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Role of TGFβ in regulation of the tumor microenvironment and drug delivery (Review)

PANAGIOTIS PAPAGEORGIS, TRIANTAFYLLOS STYLIANOPOULOS

International Journal of Oncology · 2015 · Review

doi:10.3892/ijo.2015.2816

Abstract

Deregulation of cell signaling homeostasis is a predominant feature of cancer initiation and progression. Transforming growth factor β (TGFβ) is a pleiotropic cytokine, which regulates numerous biological processes of various tissues in an autocrine and paracrine manner. Aberrant activity of TGFβ signaling is well known to play dual roles in cancer, depending on tumor stage and cellular context. The crucial roles of TGFβ in modulating the tumor microenvironment, its contribution to the accumulation of mechanical forces within the solid constituents of a tumor and its effects on the effective delivery of drugs are also becoming increasingly clear. In this review, we discuss the latest advances in the efforts to unravel the effects of TGFβ signaling in various components of the tumor microenvironment and how these influence the generation of forces and the efficacy of drugs. We also report the implications of tumor mechanics in cancer therapy and the potential usage of anti‑TGFβ agents to enhance drug delivery and augment existing therapeutic approaches. These findings provide new insights towards the significance of targeting TGFβ pathway to enhance personalized tumor treatment.

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Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

The crucial role of transforming growth factor β (TGFβ) in tumor progression, metastasis and treatment has been well recognized and has become the topic of extensive research. Among the effects, TGFβ can regulate cancer cell proliferation, contribute to epithelial-to-mesenchymal transition (EMT), suppress the function of immune cells compromising immune response, contribute to the conversion of fibroblasts to myofibroblasts and cause overproduction of extracellular matrix (ECM) in the tumor. While it has been known for over two decades that anti-cancer drugs cannot penetrate deep into collagen-rich tumors (e.g., pancreatic cancers) and, more significantly, that depletion of collagen fibers can improve drug delivery, only recently TGFβ has become a target to reduce tumor fibrosis and thus, increase intratumoral drug concentration and treatment efficacy. Preclinical data of this new strategy are promising and it has already reached clinical trials. In this review, we first present a brief description of TGFβ synthesis and activation along with its signaling pathways. Following, we discuss the effects of TGFβ on tumor progression, its pathway alterations in cancer as well as its effects on EMT, immune cells function, fibroblasts behavior and ECM remodeling. Finally, based on the above, we review the barriers to the effective delivery of drugs caused by TGFβ and how regulation of TGFβ signaling can be employed to optimize delivery of therapeutic agents and overall survival.

2. TGFβ synthesis and activation

The TGFβ superfamily encompasses around 40 secreted cytokines, including TGFβ, bone morphogenetic proteins (BMPs), activins, nodal, lefty, myostatin, anti-Müllerian hormone (AMH) and growth differentiation factors (GDFs). These cytokines regulate a plethora of biological functions such as cell proliferation and apoptosis, embryonic patterning, stem cell maintenance, cell differentiation, migration and immune surveillance. Importantly, the effects of these factors are characterized as cell-type specific as well as context dependent. The TGFβ isoforms, with most common being TGFβ1, 2 and 3, are initially synthesized as 75 kDa inactive homodimers, known as pro-TGFβ, which consist of TGFβ associated with latency-associated proteins (LAPs) at the N-terminal part of the pro-peptide. This is part of the TGFβ large latent complex (LLC), comprised of the LAPs and the latency TGFβ-binding proteins (LTBPs), and is covalently associated to the ECM via the N-terminal region of LTBPs (Fig. 1). While TGFβ is part of the LLC complex, it remains in an inactive form since the high affinity association of LAPs with TGFβ prevents the interaction with its receptors. During TGFβ activation, LAPs undergo conformational changes induced by thrombospondin-1 (TSP-1) followed by cleavage mediated by furin convertase, plasmin or matrix metalloproteinases MMP-2/9 resulting in the release of the mature 24 kDa TGFβ dimer. The active ligand is then able to bind and activate TGFβ receptors (TGFβRs) to propagate downstream intracellular signaling events. Therefore, the processing of pro-TGFβ into the active TGFβ ligand is a critical regulatory step which determines its bioavailability.

3. TGFβ signaling pathways

The TGFβ and TGFβ-like cytokines mediate downstream intracellular signaling via the Smad family of proteins, which consists of eight human structurally related members (Fig. 1). Smads can be functionally classified into three groups: the receptor activated Smads (R-Smads), which include Smad1, 2, 3, 5, 8; the common mediator Smad (Co-Smad), Smad4; and the inhibitory Smads (I-Smads), Smad6 and 7. Three types of TGFβRs are responsible for initiating signaling; TGFβRI, II and III. There are seven TGFβRI, five TGFβRII and two TGFβRIII known so far. TGFβRIs include activin receptor-like kinases 1–7 (ALK1–7), TGFβRIIs include the TGFβRII, bone morphogenetic protein receptor II (BMPRII), activin receptor II (ACTRII), ACTRIIB, anti-Müllerian hormone receptor II (AMHRII), while beta-gycan and endoglin belong to the TGFβRIIIs and mostly function as co-receptors to enhance activin signaling. In most tissues, TGFβ ligands function through heteromeric complex formation between two TGFβRI and two TGFβRII molecules. While both receptors possess Ser/Thr kinase activity, TGFβRIIs function as the ‘activator’ and TGFβRIs as the ‘signal propagating’ component. The TGFβRII-ALK5 complex transduces the signal from all three TGFβ isoforms in multiple cell types, whereas association of TGFβRII with ALK1 is involved in endothelial cells and with ALK2 in cardiovascular tissues. ALK5 activates Smad2 and 3 via the canonical TGFβ signaling pathway whereas ALK2, 3 and 6 can activate Smad1, 5 and 8, which are transducers of the BMP signaling pathway. The TGFβ signaling pathways can be classified in two major categories; the canonical or Smad-dependent and the non-canonical or Smad-independent pathways.

Canonical pathway (Smad-dependent)

Even though TGFβ isoforms may elicit diverse cellular responses, they all activate signaling via a similar sequence of events. Binding of the active TGFβ1 ligand to the Ser/Thr kinase TGFβRII followed by recruitment of the ALK5 (TGFβRI) on the cell surface initiates intracellular signaling. Within the heterotetrameric receptor-ligand complex formed, TGFβRII phosphorylates TGFβRI allowing it to interact with the R-Smads (Smad2/3) which, in turn, become phosphorylated at the conserved SSXS C-terminal motif. Recruitment of R-Smads to the activated TGFβRI is facilitated by Smad anchor for receptor activation (SARA) protein. Subsequently, this triggers the formation of a heterotrimeric complex between phosphorylated R-Smads (Smad2/3) and Co-Smad (Smad4), which can translocate into the nucleus to regulate gene expression (Fig. 1). Smads can differentially modulate gene expression by acting as transcription factors in co-operation with co-activators, such as p300/CREB-binding protein (CBP), p300/CBP-associated factor (PCAF), Smad4-interacting factor (SMIF), forkhead transcription factors 1, 3, 4 (FoxO1/3/4), specificity protein 1 (Sp1), c-Jun/c-Fos, Sertad1, or co-repressors, such as E2F4/5-p107, activating transcription factor 3 (ATF3), TGFβ-induced factor (TGIF), Ski, SnoN, forkhead transcription factor G1 (FoxG1), ecotropic viral integration site 1 protein (EVI1) and C-terminal binding protein (CTBP). In addition, Smads are able to epigenetically regulate gene expression either by inducing chromatin remodeling or by maintaining DNA methylation and silencing of selected genes. Importantly, the I-Smad, Smad7, is a key target gene induced by TGFβ signaling and acts as negative feedback regulator of the pathway. In the absence of TGFβ stimulation, Smad7 resides in the cell nucleus and translocates to the plasma membrane upon TGFβ-mediated receptor activation. Smad7 is then able to interfere and block interactions between the R-Smads and the activated receptors to inhibit downstream signaling events. In addition, Smad7 can target the TGFβRs for proteasomal degradation via the E3-ubiquitin ligases Smurf1 and 2. Finally, Smad7 antagonizes the formation of a functional Smad-DNA complex by directly binding to DNA via its MH2 domain and therefore blocks TGFβ-mediated transcriptional responses.

Non-canonical pathways (Smad-independent)

It is also well established that TGFβ-mediated effects can also be exerted through non-canonical Smad-independent pathways. TGFβ has been shown to induce activation of Erk signaling in various tissues including epithelial and endothelial cells, fibroblasts, breast and colorectal cancer cells in order to promote disassembly of adherens junctions and cell migration. TGFβRI phosphorylation can recruit and activate ShcA, thus promoting the formation of a ShcA/Grb2/Sos complex. In turn, this complex is able to activate Ras on the plasma membrane followed by sequential activation of c-Raf, MEK and Erk.

Moreover, TGFβ can mediate the activation of the c-Jun N-terminal kinase (JNK) and p38/mitogen-activated protein kinase (MAPK) pathways, which are responsible for promoting apoptosis or cell migration depending on cellular context, via the mitogen-activated protein kinase kinase (MKK)4 and 3/6, respectively. Further upstream, MKKs are phosphorylated by the TGFβ-activated kinase 1 (TAK1) which is recruited to the TGFβRs via the scaffold protein TNF receptor-associated factor 6 (TRAF6). Besides TAK1, two other mitogen-activated protein kinase kinase kinases (MAPKKKs), namely MEKK1 and mixed lineage kinase 3 (MLK3), were also shown to mediate TGFβ-induced activation of JNK and p38-MAPK by MKK4 and 3/6.

The Rho-like small GTPases, predominantly RhoA, Rac and cell division cycle 42 (cdc42), are additional molecules that mediate important TGFβ cellular functions, such as cytoskeletal organization, cell polarity, cell migration and gene expression. TGFβ is able to rapidly activate the RhoA and cdc42/Rac1 pathways, in a Smad2/3-independent manner, to promote actin polymerization, formation of stress fibers and EMT. TGFβ may also downregulate RhoA protein levels by recruitment of Par6 at the TGFβRI–II complex. Phosphorylation of Par6 by TGFβRII triggers binding of the E3 ligase Smurf1 to the complex followed by ubiquitination and degradation of RhoA at sites of cellular protrusions. Subsequently, this leads to the dissolution of tight junctions, rearrangement of actin cytoskeleton and EMT.

Some of the effects exerted by TGFβ could also be mediated by activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt (PI3K/Akt) pathway. This is evident from studies showing that TGFβ can rapidly induce PI3K activation followed by phosphorylation of its effector Akt to promote EMT, cell migration and survival. One of the most important effector molecules downstream of PI3K/Akt pathway appears to be the mammalian target of rapamycin (mTOR), a key regulator of protein synthesis, which can subsequently phosphorylate S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1). Activation of the mTOR pathway by TGFβ is thought to be important for regulating cell size, EMT and invasion (Fig. 1).

4. TGFβ signaling in cancer initiation and tumor progression

It is well established that the multipotent actions of TGFβ are highly context dependent. The complexity of these functions is increased due to the fact that TGFβ exerts distinct effects depending on the tissue type as well as the genetic and epigenetic background of cells. It is clearly evident that TGFβ plays dual roles during carcinogenesis. In early stages TGFβ promotes growth inhibition and apoptosis of normal epithelial and lymphoid cells as well as pre-malignant tumors, whereas during late stages TGFβ acquires pro-oncogenic and pro-metastatic roles, which are associated with a progressive increase in the locally secreted TGFβ levels. Therefore, one of the hallmarks of cancer is that the vast majority of cases exhibits insensitivity to TGFβ-mediated growth inhibition.

Regulation of cell proliferation

It has long been noted that TGFβ has a cytostatic effect on normal epithelial, endothelial and neuronal cells as well as certain cells of the immune system, such as T cells. These functions of TGFβ are extremely important for physiological tissue homeostasis in order to restrain cell proliferation and prevent the generation of hyperproliferative disorders, like cancer. These anti-proliferative effects primarily control the G1/S phase transition events and are mediated via induction of the cyclin-dependent kinase inhibitors CDKN2B (encoding p15/INK4B), CDKN1A (encoding p21/Cip/Waf1) and p27/Kip1 by TGFβ. Cell cycle arrest can also be achieved by repression of the proliferation-inducing transcription factors c-Myc and the family of inhibitor of DNA-binding proteins ID1, 2 and 3. On the other hand, the effects of TGFβ in proliferation can be opposing, depending on the tissue type. It is also well recognized that TGFβ enhances proliferation of fibroblasts and it is often mediated indirectly by TGFβ-induced connective tissue growth factor (CTGF) secretion, which is responsible for stimulating fibroblast proliferation and ECM synthesis. It is now unambiguously accepted that cancer-associated fibroblasts (CAFs) play critically important roles in the tumor microenvironment and cancer progression and their functions are further discussed below.

Pathway alterations in human cancers

Numerous human studies have identified that components of the TGFβ pathway become genetically or epigenetically altered in various tumor types thus explaining, at least in part, the escape from TGFβ-mediated growth control. Loss of function or truncating mutations in TGFβRI and TGFβRII as well as in Smad2 and Smad4 have been detected in colorectal, pancreatic, gastric and prostate cancers. In addition, loss of the 18q21 chromosome region, harboring the Smad4 gene, is commonly observed in ~60% of pancreatic and 30% of colorectal cancers has been shown to promote angiogenesis and tumor growth by inducing vascular endothelial growth factor (VEGF) expression. However, in other tumor types like breast, the frequency of Smad gene mutations is rare suggesting that alternative mechanisms for acquiring resistance to growth inhibition by TGFβ exist. These include activation of the Ras oncogene which leads to Erk-mediated Smad2/3 phosphorylation and suppression of functional Smad complex formation. Furthermore, overexpression of the dominant-negative CCAAT/enhancer-binding protein β (C/EBPβ) isoform LIP in breast cancer patients was found to suppress TGFβ-mediated growth inhibition. Finally, another mechanism which TGFβ may exploit in order to switch from a tumor suppressor to a metastasis-promoting factor is through differential regulation of the ID1 gene. While ID1 expression is suppressed by TGFβ in normal tissues, it was found to be induced in patient-derived metastatic breast cancer cells.

EMT and cancer metastasis

EMT is an integral process during embryonic development which can be abnormally reactivated in adult tissues under pathological conditions, such as cancer and fibrosis. It involves the activation of a coordinated reversible transcriptional program whereby epithelial cells undergo dissolution of cell junctions, lose their polarity and epithelial characteristics concomitantly with acquisition of mesenchymal features and dramatic remodeling of their cytoskeleton. During this process, the expression of epithelial genes, such as E-cadherin, γ- and β-catenin, zonula occludens (ZO), and claudins is suppressed with concurrent expression of mesenchymal components, such as N-cadherin, vimentin, fibronectin and α-smooth muscle actin (α-SMA). This program can be initiated by several pleiotropically acting transcription factors regulated by signaling pathways such as TGFβ, Wnt and receptor tyrosine kinases (RTKs). Some of the better characterized examples include Snail, Slug, zinc-finger E-box binding homeobox 1 (ZEB1/δEF1), zinc-finger E-box binding homeobox 2/Smad interacting protein 1 (ZEB2/SIP1), Twist, high mobility group AT-hook 2 (HMGA2) and forkhead box protein C2 (FOXC2). In addition, recent studies indicate that overactive TGFβ-TGFβR-Smad2 signaling axis could further contribute to the establishment of an EMT phenotype by maintaining the epigenetic silencing of epithelial genes during this process. Besides Smads, other signaling pathways have also been implicated in TGFβ-induced EMT, including Erk, PI3K/Akt, RhoA, p38-MAPK and cofilin. Induction of EMT is one of the major mechanisms by which TGFβ has been shown to promote cell motility, invasiveness and metastasis of cancer cells. EMT significantly enhances intravasation of carcinoma in situ cells through the basement membrane, survival in the circulation, extravasation at the distal tissues and formation of micrometastases in secondary organs.

5. The effects of TGFβ on the tumor microenvironment

Under physiological conditions, the sustained local release of basal TGFβ levels is sufficient to maintain normal tissue homeostasis. However, under conditions of tissue injury, the local TGFβ secretion from stromal cells and blood platelets is rapidly increased to facilitate wound repair as well as to prevent uncontrolled regenerative cell proliferation and inflammation. A similar situation is commonly observed in pre-malignant tumors where TGFβ is secreted in the microenvironment initially to control proliferation and cancer progression, but it is ultimately utilized by cancer cells to promote their malignant properties. Local TGFβ release produces a tumor microenvironment which is conducive to tumor growth, invasion and metastasis. Secretion of TGFβ can be derived from epithelial cancer cells thus regulating their own properties within the tumor mass in an autocrine or paracrine fashion. Moreover, infiltrating stromal cells, including fibroblasts, leukocytes, macrophages, bone-marrow derived endothelial, mesenchymal and myeloid precursor cells, is another major source of this cytokine. Finally, TGFβ can be stored in the ECM of the bone and can be activated during development of osteolytic metastatic lesions. In the following paragraphs, we summarize the effects of TGFβ on the main and better characterized components of the tumor microenvironment and particularly on fibroblasts, immune cells and the ECM.

Effect of TGFβ on immune cells

TGFβ exhibits immunosuppressive effects on all arms of the immune system because it functions as antagonist of several functions of the immune cells. As a result, the anti-tumor immune response is compromised, reducing cancer cell recognition and clearance. Specifically, TGFβ affects the function of natural killer cells, CD4+ and 8+ T cells, macrophages, neutrophils, dendritic, mast and B cells. Specifically, a TGFβ-rich tumor microenvironment is a suppressor of T-cell proliferation, reduces their effector function and inhibits the maturation of T helper cells. It also induces macrophage M2 polarization from a type I to a type II phenotype, which hinders the suppression of monocyte-mediated cell death, reduces effector function and increases chemotaxis. Additionally, TGFβ induces an N2 neutrophil phenotype which, as with the macrophages, reduces effector function and increases secretion of inflammatory cytokines. Finally, high levels of TGFβ can cause apoptosis of B cells, inhibit the maturation of dendritic and natural killer cells and induce chemotaxis of mast cells. The combined immuno-suppressive effects of TGFβ compromise the ability of the host to resist tumor progression and thus consist a barrier to immunotherapy.

Effect of TGFβ on fibroblasts

A primary role of TGFβ in modulating the tumor microenvironment is its contribution to the conversion of fibroblasts to myofibroblasts, also known as CAFs. Specifically, the compressive forces developed inside a tumor, due to its growth in the confined space of the host tissue, can facilitate the conversion of fibroblasts to proto-myofibroblasts. Subsequently, TGFβ increases the levels of collagens I and III and fibronectin, which promote cellular adhesion to extracellular fibers, and thus, enhances the communication of mechanical signals between the ECM of the tumor and the fibroblasts. As a result, the mechanical forces are more actively transmitted in the interior of the cell and contribute to the conversion of proto-myofibroblasts to differentiated myofibroblasts. Myofibroblasts are characterized by more extensively developed stress fibers in the cytoskeleton compared to proto-myofibroblasts, presumably to balance the extracellular forces, and by the de novo expression of α-SMA. The contraction of myofibroblasts is sustained by α-SMA stress fibers and it is regulated by Rho/ROCK signaling activation. The produced contractile forces remodel the ECM due to the ability of fibroblasts to stretch collagen fibers and produce ECM molecules. Additionally, these forces can be transmitted to the LLC via integrins. LLC is also bound to extracellular fibers (Fig. 1), which resists the pulling of the LLC by myofibroblasts and gives rise to a mechanically-induced liberation of TGFβ. The stiffer the ECM, the stronger the interactions among myofibroblasts, LLC and extracellular fibers and thus, the release of TGFβ becomes more pronounced. Therefore, myofibroblast contraction within a collagen-rich, and thus, stiff microenvironment further stimulates the release of active TGFβ from its latent form.

Effect of TGFβ on ECM

TGFβ upregulates the expression and synthesis of many matrix proteins, primarily through the recruitment of myofibroblast. Proteins upregulated by TGFβ include collagens I–V, basement membrane proteins (laminin, entactin, perlecan) and ECM proteins (fibronectin, osteopontin, thrombospontin, tenascin, osteonectin/SPARC, elastin, biglycan, decorin, and hyaluronan). Additionally, in the early stages of carcinogenesis, TGFβ stimulates myofibroblasts and other stromal cells to enhance the synthesis of collagen crosslinking enzymes, particularly lysyl oxidase, which increases the rigidity of the collagen network. On the contrary, TGFβ downregulates the synthesis of matrix-depleting proteins, such as matrix metalloproteinases (MMP-1, -8, -13). As a result, the increase in matrix protein synthesis and decrease in matrix proteinase activity, owing to the TGFβ activity, contributes to the remodeling of the tumor ECM and can result in a fibrotic response, known as desmoplasia, which is commonly observed in many types of tumors and particularly in pancreatic, colon and breast cancers as well as in various sarcomas.

Tumor fibrotic response stiffens the tumor tissue, and as a result, it increases the compressive physical forces in the interior of the tumor. Compression of cancer cells alters their gene expression profile to enhance their invasive and metastatic phenotype. Furthermore, as mentioned previously, matrix stiffening along with the high contractile forces of myofibroblasts, cause further liberation of TGFβ from the LLC. These events suggest a positive feedback loop between TGFβ activation, myofibroblast contraction and ECM remodeling and production (Fig. 2A). Finally, compression of intratumoral blood vessels reduces tumor perfusion, and thus, the delivery of oxygen. Hypo-perfusion and hypoxia, in turn contribute to immune-evasion, promote malignant progression and metastasis, and reduce the efficacy of a number of therapies including radiation treatment and systemic administration of chemo- and nanotherapy.

6. TGFβ, tumor desmoplasia and barriers to drug delivery

The desmoplastic reaction of solid tumors hinders all three transport steps of the systemic delivery of drugs, namely vascular, transvascular and interstitial transport. As mentioned above, increased levels of collagen in the ECM, result in intratumoral blood vessel compression and hypo-perfusion. Hypo-perfusion, in turn, reduces the concentration of the drug that can reach the tumor site. Apart from compromised drug delivery, hypo-perfusion also decreases the supply of oxygen rendering the tumor hypoxic, which in turn reduces the efficacy of radiation therapy. Additionally, desmoplasia reduces the hydraulic conductivity of the tumor interstitial space, i.e., the ease with which the interstitial fluid percolates through the interstitial space of a tissue. High hydraulic conductivity allows fluid to rapidly flow in the interstitial space and be drained by peripheral lymphatic vessels. The accumulation of collagen and other ECM proteins in tumors decrease the available spaces for interstitial fluid flow and because the fluid cannot freely move, the interstitial fluid pressure (IFP) increases. Interstitial hypertension is a hallmark of tumor pathophysiology. IFP reaches and even exceeds micro-vascular fluid pressure, which eliminates pressure gradients across the tumor vessel wall and thus, the transvascular transport of drugs. Therefore, the only mechanism of transport is through diffusion (i.e., due to a concentration difference), which is inversely proportional to the size of the therapeutic agent. Chemotherapeutic agents, with a size <1 nm, are able to diffuse fast and exit the tumor vasculature. Nanoparticles, however, with sizes >60 nm cannot effectively extravasate into the tumor interstitial space.

Furthermore, the dense interstitial matrix of desmoplastic tumors hinders the homogeneous distribution of large nanoparticles. As with transvascular transport, nanoparticles with a size >60 nm often cannot penetrate deep into the tumor because their size is comparable to the size of the pores of the interstitial collagen network and they often get trapped. Therefore, even if large nanoparticles extravassate from the leaky vessels of the tumor, they will not be able to effectively diffuse into the tissue but they will concentrate in the perivascular regions, causing only local effects. Apart from these steric interactions between the interstitial matrix and nanoparticles, the increased levels of collagen and hyaluronan give rise to electrostatic interactions. Indeed, hyaluronan has a highly negative charge, while collagen fibers carry a slight positive charge. Nanoparticles of a non-neutral surface charge density can be attracted electrostatically and bind to these proteins, which further inhibits their uniform delivery inside the tumor.

7. Therapeutic applications of TGFβ targeting

Pharmacological inhibition of TGFβ has been used in preclinical and clinical studies as a therapeutic strategy to either hinder tumor progression directly or modify the tumor micro-environment in order to improve perfusion and drug delivery and thus, increase indirectly the efficacy of the treatment. There is a large number of TGFβ inhibitory drugs employed in these studies. Particularly, targeting with TGFβ agents (e.g., 1D11, AP12009, SD-208) as well as non-specific targeting with other TGFβ inhibitory drugs (e.g., tranilast) have shown to reduce tumor progression and metastasis in vivo, mainly owing to augmentation of the immune response and inhibition of EMT. However, there are also studies that relate inhibition of TGFβ with promotion of tumor progression owing to an increase in inflammatory cell infiltration. Particularly, it has been shown that inflammatory infiltrates mediate the pro-tumorigenic functions of fibroblasts that lack TGFβ signalling. Clinical trials for the use of TGFβ inhibitory drugs have been in progress (ClinicalTrials.gov identifiers: NCT00368082, NCT01582269 and NCT00844064), but their results are not conclusive yet, presumably owing to differences in the degree of desmoplasia among tumor types or even among tumors of the same type, but also owing to the various effects of TGFβ on tumor biology.

Targeting of TGFβ to reduce desmoplasia has the ability to alleviate physical forces in tumors, decompress tumor blood vessels and improve perfusion (Fig. 2B). Restoration of tumor perfusion, however, can increase nutrients supply to the tumor, and thus, increase its growth rate. Also, the decompressed vessels could allow more metastatic cells to leave the primary tumor. Indeed, in some cases, inhibition of TGFβ has been shown to facilitate tumor progression and metastases in mouse tumor models, whereas other studies, not related to TGFβ, have shown a correlation between improved perfusion and increased metastases. Therefore, based on this rationale, judicious doses of TGFβ inhibitory drugs should be used to alleviate physical forces, decompress blood vessels and improve perfusion when these agents are combined with cytotoxic treatments, such as chemo-, nano-, immuno- and radiotherapy. In these combined treatments the role of the anti-TGFβ drug is to enhance the delivery of the cytotoxic agent and thus, optimize its efficacy. This therapeutic strategy is known as stress alleviation treatment.

Detailed in vivo studies have shown that re-purposing the anti-hypertensive, angiotensin receptor blocker (ARB) drug losartan reduced expression of TGFβ1 and decreased stromal collagen and hyaluronan production, in doses that did not affect blood pressure. Reduction of collagen and hyaluronan, in turn, reduced stress levels in the tumor decompressing intratumoral blood vessels and improving perfusion. Furthermore, reduction of the ECM components improved the interstitial fluid flow and thus, reduced levels of IFP. Improved perfusion and reduced IFP enhanced the delivery and efficacy of chemotherapy in orthotopic breast and pancreatic murine tumor models. Also, in another study combined treatment of mice bearing tumors with losartan and nanomedicine (Doxil) increased the distribution of the drug and the overall survival of the mice. Furthermore, retrospective analyses of clinical data have shown increased survival in patients with lung or renal cancers treated with ARBs. Similar retrospective analysis has shown that patients with pancreatic ductal adenocarcinomas (PDACs) receiving ARBs survived ~6 months longer than those who did not. These preclinical and clinical data have led to a phase II clinical trial with losartan and FOLFIRINOX in PDAC patients (ClinicalTrials.gov identifier NCT01821729). Apart from the use of ARBs, the TGFβ neutralizing antibody 1D11 improved the distribution and efficacy of therapeutics in breast carcinomas by reducing the tumor stroma. Additionally, re-purposing the drug pirfenidone, a TGFβ inhibitor clinically approved for the treatment of idiopathic pulmonary fibrosis, was shown to suppress desmoplasia in mice bearing pancreatic tumors and improve the efficacy of chemotherapy. Apart from chemotherapy, radiation therapy has been also improved after treatment with TGFβ inhibitors. Efficacy of radiotherapy depends on the oxygenation of the tissue, which is regulated by tumor perfusion.

8. Conclusions and future perspectives

Owing to the pleiotropic effects of TGFβ on tumor microenvironment and progression, targeting TGFβ signaling to directly treat tumor growth remains controversial. Recent studies have suggested an alternative therapeutic strategy, which involves the use of anti-TGFβ agents in a stress alleviation treatment. The scope of this strategy is to hinder but not completely inhibit the activation of TGFβ ultimately aiming to reduce tumor desmoplasia and particularly the levels of collagen. As described in this review, reduced collagen levels can lead to improved delivery of both chemo- and nano-therapeutics by alleviating mechanical forces and decompressing intratumoral blood vessels. Thus, blocking of TGFβ can improve indirectly the efficacy of conventional treatments. It is promising that many anti-TGFβ agents exist that are already clinically approved for other diseases (e.g., ARBs for hypertension). Re-purposing of these drugs can lead to more effective anti-cancer therapies. Therefore, we need to identify safe and well-tolerated pharmaceutical agents that may complement the treatment regimen of cancer patients. Anti-TGFβ agents are not the only drugs that have the ability to modify the tumor microenvironment. In principle, any clinically approved agent that has the ability to reduce collagen levels could be employed as an alternative strategy. Also, collagen is not the only target for the stress alleviation treatment. Reduction of stromal cells or hyaluronan has also the potential to enhance drug delivery through the same mechanism.

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    Not in our library10.1016/s0092-8674(00)81696-7

  17. 17.

    Massagué J. TGF-beta signal transduction. Annu Rev Biochem. 1998;67:753-791.

    Not in our library10.1146/annurev.biochem.67.1.753

  18. 18.

    Riggins GJ, Thiagalingam S, Rozenblum E, et al. Mad-related genes in the human. Nat Genet. 1996;13:347-349.

    Not in our library10.1038/ng0796-347

  19. 19.

    Lagna G, Hata A, Hemmati-Brivanlou A, Massagué J. Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways. Nature. 1996;383:832-836.

    Not in our library10.1038/383832a0

  20. 20.

    Nakao A, Imamura T, Souchelnytskyi S, et al. TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J. 1997;16:5353-5362.

    Not in our library10.1093/emboj/16.17.5353

  21. 21.

    Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997;390:465-471.

    Not in our library10.1038/37284

  22. 22.

    Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006;6:506-520.

    Not in our library10.1038/nrc1926

  23. 23.

    Lewis KA, Gray PC, Blount AL, et al. Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. Nature. 2000;404:411-414.

    Not in our library10.1038/35006129

  24. 24.

    Wrana JL, Attisano L, Wieser R, Ventura F, Massagué J. Mechanism of activation of the TGF-beta receptor. Nature. 1994;370:341-347.

    Not in our library10.1038/370341a0

  25. 25.

    Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113:685-700.

    Not in our library10.1016/s0092-8674(03)00432-x

  26. 26.

    Miyazono K, Maeda S, Imamura T. BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev. 2005;16:251-263.

    Not in our library10.1016/j.cytogfr.2005.01.009

  27. 27.

    Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425:577-584.

    Not in our library10.1038/nature02006

  28. 28.

    Abdollah S, Macías-Silva M, Tsukazaki T, Hayashi H, Attisano L, Wrana JL. TbetaRI phosphorylation of Smad2 on Ser465 and Ser467 is required for Smad2-Smad4 complex formation and signaling. J Biol Chem. 1997;272:27678-27685.

    Not in our library10.1074/jbc.272.44.27678

  29. 29.

    Zhang Y, Feng X, We R, Derynck R. Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. Nature. 1996;383:168-172.

    Not in our library10.1038/383168a0

  30. 30.

    Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL. SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell. 1998;95:779-791.

    Not in our library10.1016/s0092-8674(00)81701-8

  31. 31.

    Feng XH, Zhang Y, Wu RY, Derynck R. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation. Genes Dev. 1998;12:2153-2163.

    Not in our library10.1101/gad.12.14.2153

  32. 32.

    Janknecht R, Wells NJ, Hunter T. TGF-beta-stimulated cooperation of smad proteins with the coactivators CBP/p300. Genes Dev. 1998;12:2114-2119.

    Not in our library10.1101/gad.12.14.2114

  33. 33.

    Itoh S, Ericsson J, Nishikawa J, Heldin CH, ten Dijke P. The transcriptional co-activator P/CAF potentiates TGF-beta/Smad signaling. Nucleic Acids Res. 2000;28:4291-4298.

    Not in our library10.1093/nar/28.21.4291

  34. 34.

    Bai RY, Koester C, Ouyang T, et al. SMIF, a Smad4-interacting protein that functions as a co-activator in TGFbeta signalling. Nat Cell Biol. 2002;4:181-190.

    Not in our library10.1038/ncb753

  35. 35.

    Chen CR, Kang Y, Siegel PM, Massagué J. E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell. 2002;110:19-32.

    Not in our library10.1016/s0092-8674(02)00801-2

  36. 36.

    Kang Y, Chen CR, Massagué J. A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol Cell. 2003;11:915-926.

    Not in our library10.1016/s1097-2765(03)00109-6

  37. 37.

    Wotton D, Knoepfler PS, Laherty CD, Eisenman RN, Massagué J. The Smad transcriptional corepressor TGIF recruits mSin3. Cell Growth Differ. 2001;12:457-463.

    Not in our library

  38. 38.

    Akiyoshi S, Inoue H, Hanai J, et al. c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads. J Biol Chem. 1999;274:35269-35277.

    Not in our library10.1074/jbc.274.49.35269

  39. 39.

    Luo K, Stroschein SL, Wang W, et al. The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling. Genes Dev. 1999;13:2196-2206.

    Not in our library10.1101/gad.13.17.2196

  40. 40.

    Stroschein SL, Wang W, Zhou S, Zhou Q, Luo K. Negative feedback regulation of TGF-beta signaling by the SnoN onco-protein. Science. 1999;286:771-774.

    Not in our library10.1126/science.286.5440.771

  41. 41.

    Sun Y, Liu X, Eaton EN, Lane WS, Lodish HF, Weinberg RA. Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signaling. Mol Cell. 1999;4:499-509.

    Not in our library10.1016/s1097-2765(00)80201-4

  42. 42.

    Seoane J, Le HV, Shen L, Anderson SA, Massagué J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell. 2004;117:211-223.

    Not in our library10.1016/s0092-8674(04)00298-3

  43. 43.

    Pardali K, Kurisaki A, Morén A, ten Dijke P, Kardassis D, Moustakas A. Role of Smad proteins and transcription factor Sp1 in p21(Waf1/Cip1) regulation by transforming growth factor-beta. J Biol Chem. 2000;275:29244-29256.

    Not in our library10.1074/jbc.m909467199

  44. 44.

    Zhang Y, Feng XH, Derynck R. Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription. Nature. 1998;394:909-913.

    Not in our library10.1038/29814

  45. 45.

    Lin X, Liang YY, Sun B, et al. Smad6 recruits transcription corepressor CtBP to repress bone morphogenetic protein-induced transcription. Mol Cell Biol. 2003;23:9081-9093.

    Not in our library10.1128/mcb.23.24.9081-9093.2003

  46. 46.

    Peng Y, Zhao S, Song L, Wang M, Jiao K. Sertad1 encodes a novel transcriptional co-activator of SMAD1 in mouse embryonic hearts. Biochem Biophys Res Commun. 2013;441:751-756.

    Not in our library10.1016/j.bbrc.2013.10.127

  47. 47.

    Izutsu K, Kurokawa M, Imai Y, Maki K, Mitani K, Hirai H. The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling. Blood. 2001;97:2815-2822.

    Not in our library10.1182/blood.v97.9.2815

  48. 48.

    Xi Q, Wang Z, Zaromytidou AI, et al. A poised chromatin platform for TGF-β access to master regulators. Cell. 2011;147:1511-1524.

    Not in our library10.1016/j.cell.2011.11.032

  49. 49.

    Ross S, Cheung E, Petrakis TG, Howell M, Kraus WL, Hill CS. Smads orchestrate specific histone modifications and chromatin remodeling to activate transcription. EMBO J. 2006;25:4490-4502.

    Not in our library10.1038/sj.emboj.7601332

  50. 50.

    Papageorgis P, Lambert AW, Ozturk S, et al. Smad signaling is required to maintain epigenetic silencing during breast cancer progression. Cancer Res. 2010;70:968-978.

    Not in our library10.1158/0008-5472.can-09-1872

  51. 51.

    Nakao A, Afrakhte M, Morén A, et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature. 1997;389:631-635.

    Not in our library10.1038/39369

  52. 52.

    Itóh S, Landström M, Hermansson A, et al. Transforming growth factor beta1 induces nuclear export of inhibitory Smad7. J Biol Chem. 1998;273:29195-29201.

    Not in our library10.1074/jbc.273.44.29195

  53. 53.

    Hayashi H, Abdollah S, Qiu Y, et al. The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell. 1997;89:1165-1173.

    Not in our library10.1016/s0092-8674(00)80303-7

  54. 54.

    Ebisawa T, Fukuchi M, Murakami G, et al. Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem. 2001;276:12477-12480.

    Not in our library10.1074/jbc.c100008200

  55. 55.

    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. 2000;6:1365-1375.

    Not in our library10.1016/s1097-2765(00)00134-9

  56. 56.

    Zhang S, Fei T, Zhang L, et al. Smad7 antagonizes transforming growth factor beta signaling in the nucleus by interfering with functional Smad-DNA complex formation. Mol Cell Biol. 2007;27:4488-4499.

    Not in our library10.1128/mcb.01636-06

  57. 57.

    Zhang YE. Non-Smad pathways in TGF-beta signaling. Cell Res. 2009;19:128-139.

    Not in our library10.1038/cr.2008.328

  58. 58.

    Hartsough MT, Mulder KM. Transforming growth factor beta activation of p44mapk in proliferating cultures of epithelial cells. J Biol Chem. 1995;270:7117-7124.

    Not in our library10.1074/jbc.270.13.7117

  59. 59.

    Frey RS, Mulder KM. TGFbeta regulation of mitogen-activated protein kinases in human breast cancer cells. Cancer Lett. 1997;117:41-50.

    Not in our library10.1016/s0304-3835(97)00211-5

  60. 60.

    Papageorgis P, Cheng K, Ozturk S, et al. Smad4 inactivation promotes malignancy and drug resistance of colon cancer. Cancer Res. 2011;71:998-1008.

    Not in our library10.1158/0008-5472.can-09-3269

  61. 61.

    Finlay GA, Thannickal VJ, Fanburg BL, Paulson KE. Transforming growth factor-beta 1-induced activation of the ERK pathway/activator protein-1 in human lung fibroblasts requires the autocrine induction of basic fibroblast growth factor. J Biol Chem. 2000;275:27650-27656.

    Not in our library10.1074/jbc.m000893200

  62. 62.

    Vinals F, Pouysségur J. Transforming growth factor beta1 (TGF-beta1) promotes endothelial cell survival during in vitro angiogenesis via an autocrine mechanism implicating TGF-alpha signaling. Mol Cell Biol. 2001;21:7218-7230.

    Not in our library10.1128/mcb.21.21.7218-7230.2001

  63. 63.

    Ellenrieder V, Hendler SF, Boeck W, et al. Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extra-cellular signal-regulated kinase 2 activation. Cancer Res. 2001;61:4222-4228.

    Not in our library

  64. 64.
    Activation of the Erk Pathway Is Required for TGF-β1-Induced EMT In Vitro · 2004
    Not checked
  65. 65.

    Lee MK, Pardoux C, Hall MC, et al. TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J. 2007;26:3957-3967.

    Not in our library10.1038/sj.emboj.7601818

  66. 66.

    Liao JH, Chen JS, Chai MQ, Zhao S, Song JG. The involvement of p38 MAPK in transforming growth factor beta1-induced apoptosis in murine hepatocytes. Cell Res. 2001;11:89-94.

    Not in our library10.1038/sj.cr.7290072

  67. 67.

    Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T. BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. J Biol Chem. 2000;275:17647-17652.

    Not in our library10.1074/jbc.m908622199

  68. 68.

    Bakin AV, Rinehart C, Tomlinson AK, Arteaga CL. p38 mitogen-activated protein kinase is required for TGFbeta-mediated fibroblastic transdifferentiation and cell migration. J Cell Sci. 2002;115:3193-3206.

    Not in our library10.1242/jcs.115.15.3193

  69. 69.

    Hocevar BA, Brown TL, Howe PH. TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. EMBO J. 1999;18:1345-1356.

    Not in our library10.1093/emboj/18.5.1345

  70. 70.

    Yu L, Hébert MC, Zhang YE. TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. EMBO J. 2002;21:3749-3759.

    Not in our library10.1093/emboj/cdf366

  71. 71.

    Yamaguchi K, Shirakabe K, Shibuya H, et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science. 1995;270:2008-2011.

    Not in our library10.1126/science.270.5244.2008

  72. 72.

    Shim JH, Xiao C, Paschal AE, et al. TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev. 2005;19:2668-2681.

    Not in our library10.1101/gad.1360605

  73. 73.

    Sorrentino A, Thakur N, Grimsby S, et al. The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat Cell Biol. 2008;10:1199-1207.

    Not in our library10.1038/ncb1780

  74. 74.

    Yamashita M, Fatyol K, Jin C, Wang X, Liu Z, Zhang YE. TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. Mol Cell. 2008;31:918-924.

    Not in our library10.1016/j.molcel.2008.09.002

  75. 75.

    Zhang L, Wang W, Hayashi Y, et al. A role for MEK kinase 1 in TGF-beta/activin-induced epithelium movement and embryonic eyelid closure. EMBO J. 2003;22:4443-4454.

    Not in our library10.1093/emboj/cdg440

  76. 76.

    Kim KY, Kim BC, Xu Z, Kim SJ. Mixed lineage kinase 3 (MLK3)-activated p38 MAP kinase mediates transforming growth factor-beta-induced apoptosis in hepatoma cells. J Biol Chem. 2004;279:29478-29484.

    Not in our library10.1074/jbc.m313947200

  77. 77.

    Jaffe AB, Hall A. Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol. 2005;21:247-269.

    Not in our library10.1146/annurev.cellbio.21.020604.150721

  78. 78.

    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. 2001;12:27-36.

    Not in our library10.1091/mbc.12.1.27

  79. 79.

    Edlund S, Landström M, Heldin CH, Aspenström P. Transforming growth factor-beta-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA. Mol Biol Cell. 2002;13:902-914.

    Not in our library10.1091/mbc.01-08-0398

  80. 80.

    Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science. 2005;307:1603-1609.

    Not in our library10.1126/science.1105718

  81. 81.

    Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem. 2000;275:36803-36810.

    Not in our library10.1074/jbc.m005912200

  82. 82.

    Shin I, Bakin AV, Rodeck U, Brunet A, Arteaga CL. Transforming growth factor beta enhances epithelial cell survival via Akt-dependent regulation of FKHRL1. Mol Biol Cell. 2001;12:3328-3339.

    Not in our library10.1091/mbc.12.11.3328

  83. 83.

    Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene. 2000;19:6680-6686.

    Not in our library10.1038/sj.onc.1204091

  84. 84.

    Lamouille S, Derynck R. Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J Cell Biol. 2007;178:437-451.

    Not in our library10.1083/jcb.200611146

  85. 85.

    Roberts AB, Wakefield LM. The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci USA. 2003;100:8621-8623.

    Not in our library10.1073/pnas.1633291100

  86. 86.

    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. 2003;112:1116-1124.

    Not in our library10.1172/jci200318899

  87. 87.

    Wakefield LM, Roberts AB. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev. 2002;12:22-29.

    Not in our library10.1016/s0959-437x(01)00259-3

  88. 88.

    Siegel PM, Shu W, Cardiff RD, Muller WJ, Massagué J. Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci USA. 2003;100:8430-8435.

    Not in our library10.1073/pnas.0932636100

  89. 89.

    Siegel PM, Massagué J. Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer. 2003;3:807-821.

    Not in our library10.1038/nrc1208

  90. 90.

    Choi ME, Ballermann BJ. Inhibition of capillary morphogenesis and associated apoptosis by dominant negative mutant transforming growth factor-beta receptors. J Biol Chem. 1995;270:21144-21150.

    Not in our library10.1074/jbc.270.36.21144

  91. 91.

    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. 2002;132:173-179.

    Not in our library10.1067/msy.2002.125304

  92. 92.

    Rich JN, Zhang M, Datto MB, Bigner DD, Wang XF. Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. J Biol Chem. 1999;274:35053-35058.

    Not in our library10.1074/jbc.274.49.35053

  93. 93.

    Yang X, Letterio JJ, Lechleider RJ, et al. Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO J. 1999;18:1280-1291.

    Not in our library10.1093/emboj/18.5.1280

  94. 94.

    Laiho M, DeCaprio JA, Ludlow JW, Livingston DM, Massagué J. Growth inhibition by TGF-beta linked to suppression of retinoblastoma protein phosphorylation. Cell. 1990;62:175-185.

    Not in our library10.1016/0092-8674(90)90251-9

  95. 95.

    Hannon GJ, Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 1994;371:257-261.

    Not in our library10.1038/371257a0

  96. 96.

    Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y, Wang XF. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci USA. 1995;92:5545-5549.

    Not in our library10.1073/pnas.92.12.5545

  97. 97.

    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. 1994;8:9-22.

    Not in our library10.1101/gad.8.1.9

  98. 98.

    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. 1990;61:777-785.

    Not in our library10.1016/0092-8674(90)90188-k

  99. 99.

    Norton JD. ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis. J Cell Sci. 2000;113:3897-3905.

    Not in our library10.1242/jcs.113.22.3897

  100. 100.

    Grotendorst GR. Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev. 1997;8:171-179.

    Not in our library10.1016/s1359-6101(97)00010-5

  101. 101.

    Park K, Kim SJ, Bang YJ, et al. Genetic changes in the transforming growth factor beta (TGF-beta) type II receptor gene in human gastric cancer cells: correlation with sensitivity to growth inhibition by TGF-beta. Proc Natl Acad Sci USA. 1994;91:8772-8776.

    Not in our library10.1073/pnas.91.19.8772

  102. 102.

    Kim IY, Ahn HJ, Zelner DJ, et al. Genetic change in transforming growth factor beta (TGF-beta) receptor type I gene correlates with insensitivity to TGF-beta 1 in human prostate cancer cells. Cancer Res. 1996;56:44-48.

    Not in our library

  103. 103.

    Markowitz S, Wang J, Myeroff L, et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995;268:1336-1338.

    Not in our library10.1126/science.7761852

  104. 104.

    Riggins GJ, Kinzler KW, Vogelstein B, Thiagalingam S. Frequency of Smad gene mutations in human cancers. Cancer Res. 1997;57:2578-2580.

    Not in our library

  105. 105.

    Schutte M, Hruban RH, Hedrick L, et al. DPC4 gene in various tumor types. Cancer Res. 1996;56:2527-2530.

    Not in our library

  106. 106.

    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. 1996;86:543-552.

    Not in our library10.1016/s0092-8674(00)80128-2

  107. 107.

    Hahn SA, Hoque AT, Moskaluk CA, et al. Homozygous deletion map at 18q21.1 in pancreatic cancer. Cancer Res. 1996;56:490-494.

    Not in our library

  108. 108.

    Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996;271:350-353.

    Not in our library10.1126/science.271.5247.350

  109. 109.

    Thiagalingam S, Lengauer C, Leach FS, et al. Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nat Genet. 1996;13:343-346.

    Not in our library10.1038/ng0796-343

  110. 110.
    Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis · 2000
    Not checked
  111. 111.

    Kretzschmar M, Doody J, Timokhina I, Massagué J. A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev. 1999;13:804-816.

    Not in our library10.1101/gad.13.7.804

  112. 112.

    Kretzschmar M, Doody J, Massagué J. Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1. Nature. 1997;389:618-622.

    Not in our library10.1038/39348

  113. 113.

    Massagué J. Integration of Smad and MAPK pathways: a link and a linker revisited. Genes Dev. 2003;17:2993-2997.

    Not in our library10.1101/gad.1167003

  114. 114.

    Gomis RR, Alarcón C, Nadal C, Van Poznak C, Massagué J. C/EBPbeta at the core of the TGFbeta cytostatic response and its evasion in metastatic breast cancer cells. Cancer Cell. 2006;10:203-214.

    Not in our library10.1016/j.ccr.2006.07.019

  115. 115.

    Padua D, Zhang XH, Wang Q, et al. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell. 2008;133:66-77.

    Not in our library10.1016/j.cell.2008.01.046

  116. 116.

    Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442-454.

    Not in our library10.1038/nrc822

  117. 117.

    Yang J, Mani SA, Donaher JL, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117:927-939.

    Not in our library10.1016/j.cell.2004.06.006

  118. 118.

    Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 2009;19:156-172.

    Not in our library10.1038/cr.2009.5

  119. 119.

    Cano A, Pérez-Moreno MA, Rodrigo I, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2:76-83.

    Not in our library10.1038/35000025

  120. 120.

    Savagner P, Yamada KM, Thiery JP. The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition. J Cell Biol. 1997;137:1403-1419.

    Not in our library10.1083/jcb.137.6.1403

  121. 121.

    Eger A, Aigner K, Sonderegger S, et al. DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene. 2005;24:2375-2385.

    Not in our library10.1038/sj.onc.1208429

  122. 122.

    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. 2001;7:1267-1278.

    Not in our library10.1016/s1097-2765(01)00260-x

  123. 123.

    Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin CH, Moustakas A. Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition. J Cell Biol. 2006;174:175-183.

    Not in our library10.1083/jcb.200512110

  124. 124.

    Mani SA, Yang J, Brooks M, et al. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci USA. 2007;104:10069-10074.

    Not in our library10.1073/pnas.0703900104

  125. 125.

    Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 2001;29:117-129.

    Not in our library10.1038/ng1001-117

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    Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14:818-829.

    Not in our library10.1016/j.devcel.2008.05.009

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    Zhu B, Fukada K, Zhu H, Kyprianou N. Prohibitin and cofilin are intracellular effectors of transforming growth factor beta signaling in human prostate cancer cells. Cancer Res. 2006;66:8640-8647.

    Not in our library10.1158/0008-5472.can-06-1443

  128. 128.

    Deckers M, van Dinther M, Buijs J, et al. The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res. 2006;66:2202-2209.

    Not in our library10.1158/0008-5472.can-05-3560

  129. 129.

    Kang Y, Massagué J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 2004;118:277-279.

    Not in our library10.1016/j.cell.2004.07.011

  130. 130.

    Grande JP. Role of transforming growth factor-beta in tissue injury and repair. Proc Soc Exp Biol Med. 1997;214:27-40.

    Not in our library10.3181/00379727-214-44066

  131. 131.

    Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341:738-746.

    Not in our library10.1056/nejm199909023411006

  132. 132.

    Pickup M, Novitskiy S, Moses HL. The roles of TGFβ in the tumour microenvironment. Nat Rev Cancer. 2013;13:788-799.

    Not in our library10.1038/nrc3603

  133. 133.

    Dalal BI, Keown PA, Greenberg AH. Immunocytochemical localization of secreted transforming growth factor-beta 1 to the advancing edges of primary tumors and to lymph node metastases of human mammary carcinoma. Am J Pathol. 1993;143:381-389.

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  134. 134.

    Kingsley LA, Fournier PG, Chirgwin JM, Guise TA. Molecular biology of bone metastasis. Mol Cancer Ther. 2007;6:2609-2617.

    Not in our library10.1158/1535-7163.mct-07-0234

  135. 135.

    Prud’homme GJ. Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations. Lab Invest. 2007;87:1077-1091.

    Not in our library10.1038/labinvest.3700669

  136. 136.

    Wrzesinski SH, Wan YY, Flavell RA. Transforming growth factor-beta and the immune response: implications for anti-cancer therapy. Clin Cancer Res. 2007;13:5262-5270.

    Not in our library10.1158/1078-0432.ccr-07-1157

  137. 137.

    Akhurst RJ, Hata A. Targeting the TGFβ signalling pathway in disease. Nat Rev Drug Discov. 2012;11:790-811.

    Not in our library10.1038/nrd3810

  138. 138.

    Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limón P. The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol. 2010;10:554-567.

    Not in our library10.1038/nri2808

  139. 139.

    Laouar Y, Sutterwala FS, Gorelik L, Flavell RA. Transforming growth factor-beta controls T helper type 1 cell development through regulation of natural killer cell interferon-gamma. Nat Immunol. 2005;6:600-607.

    Not in our library10.1038/ni1197

  140. 140.

    Rubtsov YP, Rudensky AY. TGFbeta signalling in control of T-cell-mediated self-reactivity. Nat Rev Immunol. 2007;7:443-453.

    Not in our library10.1038/nri2095

  141. 141.

    Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549-555.

    Not in our library10.1016/s1471-4906(02)02302-5

  142. 142.
    TGFβ signaling plays a critical role in promoting alternative macrophage activation · 2012
    No notice
  143. 143.

    Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell. 2009;16:183-194.

    Not in our library10.1016/j.ccr.2009.06.017

  144. 144.

    Yamaguchi Y, Tsumura H, Miwa M, Inaba K. Contrasting effects of TGF-beta 1 and TNF-alpha on the development of dendritic cells from progenitors in mouse bone marrow. Stem Cells. 1997;15:144-153.

    Not in our library10.1002/stem.150144

  145. 145.

    Ramesh S, Wildey GM, Howe PH. Transforming growth factor beta (TGFbeta)-induced apoptosis: the rise & fall of Bim. Cell Cycle. 2009;8:11-17.

    Not in our library10.4161/cc.8.1.7291

  146. 146.

    Marcoe JP, Lim JR, Schaubert KL, et al. TGF-β is responsible for NK cell immaturity during ontogeny and increased susceptibility to infection during mouse infancy. Nat Immunol. 2012;13:843-850.

    Not in our library10.1038/ni.2388

  147. 147.

    Wipff PJ, Rifkin DB, Meister JJ, Hinz B. Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol. 2007;179:1311-1323.

    Not in our library10.1083/jcb.200704042

  148. 148.

    Wipff PJ, Hinz B. Myofibroblasts work best under stress. J Bodyw Mov Ther. 2009;13:121-127.

    Not in our library10.1016/j.jbmt.2008.04.031

  149. 149.

    Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3:349-363.

    Not in our library10.1038/nrm809

  150. 150.

    Karagiannis GS, Poutahidis T, Erdman SE, Kirsch R, Riddell RH, Diamandis EP. Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Mol Cancer Res. 2012;10:1403-1418.

    Not in our library10.1158/1541-7786.mcr-12-0307

  151. 151.

    Paszek MJ, Zahir N, Johnson KR, et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005;8:241-254.

    Not in our library10.1016/j.ccr.2005.08.010

  152. 152.

    Samuel MS, Lopez JI, McGhee EJ, et al. Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth. Cancer Cell. 2011;19:776-791.

    Not in our library10.1016/j.ccr.2011.05.008

  153. 153.

    Branton MH, Kopp JB. TGF-beta and fibrosis. Microbes Infect. 1999;1:1349-1365.

    Not in our library10.1016/s1286-4579(99)00250-6

  154. 154.

    Egeblad M, Rasch MG, Weaver VM. Dynamic interplay between the collagen scaffold and tumor evolution. Curr Opin Cell Biol. 2010;22:697-706.

    Not in our library10.1016/j.ceb.2010.08.015

  155. 155.

    Smith NR, Baker D, Farren M, et al. Tumor stromal architecture can define the intrinsic tumor response to VEGF-targeted therapy. Clin Cancer Res. 2013;19:6943-6956.

    Not in our library10.1158/1078-0432.ccr-13-1637

  156. 156.

    Stylianopoulos T, Jain RK. Combining two strategies to improve perfusion and drug delivery in solid tumors. Proc Natl Acad Sci USA. 2013;110:18632-18637.

    Not in our library10.1073/pnas.1318415110

  157. 157.

    Stylianopoulos T, Martin JD, Chauhan VP, et al. Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors. Proc Natl Acad Sci USA. 2012;109:15101-15108.

    Not in our library10.1073/pnas.1213353109

  158. 158.

    Demou ZN. Gene expression profiles in 3D tumor analogs indicate compressive strain differentially enhances metastatic potential. Ann Biomed Eng. 2010;38:3509-3520.

    Not in our library10.1007/s10439-010-0097-0

  159. 159.

    Tse JM, Cheng G, Tyrrell JA, et al. Mechanical compression drives cancer cells toward invasive phenotype. Proc Natl Acad Sci USA. 2012;109:911-916.

    Not in our library10.1073/pnas.1118910109

  160. 160.

    Chauhan VP, Martin JD, Liu H, et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumor blood vessels. Nat Commun. 2013;4:2516.

    Not in our library10.1038/ncomms3516

  161. 161.

    Facciabene A, Peng X, Hagemann IS, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature. 2011;475:226-230.

    Not in our library10.1038/nature10169

  162. 162.

    Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11:393-410.

    Not in our library10.1038/nrc3064

  163. 163.

    Jain RK, Martin JD, Stylianopoulos T. The role of mechanical forces in tumor growth and therapy. Annu Rev Biomed Eng. 2014;16:321-346.

    Not in our library10.1146/annurev-bioeng-071813-105259

  164. 164.

    Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol. 2010;7:653-664.

    Not in our library10.1038/nrclinonc.2010.139

  165. 165.

    Chauhan VP, Jain RK. Strategies for advancing cancer nanomedicine. Nat Mater. 2013;12:958-962.

    Not in our library10.1038/nmat3792

  166. 166.

    Popovi Z, Liu W, Chauhan VP, et al. A nanoparticle size series for in vivo fluorescence imaging. Angew Chem Int Ed Engl. 2010;49:8649-8652.

    Not in our library10.1002/anie.201003142

  167. 167.

    Stylianopoulos T, Poh MZ, Insin N, et al. Diffusion of particles in the extracellular matrix: the effect of repulsive electrostatic interactions. Biophys J. 2010;99:1342-1349.

    Not in our library10.1016/j.bpj.2010.06.016

  168. 168.

    Zhong Z, Carroll KD, Policarpio D, et al. Anti-transforming growth factor beta receptor II antibody has therapeutic efficacy against primary tumor growth and metastasis through multi-effects on cancer, stroma, and immune cells. Clin Cancer Res. 2010;16:1191-1205.

    Not in our library10.1158/1078-0432.ccr-09-1634

  169. 169.

    Uhl M, Aulwurm S, Wischhusen J, et al. SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res. 2004;64:7954-7961.

    Not in our library10.1158/0008-5472.can-04-1013

  170. 170.

    Kim S, Buchlis G, Fridlender ZG, et al. Systemic blockade of transforming growth factor-beta signaling augments the efficacy of immunogene therapy. Cancer Res. 2008;68:10247-10256.

    Not in our library10.1158/0008-5472.can-08-1494

  171. 171.

    Chakrabarti R, Subramaniam V, Abdalla S, Jothy S, Prud’homme GJ. Tranilast inhibits the growth and metastasis of mammary carcinoma. Anticancer Drugs. 2009;20:334-345.

    Not in our library10.1097/cad.0b013e328327994e

  172. 172.
    Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-β signaling. · 2013
    Not checked
  173. 173.

    Bragado P, Estrada Y, Parikh F, et al. TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling. Nat Cell Biol. 2013;15:1351-1361.

    Not in our library10.1038/ncb2861

  174. 174.

    Biswas T, Gu X, Yang J, Ellies LG, Sun LZ. Attenuation of TGF-β signaling supports tumor progression of a mesenchymal-like mammary tumor cell line in a syngeneic murine model. Cancer Lett. 2014;346:129-138.

    Not in our library10.1016/j.canlet.2013.12.018

  175. 175.

    Stockmann C, Doedens A, Weidemann A, et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature. 2008;456:814-818.

    Not in our library10.1038/nature07445

  176. 176.

    Rhim AD, Mirek ET, Aiello NM, et al. EMT and dissemination precede pancreatic tumor formation. Cell. 2012;148:349-361.

    Not in our library10.1016/j.cell.2011.11.025

  177. 177.

    Diop-Frimpong B, Chauhan VP, Krane S, Boucher Y, Jain RK. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci USA. 2011;108:2909-2914.

    Not in our library10.1073/pnas.1018892108

  178. 178.

    Wilop S, von Hobe S, Crysandt M, Esser A, Osieka R, Jost E. Impact of angiotensin I converting enzyme inhibitors and angiotensin II type 1 receptor blockers on survival in patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy. J Cancer Res Clin Oncol. 2009;135:1429-1435.

    Not in our library10.1007/s00432-009-0587-3

  179. 179.

    Keizman D, Huang P, Eisenberger MA, et al. Angiotensin system inhibitors and outcome of sunitinib treatment in patients with metastatic renal cell carcinoma: a retrospective examination. Eur J Cancer. 2011;47:1955-1961.

    Not in our library10.1016/j.ejca.2011.04.019

  180. 180.

    Nakai Y, Isayama H, Ijichi H, et al. Phase I trial of gemcitabine and candesartan combination therapy in normotensive patients with advanced pancreatic cancer: GECA1. Cancer Sci. 2012;103:1489-1492.

    Not in our library10.1111/j.1349-7006.2012.02311.x

  181. 181.

    Liu J, Liao S, Diop-Frimpong B, et al. TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proc Natl Acad Sci USA. 2012;109:16618-16623.

    Not in our library10.1073/pnas.1117610109

  182. 182.

    Kozono S, Ohuchida K, Eguchi D, et al. Pirfenidone inhibits pancreatic cancer desmoplasia by regulating stellate cells. Cancer Res. 2013;73:2345-2356.

    Not in our library10.1158/0008-5472.can-12-3180

  183. 183.

    Bouquet F, Pal A, Pilones KA, et al. TGFβ1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo. Clin Cancer Res. 2011;17:6754-6765.

    Not in our library10.1158/1078-0432.ccr-11-0544

  184. 184.

    Zhang M, Kleber S, Röhrich M, et al. Blockade of TGF-β signaling by the TGFβR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Res. 2011;71:7155-7167.

    Not in our library10.1158/0008-5472.can-11-1212

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