TY - JOUR
AU - Xin-Hua, Feng,
AB - Abstract Signals from the transforming growth factor-β (TGF-β) superfamily mediate a broad spectrum of cellular processes and are deregulated in many diseases, including cancer. TGF-β signaling has dual roles in tumorigenesis. In the early phase of tumorigenesis, TGF-β has tumor suppressive functions, primarily through cell cycle arrest and apoptosis. However, in the late stage of cancer, TGF-β acts as a driver of tumor progression and metastasis by increasing tumor cell invasiveness and migration and promoting chemo-resistance. Here, we briefly review the mechanisms and functions of TGF-β signaling during tumor progression and discuss the therapeutic potentials of targeting the TGF-β pathway in cancer. TGF-β, cancer, EMT, immune, cancer treatment Introduction The transforming growth factor-β (TGF-β) family secreted factors are comprised of over 30 members in mammals, including activins, nodals, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs). They control numerous aspects of animal biology including embryonic development, organogenesis, cell fate decisions, immune modulation, stress responses, and stem cell function [1–3]. Because of its widespread functional diversity, malfunctions of TGF-β signaling are associated with human diseases including cancer, fibrosis, systemic sclerosis, and hereditary disorders [4–7]. TGF-β often inhibits cell proliferation and stimulates differentiation in normal cells, therefore acting as a tumor suppressor [1,2]. In contrast, in advanced cancer, it promotes tumor progression and metastasis, thus serving as an oncogenic factor [8,9]. Researchers have made tremendous effort in elucidating mechanisms underlying these contradictory phenomena. Recent studies have uncovered complex interactions at various levels by using combinatorial approaches from molecular and cellular to animal models and human samples. This review will summarize the mechanisms of TGF-β signaling from tumor suppression to tumor promotion and discuss the implication of this process for understanding cancer biology and therapies. TGF-β Superfamily Signaling Pathway On the cell surface, the TGF-β ligand first binds to the high affinity receptors and stabilizes the formation of a hetero-tetrameric complex of type I and type II serine/threonine kinase receptors [1,2]. For example, TGF-β first binds to the TGF-β type II receptor (i.e. TβRII) and induces the formation of the hetero-tetrameric complex of TβRII and the TGF-β type I receptor (i.e. TβRI). In the receptor complex, TβRII acts as an upstream kinase to phosphorylate TβRI in the serine-rich GS motif, leading to the activation of TβRI (Fig. 1). The human genome encodes seven type I receptors (i.e. ALK1–7) and five type II receptors (i.e. TβRII, ActRII, ActRIIB, BMPRII, and AMHRII) [1,2]. A TGF-β ligand often acts through specific combinations of the type I and type II receptors (Fig. 2). The ligand-mediated interactions between the ligand and the receptors as well as between the type I and type II receptors dictate the specificity of receptor signaling. Figure 1. View largeDownload slide The TGF-β signaling pathway TGF-β is presented to TβRII, which leads to the formation of a hetero-tetrameric complex between the serine/threonine kinases TβRI and TβRII. The constitutive active TβRII phosphorylates TβRI, which in turn recruits, phosphorylates and activates Smad2 and Smad3. Activated Smad2 and/or Smad3 bind(s) to Smad4 to form a heterotrimer. The Smad complex becomes accumulated in the nucleus and drives transcription in cooperation with large number of specific transcription factors or cofactors in a context-dependent manner. In addition to the canonical Smad-mediated signaling, TGF-β also activates several other signaling cascades such as TRAF6–TAK1–p38/JNK, RhoA–Rhock1, and Par6. Figure 1. View largeDownload slide The TGF-β signaling pathway TGF-β is presented to TβRII, which leads to the formation of a hetero-tetrameric complex between the serine/threonine kinases TβRI and TβRII. The constitutive active TβRII phosphorylates TβRI, which in turn recruits, phosphorylates and activates Smad2 and Smad3. Activated Smad2 and/or Smad3 bind(s) to Smad4 to form a heterotrimer. The Smad complex becomes accumulated in the nucleus and drives transcription in cooperation with large number of specific transcription factors or cofactors in a context-dependent manner. In addition to the canonical Smad-mediated signaling, TGF-β also activates several other signaling cascades such as TRAF6–TAK1–p38/JNK, RhoA–Rhock1, and Par6. Figure 2. View largeDownload slide Schematic illustration of the selective binding of members of TGF-β superfamily receptors TGF-β ligands bind to specific combination of TβRII-TβRI heterotetramers at the surface. Subsequent activation of R-Smads is shown at right. While ActRII and ActRIIB are encoded by different genes, BMPRII and BMPRIIB are two isoforms encoded by the same gene. Figure 2. View largeDownload slide Schematic illustration of the selective binding of members of TGF-β superfamily receptors TGF-β ligands bind to specific combination of TβRII-TβRI heterotetramers at the surface. Subsequent activation of R-Smads is shown at right. While ActRII and ActRIIB are encoded by different genes, BMPRII and BMPRIIB are two isoforms encoded by the same gene. Smad proteins are the major intracellular mediators for TGF-β superfamily signaling [10]. They are classified into three groups. The first group is the receptor-activated Smads (R-Smads). Once activated by the type II receptor, the type I receptor phosphorylates R-Smads. For instance, Smad1, 5, and 8 are primarily activated by the BMP-specific type I receptors, while Smad2 and Smad3 are activated by the TGF-β/activin-specific type I receptors (Fig. 2). This specificity of type I receptor-mediated R-Smad activation is determined by the paired interactions of the L45 loop on the type I receptor and the L3 loop of the R-Smads as well as the GS motif of the receptor and the basic patch on the R-Smads. The second group is the common mediator Smad (Co-Smad, Smad4). Activated R-Smads form a complex with Smad4 and become accumulated the nucleus [10,11]. As the activated Smad complexes have a weak binding affinity for DNA, additional transcription factors are required for the high affinity interaction and specificity on chromatin [2,10,12]. A variety of transcription factor families have been reported to act in concert with Smad proteins such as p300/CBP, Sp1, AP1, Ets, and Fox proteins in transcription [10]. The third Smad group includes inhibitory Smads (I-Smads, e.g. Smad6 and Smad7). The inhibitory Smads are often induced by the TGF-β/BMP family signaling and act in a negative feedback loop [1,13]. While Smad6 mainly inhibits BMP signaling, Smad7 is able to prevent both BMP and TGF-β signaling. TGF-β has also been shown to signal independently of Smads, as it can activate signaling from other signaling molecules or pathways such as TAK1 (TGF-β-associated kinase 1), Erk (extracellular signal regulated kinase), p38, MAPK (mitogen-activated protein kinase), and Akt [14,15]. TGF-β Cytostatic Signaling in Normal Cells and Early Stages of Cancer TGF-β plays a crucial role in cancer, acting as a tumor suppressor during the initial stages of tumorigenesis. In normal epithelial cells, TGF-β can inhibit cell proliferation, while it also promotes cell differentiation and apoptosis. TGF-β inhibits cell proliferation mainly through two transcriptional events, i.e. induction of cyclin-dependent kinase (CDK) inhibitors and suppression of c-Myc expression. In epithelial, endothelial and neuronal cells, TGF-β induces expression of the CDK inhibitors such as p15INK4b and p21WAF1 [16–21]. It has been well established that cooperative actions of the Smad complex with transcription factor Sp1 activate transcription of p15INK4b and p21WAF1 in response to TGF-β [16–21]. p15INK4b inhibits cell cycle progression at the late G1 phase by preventing the formation of cyclin D complexes with CDK4 or CDK6 [22]. p21CIP1 inhibits the formation of cyclin E complexes with CDK2 [22]. In haematopoietic cells, TGF-β mediates its growth inhibition through up-regulation of the CDK inhibitor p57 [23]. Simultaneously, TGF-β down-regulates expression of the c-Myc oncogene which promotes cell proliferation. c-Myc is a major transcriptional factor of cell growth and division. In epithelial cells, downregulation of c-Myc expression is mediated by the TGF-β-induced Smad complex in cooperation with the transcription factors p107, E2F4/E2F5 [24], and CCAAT/enhancer binding protein β (C/EBPβ) [25,26]. Interestingly, C/EBPβ is required for both the repression of c-Myc expression and activation of p15INK4b expression [27]. In proliferating cells, c-Myc can also directly bind to Smad2/3 and blocks the transcriptional activities of Smad2/3 in transactivating transcription of p15INK4b and p21WAF1, which also explains why c-Myc is repressed by TGF-β [28]. In addition, the transcription factor c-Myc-interacting Zn finger protein-1 (Miz-1) recruits c-Myc as a repressor to the transcriptional start regions of the p15INK4b and p21WAF1 promoters [29,30]. Smad-independent pathways of TGF-β have been also implicated in the anti-proliferative response [14]. For example, TGF-β dephosphorylates p70S6K by PP2A, which leads to cell cycle arrest [31]. In addition to the regulatory role of TGF-β in cell cycle progression, TGF-β can also trigger apoptosis in a variety of cell types under physiological circumstances. However, the molecular mechanisms remain less defined. It has been reported that TGF-β increases expression of death-associated protein kinase DAPK in hepatoma cells [32] and expression of the signaling factor GADD45β (growth arrest and DNA damage 45β) in hepatocytes [33]. It also promotes the activation of death receptor FAS and binding of the pro-apoptotic effector Bim to Bcl-2 and Bcl-XL in gastric carcinoma cell lines [34]. In hepatocytes and B lymphocytes, TGF-β triggers apoptosis through increasing expression of phosphatase MKP2, which enhances the pro-apoptotic effect of Bim [35]. It is generally thought that TGF-β-mediated expression of these apoptotic regulators is mediated or coordinated by the canonical Smad signaling. In addition, TGF-β-induced apoptosis also involves the TRAF6–TAK1–JNK/p38 pathway in some cell types [36,37]. The TβRII-TβRI complex leads to auto-ubiquitylation of TRAF6, and active TRAF6 subsequently activates TAK1 by polyubiquitylation. Activated TAK1 phosphorylates MKK3 or MKK6, which in turn activates p38 MAPK and then leads to apoptosis [38,39]. TGF-β can be also linked to the tumor suppressor p53 [40], which in turn is regulated by p38 MAPK and Smads. In hepatocytes, TGF-β induces cell death through reactive oxygen species (ROS) production [41]. TGF-β-induced ROS production can promote apoptosis through the modulation of various members of the Bcl-2 family [42]. TGF-β may also induce cellular differentiation in some tumors. TGF-β regulates differentiation by controlling the expression of Id1 protein, which has been reported to enhance Ras-driven mammary tumorigenesis in mice bypassing senescence [43]. In an xenograft model using a Ras-transformed human breast epithelial cell line, TGF-β can down-regulate Id1, thereby suppressing tumor formation by Ras signaling and imposing a less proliferative phenotype [44]. These findings suggest that Id1 repression mediates cell differentiation as a tumor suppressive response to TGF-β. Due to its potent tumor suppressive effects, TGF-β signaling is lost in cancers, which is a hallmark in cancer [45]. Mutations or deletions of genes encoding components of the pathway frequently occur in a variety of cancers such as colon, pancreatic, and gastric cancers. Taking Smad4 as an example, its mutations or deletions are found in about half of pancreatic cancer patients [8,9]. However, such somatic mutations are rare in other cancers such as breast, prostate, and skin cancers [46]. Because loss of TGF-β responses is common in all types of cancers, there are alternative mechanisms underlying TGF-β resistance in those cancer types without somatic mutations in the TGF-β pathway. Much effort has been made to understand the tumor suppressive functions of TGF-β in those cancers without genetic inactivation of Smads or TGF-β receptors. Accumulating evidence has demonstrated that the tumor suppressor functions of Smads are compromised by oncogene products such as c-Ski, Bcl-6, c-Myc, Evi-1, and Stat3 through direct Smad–oncoprotein interactions [47–53], suggesting that activation of oncogenes can suppress TGF-β growth inhibitory response. Since different sets of oncogenes were found in different cancer types, it is anticipated that more interactions between oncogenes and the TGF-β pathway will be identified. Such studies will provide more insights into the loss of TGF-β tumor suppressive signaling in a particular cancer. TGF-β Tumor-promoting Signaling in Advanced Cancer In many cancers, there are mutations or deletions of TGF-β receptors or Smads in the TGF-β pathway, which lead to inactivation or perturbation of signaling responses [1,8]. Tumors can exploit certain aspects of TGF-β signaling to actively promote tumor cell. Different types of tumors such as gliomas, breast cancer, and prostate cancer seem to obtain mutations preferentially not in the core components of TGF-β signaling [1,8]. Such human tumors retain the ability to exploit TGF-β signaling to induce signaling that promotes EMT, tumor invasion, metastatic dissemination, and evasion of the immune system [1,8]. Under these conditions, tumors with such a signature are highly aggressive. EMT is crucial for the embryonic development. It is also important during wound healing, fibrosis, and cancer progression. Cells undergoing EMT are characterized by loss of E-cadherin expression and epithelial cell junctions, and a rearrangement of the cytoskeleton into a mesenchymal pattern. TGF-β is a key driver of EMT in epithelial cancers [1,8]. TGF-β-induced EMT supports tumor invasion and dissemination by releasing tumor cells into the surrounding environment and promoting their motility. In many cancers, TGF-β-induces EMT transcriptionally regulates E-cadherin, Snail, N-cadherin, and vimentin [54,55]. It also induces the expression of Sox4 and promotes mesenchymal programs, tumor progression and invasiveness in breast cancer [56]. More importantly, TGF-β-induced Snail or Twist1 can in turn drive epigenetic changes that influence EMT [54,55]. TGF-β increases cell motility, dissemination, and metastasis by regulating gene expression of integrin in both lung and breast cancer [57–60]. In HCC, TGF-β-driven EMT promotes cell dissemination and intrahepatic metastasis by inducing Snail1, which confers ability of resistance of apoptosis [61]. Additionally, TGF-β promotes CXCR4 expression in HCC cells, driving cell migration and invasion [62]. In prostate cancer, TGF-β increases the metastasis by repressing the expression of E-cadherin and promoting the expression of N-cadherin, ZEB1, TWIST, fibronectin, and Snail1 [63–65]. During the final stage of metastasis, mesenchymal-to-epithelial transition (MET), which is the reverse process of EMT, is also required to colonize distant sites and form metastases [66]. TGF-β has also been reported to regulate Id1 expression which promotes metastatic colonization in breast cancer cells [67] and repress Twist expression in basal breast cancer cells which infiltrate the lung parenchyma [68]. Although it is well established that TGF-β mediates EMT before cell dissemination from the primary tumor, it is unknown when or where MET occurs and to what extent TGF-β contributes in this process. Collectively, EMT driven by TGF-β confers invasiveness, motility, and progenitor-like features in cancer cell. In addition, EMT also contributes to chemo-resistance in breast and pancreatic cancer [69]. TGF-β signaling drives cell motility and local invasion in non-epithelial cancers as in epithelial cancers. In glioblastoma, TGF-β has been reported to activate EMT drivers ZEB1 and Snail1 [70] as well as surface molecules such as cadherin-11 [71] and integrin [72], which together promote cell motility and local invasion. Moreover, activation of integrin also contributes to TGF-β activation and its transcriptional responses in a positive feedback loop [73]. In particular, TGF-β–Smad2–CITED1-mediated transcription promotes melanoma amoeboid invasion [74]. Taken together, many different studies implicate TGF-β signaling in metastatic dissemination. However, conflicting results have been reported in mouse models. Different tumor types and the use of different interfering strategies sometimes yield opposing results in the potential of TGF-β signaling to initiate the tumor metastasis. For example, TβRII depletion by targeted gene inactivation or dominant-negative interference increases metastasis in polyoma middle-T antigen (PyMT)-tumors [75], but inhibits metastasis of prostate cancer xenografted in mice [76]. In addition, expression of a dominant-negative TβRII promotes metastasis in ErbB2/Neu mouse mammary tumors [77], but expression of activated TGF-β1 has been reported to enhance metastasis in the same model [78]. Overall, the contribution of TGF-β signaling to metastasis still requires further and more comprehensive investigation. On the whole, TGF-β inhibits cell proliferation and stimulates differentiation in normal cells, thus acting as a tumor suppressor. On the contrary, it induces tumor progression and metastasis in advanced cancer, thus serving as a tumor promoter. The dual role of TGF-β on cancer can be explained by the pleiotropic nature of TGF-β. Smad4 may serve as a switch between tumor-suppressive and tumor-promoting activities of TGF-β in pancreatic cancer cells [79]. Mechanistically, TGF-β increases the expression of Sox4 in a Smad4-independent manner, which cooperates with the epithelial lineage determinant Kruppel like factor 5 (Klf5) to promote oncogenic growth. Restoration of Smad4 activity destroys the Sox4–KLF5 interaction and changes Sox4 to induce the transcription of pro-apoptotic genes through a lethal EMT [79]. The tumor-promoting effects of TGF-β on cancer can also be achieved through TGF-β-mediated regulation on tumor microenvironment, including the stroma, and immune responses. Effect of TGF-β on Immune Response in Cancers Cancer progression is dependent on escaping immune surveillance, while TGF-β plays an integral role in regulating immune responses and tumor microenvironment [1,3,80]. TGF-β has pleiotropic effects on both innate and adaptive immune cells, including dendritic cells, macrophages, natural killer (NK) cells, and CD4+ and CD8+ T cells. TGF-β has been reported in stimulating the differentiation of the immune-suppressive regulatory (Treg) cells [1,3]. Given these fundamental roles in immune regulation, TGF-β is therefore an attractive therapeutic target in many immune disorders and in cancer. TGF-β has a profound impact on the myeloid lineage. TGF-β induces monocyte recruitment and promotes differentiation and polarization from M1 into M2 tumor-associated macrophages (TAMs). The M2 TAMs can successively secrete TGF-β supporting tumor promotion [81]. Tumor-derived TGF-β also promotes tumor-associated neutrophils (TANs) [82]. These findings suggest that TGF-β regulates N1–N2 polarization of neutrophils, which in turn decreases activation of intra-tumoral CD8+ T cells. Furthermore, TGF-β signaling can inhibit DC migration and induce their apoptosis [83–85]. The NK cells are a type of cytotoxic lymphocyte critical to the innate immune system [86]. TGF-β has been reported to inhibit NK cell proliferation and function. And in this way, it contributes to a permissive microenvironment for tumor progression. In lung and colorectal cancer, TGF-β inhibits the cytotoxic function of NK cells by down-regulating the NK cell-specific receptor, NKG2D [87]. Moreover, TGF-β decreases NK cell-mediated tumor cell death by inducing repression of MHC class I expression in tumor cells [88]. Overall, increased TGF-β expression within the tumor microenvironment can lead to reduced NK cell cytotoxic activity, decrease the recognition of tumor cells by NK cells and thus block the NK cell-mediated clearance of tumor cells. TGF-β secreted by cancer cells can impact T cell activity by regulating their transcriptional profile. The effect of TGF-β on T cells has been clearly demonstrated by genetic ablation or attenuation of TGF-β signaling. Transgenic mice with a dominant-negative TβRII under a T cell-specific promoter exhibit spontaneous T cell differentiation and autoimmune disease [89]. TGF-β represses cytotoxic gene expression, such as granzyme A, granzyme B, perforin, IFN-γ, and FasL in cytotoxic T cells (CTLs), resulting in tumor cells to escape from immune surveillance [90]. Blockade of TGF-β signaling in T cells supports tumor-specific CD8+ cytotoxic T cells and the clonal expansion of CD8+ T cells in vivo [91]. Inhibition of proliferation and repression of the cytotoxic gene program in are two distinct effects, which ultimately favor tumor progression [91]. TGF-β can act on T helper cell differentiation. TGF-β induces FoxP3 expression and generates induced Treg cells, which supports their phenotype and suppressive functions. In lung tumor, TGF-β secreted by lung cancer cells induces Treg cells in tumor microenvironment [92]. In HCC, TGF-β promotes the differentiation of Treg cells, and the blockade of TGF-β decreases Treg cells in liver tissues and reduces HCC progression [93]. In addition to Treg cells, TGF-β and IL-6 cooperatively induce Th17 cells, which are involved in inflammation [94,95] and inhibit IL-2-dependent T cell proliferation [96]. Moreover, myeloid-derived suppressor cells (MDSCs) can secrete TGF-β [81]. Thus, TGF-β helps tumor cells escape from the immune surveillance and support tumor progression. In general, TGF-β is a potent physiological immune-suppressor in humans. The immunosuppressive response to TGF-β allows tumors to escape from the anti-tumor immune response. In mouse models that systemically lack TGF-β1 also die of systemic inflammation and severe autoimmunity [97,98]. Increased TGF-β in the tumor microenvironment represents a primary mechanism of immune evasion in colon cancer [99]. TGF-β shapes the tumor microenvironment to restrain anti-tumor immunity by restricting T cell infiltration [100]. Generally, TGF-β may be considered an appealing therapeutic target in the context of cancer immunomodulation. TGF-β Targeted Cancer Therapy Drugs that target many different components of the canonical TGF-β signaling pathway have been developed. For instance, strategies include interference with the ligand expression or activity, including ligand traps and antisense oligonucleotides, and inhibition of the intracellular signaling components such as receptor kinase inhibitors and anti-Smad peptide aptamers. Each type has distinct advantages and disadvantages that have to be considered in evaluating their potential for use in the clinic. Fully humanized pan-TGF-β monoclonal neutralizing antibodies have been developed by Genzyme, including Lerdelimumab [101,102], Metelimumab [103], and Fresolimumab (GC1008) [104]. Fresolimumab has shown partial and stable response in a phase I study of advanced melanoma [105]. Fresolimumab had been effectively delivered to recurrent high-grade gliomas but did not result in clinical benefit, probably due to breakdown of the blood brain barrier in this neoplastic tissue [106]. Results to date have provided evidence that Fresolimumab is well tolerated and is not associated with irreversible, life-threatening complications. It indicates that antibody targeting TGF-β may be a novel and productive therapeutic strategy for the treatment of certain cancers. Antisense oligonucleotides have been engineered into immune cells to prevent TGF-β synthesis. Trabedersen (AP12009) is one good example of antisense oligonucleotide that specifically inhibits TGF-β2 expression. In an initial Phase I/II study in patients with high-grade glioma, Trabedersen shows a significant survival benefit over standard chemotherapy [107]. Belagenpumatucel-L, which is an allogeneic tumor cell vaccine that inhibits expression of TGF-β2 and demonstrates enhancement of tumor antigen recognition, is well tolerated and shows survival advantages in a phase II trial in NSCLC at different stages [108]. Although the Phase III trial investigating belagenpumatucel-L in stage III/IV patients did not meet its primary end point, some of the patients experience a survival benefit [109]. Many preclinical studies evaluating TβRI inhibitor drugs have been undertaken [110]. Galunisertib (LY2157299) is a small molecule inhibitor selectively inhibiting the kinase activity of TβRI. It has been investigated either as monotherapy or in combination with standard anti-tumor regimens in different cancer patients, such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma [111]. Galunisertib has completed Phase I [112] and is currently under investigation in several Phase II trials. In the initial Phase I trial this compound showed promising activity in patients with glioblastoma [112]. However, in Phase II trials it failed to show improvement compare with lomustine in second line glioblastoma [113]. On the other side, galunisertib did show superiority over gemcitabine in patients with pancreas cancer [114]. And it has been well tolerated as a first-in-class, oral cancer therapy [111]. All this indicate galunisertib remains a promising compound in clinical development. Another strategy to block TGF-β signaling for cancer is to interfere with the TGF-β signaling molecules such as Smads. This may be achieved by using peptide aptamers. The Trx-SARA aptamer have been designed that bind to Smad2 and Smad3, consequently disrupting their interactions with Smad4. Treatment with Trx-SARA can reduce the level of Smad2/3 in complex with Smad4 after TGF-β stimulation. Furthermore, Trx-SARA treatment has been reported to inhibit TGF-β-induced EMT in NMuMG murine mammary epithelial cells in vitro [115]. Although TGF-β signaling inhibition results in a significant reduction in metastasis in mouse models, clinically the effects have been less obvious as it hoped for. Additionally, it is more difficult to demonstrate inhibition of primary tumors. All these facts suggest that combinatorial therapy may increase the efficacy of TGF-β inhibitors in a clinical setting. Thus, in the next stage of drug development, major efforts may involve the most efficacious drug combinations of TGF-β blockade for each oncological disease application with radiation, chemotherapy, pathway targeted therapies and immunotherapy. Some studies have shown the benefits of combined treatment. For instance, the TβRI/II kinase inhibitor LY2109761 in combination with temozolomine and radiotherapy in a glioblastoma model shows delayed tumor growth compared to controls [116]. Therapeutic co-administration of TGF-β blocker and anti-PD-L1 antibodies in stromal cells facilitates T cell penetration into the center of tumors, and provokes vigorous anti-tumor immunity and tumor regression [100]. On the other hand, as there is considerable variation in both therapeutic and toxicological responses among different patients, development of predictive biomarkers of TGF-β blockade is vitally important. Conclusions and Perspectives The role of TGF-β signaling in tumor cells and stroma has been established based on in vitro and in vivo studies. Strong evidence indicates that in early cancer progression, TGF-β plays a tumor suppressive role, but in later stages it is a potent pro-metastatic mediator. Therefore, a comprehensive understanding of the TGF-β biology in cancer is required to design successful therapeutic approaches. Nowadays, several inhibitors of the TGF-β pathway are being developed and clinically tested for a number of cancers such as glioma, pancreatic cancer, NSCLC, HCC, and melanoma [117]. Although TGF-β targeting agents, such as galunisertib, have shown dramatic therapeutic effects in animal cancer models and in some cancer patients, it is still not clear how the therapeutic effect in cancer patients is achieved. Therefore, it is crucial to consider the complexities in TGF-β signaling when applying TGF-β-related small molecules or protein drugs in clinics. While most translational research has often centered on the pro-tumorigenic of TGF-β on tumor cells in the past, the role of TGF-β to regulate immune evasion has been overlooked. As more and more immune checkpoint inhibitors show promising results in clinical trials, the role of TGF-β as an immune regulator is becoming more valuably investigated. 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TI - TGF-β signaling in cancer
JF - Acta Biochimica et Biophysica Sinica
DO - 10.1093/abbs/gmy092
DA - 2018-10-01
UR - https://www.deepdyve.com/lp/oxford-university-press/tgf-signaling-in-cancer-aFS0h0QD0c
SP - 941
VL - 50
IS - 10
DP - DeepDyve
ER -