ito N, Tamura S, et al: Circulating transforming growth factor beta 1 as a predictor of liver metastasis after resection in colorectal cancer. Clin Cancer Res 7:1258-1262, 2001
189. Shariat SF, Shalev M, Menesses-Diaz A, et al: Preoperative plasma levels of transforming growth factor beta(1) (TGF-beta(1)) strongly predict progression in patients undergoing radical prostatectomy. J Clin Oncol 19:2856-2864, 2001 190. Shariat SF, Kim JH, Andrews B, et al: Preoperative plasma levels of transforming growth factor beta(1) strongly predict clinical outcome in patients with bladder carcinoma. Cancer 92:2985-2992, 2001[CrossRef][Medline] 191. Saito H, Tsujitani S, Oka S, et al: An elevated serum level of transforming growth factor-beta 1 (TGF-beta 1) significantly correlated with lymph node metastasis and poor prognosis in patients with gastric carcinoma. Anticancer Res 20:4489-4493, 2000[Medline] 192. Li C, Wilson PB, Levine E, et al: TGF-beta1 levels in pre-treatment plasma identify breast cancer patients at risk of developing post-radiotherapy fibrosis. Int J Cancer 84:155-159, 1999[CrossRef][Medline]
193. Anscher MS, Peters WP, Reisenbichler H, et al: Transforming growth factor beta as a predictor of liver and lung fibrosis after autologous bone marrow transplantation for advanced breast cancer. N Engl J Med 328:1592-1598, 1993 194. Liem LM, Fibbe WE, van Houwelingen HC, et al: Serum transforming growth factor-beta1 levels in bone marrow transplant recipients correlate with blood cell counts and chronic graft-versus- host disease. Transplantation 67:59-65, 1999[CrossRef][Medline]
195. Anscher MS, Marks LB, Shafman TD, et al: Using plasma transforming growth factor beta-1 during radiotherapy to select patients for dose escalation. J Clin Oncol 19:3758-3765, 2001
196. Watanabe T, Wu TT, Catalano PJ, et al: Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 344:1196-1206, 2001 197. Boulay JL, Mild G, Lowy A, et al: SMAD4 is a predictive marker for 5-fluorouracil-based chemotherapy in patients with colorectal cancer. Br J Cancer 87:630-634, 2002[CrossRef][Medline] 198. Miyajima A, Asano T, Seta K, et al: Loss of expression of transforming growth factor-beta receptor as a prognostic factor in patients with renal cell carcinoma. Urology 61:1072-1077, 2003[CrossRef][Medline]
199. Dales JP, Garcia S, Bonnier P, et al: CD105 expression is a marker of high metastatic risk and poor outcome in breast carcinomas: Correlations between immunohistochemical analysis and long-term follow-up in a series of 929 patients. Am J Clin Pathol 119:374-380, 2003 200. Li C, Gardy R, Seon BK, et al: Both high intratumoral microvessel density determined using CD105 antibody and elevated plasma levels of CD105 in colorectal cancer patients correlate with poor prognosis. Br J Cancer 88:1424-1431, 2003[CrossRef][Medline]
201. Tanaka F, Otake Y, Yanagihara K, et al: Evaluation of angiogenesis in non-small cell lung cancer: Comparison between anti-CD34 antibody and anti-CD105 antibody. Clin Cancer Res 7:3410-3415, 2001
202. Ziv E, Cauley J, Morin PA, et al: Association between the T29->C polymorphism in the transforming growth factor beta1 gene and breast cancer among elderly white women: The Study of Osteoporotic Fractures. JAMA 285:2859-2863, 2001
203. McDonald CC, Alexander FE, Whyte BW, et al: Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial: The Scottish Cancer Trials Breast Group. BMJ 311:977-980, 1995 204. Comerci JT Jr, Runowicz CD, Fields AL, et al: Induction of transforming growth factor beta-1 in cervical intraepithelial neoplasia in vivo after treatment with beta-carotene. Clin Cancer Res 3:157-160, 1997[Abstract]
205. Park SH, Lee SR, Kim BC, et al: Transcriptional regulation of the transforming growth factor beta type II receptor gene by histone acetyltransferase and deacetylase is mediated by NF-Y in human breast cancer cells. J Biol Chem 277:5168-5174, 2002 206. Miyajima A, Asano T, Hayakawa M: Captopril restores transforming growth factor-beta type II receptor and sensitivity to transforming growth factor-beta in murine renal cell cancer cells. J Urol 165:616-620, 2001[CrossRef][Medline] 207. Adnane J, Bizouarn FA, Chen Z, et al: Inhibition of farnesyltransferase increases TGFbeta type II receptor expression and enhances the responsiveness of human cancer cells to TGFbeta. Oncogene 19:5525-5533, 2000[CrossRef][Medline]
208. Venkatasubbarao K, Ammanamanchi S, Brattain MG, et al: Reversion of transcriptional repression of Sp1 by 5 aza-2' deoxycytidine restores TGF-beta type II receptor expression in the pancreatic cancer cell line MIA PaCa-2. Cancer Res 61:6239-6247, 2001 209. Kavsak P, Rasmussen RK, Causing CG, et al: Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell 6:1365-1375, 2000[CrossRef][Medline] 210. Stander M, Naumann U, Dumitrescu L, et al: Decorin gene transfer-mediated suppression of TGF-beta synthesis abrogates experimental malignant glioma growth in vivo. Gene Ther 5:1187-1194, 1998[CrossRef][Medline]
211. Rowland-Goldsmith MA, Maruyama H, Matsuda K, et al: Soluble type II transforming growth factor-beta receptor attenuates expression of metastasis-associated genes and suppresses pancreatic cancer cell metastasis. Mol Cancer Ther 1:161-167, 2002 212. Lei X, Bandyopadhyay A, Le T, et al: Autocrine TGFbeta supports growth and survival of human breast cancer MDA-MB-231 cells. Oncogene 21:7514-7523, 2002[CrossRef][Medline] 213. Cordeiro MF: Technology evaluation: Lerdelimumab, Cambridge Antibody Technology. Curr Opin Mol Ther 5:199-203, 2003[Medline]
214. Andres JL, Stanley K, Cheifetz S, et al: Membrane-anchored and soluble forms of betaglycan, a polymorphic proteoglycan that binds transforming growth factor-beta. J Cell Biol 109:3137-3145, 1989
215. Inman GJ, Nicolas FJ, Callahan JF, et al: SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol 62:65-74, 2002 216. Sawyer JS, Anderson BD, Beight DW, et al: Synthesis and activity of new aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. J Med Chem 46:3953-3956, 2003[CrossRef][Medline] 217. Yang YA, Dukhanina O, Tang B, et al: Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. J Clin Invest 109:1607-1615, 2002[CrossRef][Medline] 218. Muraoka RS, Dumont N, Ritter CA, et al: Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J Clin Invest 109:1551-1559, 2002[CrossRef][Medline]
219. Matsuno F, Haruta Y, Kondo M, et al: Induction of lasting complete regression of preformed distinct solid tumors by targeting the tumor vasculature using two new anti-endoglin monoclonal antibodies. Clin Cancer Res 5:371-382, 1999 220. Wojtowicz-Praga S, Verma UN, Wakefield L, et al: Modulation of B16 melanoma growth and metastasis by anti-transforming growth factor beta antibody and interleukin-2. J Immunother Emphasis Tumor Immunol 19:169-175, 1996[Medline] 221. Matthews E, Yang T, Janulis L, et al: Down-regulation of TGF-beta1 production restores immunogenicity in prostate cancer cells. Br J Cancer 83:519-525, 2000[CrossRef][Medline] 222. Gorelik L, Flavell RA: Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 7:1118-1122, 2001[CrossRef][Medline] 223. Bosher JM, Labouesse M: RNA interference: Genetic wand and genetic watchdog. Nat Cell Biol 2:E31-E36, 2000[CrossRef][Medline] Submitted February 4, 2004; accepted October 5, 2004.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
,
