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STAT1 and STAT3 in Tumorigenesis: Two Sides of the Same Coin?

, , , , and *.

* Corresponding Author: Valeria Poli—Molecular Biotechnology Center, Via Nizza 52, 10126 Turin, Italy. Email:ti.otinu@ilop.airelav

© 2009 Landes Bioscience
Read this chapter in the Madame Curie Bioscience Database here.

The transcription factors STAT1 and STAT3 appear to play opposite roles in tumorigenesis. While STAT3 promotes cell survival/proliferation, motility and immune tolerance and is considered as an oncogene, STAT1 enhances inflammation and innate and adaptive immunity, triggering in most instances anti-proliferative and pro-apoptotic responses in tumor cells. Despite being activated downstream of common cytokine and growth factor receptors, their activation is reciprocally regulated and perturbation in their balanced expression or phosphorylation levels may redirect cytokine/growth factor signals from proliferative to apoptotic, or from inflammatory to anti-inflammatory. Here we review the functional canonical and non canonical effects of STAT1 and STAT3 activation in tumorigenesis and their potential cross-regulation mechanisms and discuss the hypothesis that perturbation of their expression and/or activation levels may provide novel cancer therapeutic strategies.

Differential STAT1 and STAT3 Activation by Cytokines and Growth Factor Receptors

Activation of Signal transducer and activator of transcription (STAT ) transcriptional regulators by cytokine and growth factor receptors is typically fast but transient, due to specific negative feedback mechanisms. Abnormal activation, due for example to unbalanced signaling or to altered levels of either specific STATs or their negative regulators, often lead to pathological conditions such as chronic inflammation, defective immune responses or cancer. There is an intriguing convergence of distinct cytokine and growth factor receptors signaling on overlapping sets of STAT factors, particularly on STAT1 and STAT3. Indeed, both of these factors are targets for activation by distinct signals, particularly Interferons (IFNs) and cytokines belonging to the gp130 family such as interleukin (IL)-6, leukemia inhibitory factor (LIF) and Oncostatin M (OSM). Despite their activation of common STATs , these soluble mediators exert distinct and often opposing effects on target cells, correlating with specific patterns and duration of STATs activation. In addition, the final outcome of cytokines/growth factors stimulation is distinct in different contexts, partly reflecting how specific cell types can integrate and interpret the complex and often contrasting signals they receive.1 - 4

STAT1 is a central mediator of both Type I (alpha and beta) and type II (gamma) IFNs, a family of multifunctional secreted proteins involved in cell growth regulation and antiviral and immune defense. Type I and II IFN receptor chains (IFNR) can recruit different Janus kinase (JAK) members to activate common and distinct STAT factors and induce a set of interferon-inducible genes through specific type I or II IFN promoter responsive elements.5 IFN-gamma (IFNγ), through JAK1 and JAK2, mainly triggers prolonged STAT1 activation that induces gene expression by binding to gamma-activated sequences (GAS). In contrast, type I IFNs recruit JAK1 and TYK2 and activate both STAT1 and STAT2 triggering the formation of ISGF3, a distinct transcriptional complex that also includes p48/IRF-9. Both IFN types can in addition activate STAT3, albeit to a lesser extent/more transiently.6 , 7

The IL-6 family of cytokines acts instead through homo-or hetero-dimerization of a common signal transduction subunit, gp130, with other specific receptors such as the LIFR. gp130-mediated signaling can trigger activation of JAK1, JAK2 or TYK2, depending on the cell system, leading in most cases to prolonged phosphorylation of STAT3 and transient phosphorylation of STAT1 (reviewed in 8). STAT1 and STAT3 can heterodimerize and bind to similar cognate sites, at least in vitro. However, in vivo functional selectivity is much more stringent and the repertoire of genes regulated by these two factors is mostly distinct.9 Importantly, also growth factor receptors with intrinsic tyrosine kinase activity such as platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR) can activate both STAT3 and STAT1, at least partly through activation of nonreceptor tyrosine kinases belonging to the Src family.10 In addition, STAT3 can be activated by a number of oncogenes such as, for example, v-Src, v-Fps, v-Sis, Met and polyoma middle T antigen.11

Reciprocal Roles of STAT1 and STAT3 in Tumorigenesis

STAT1 and STAT3 are thought to play opposite roles in tumorigenesis. STAT1 exerts a complex array of functions on both tumor cells and the immune system and is usually considered as a tumor suppressor.12 In contrast, STAT3 is considered as an oncogene and its constitutive activation is reported in nearly 70% of solid and hematological tumors.11 , 13 - 19 Moreover, the over-expression of its constitutively active form, STAT3C, is sufficient to transform fibroblasts and other nonmalignant cell types such as breast and prostate epithelial cells.20 - 22 Both STAT1 and STAT3 can exert their opposite effects on tumorigenesis either directly, through transcriptional regulation of target genes in the neoplastic cell, or indirectly, by modulating tumor angiogenesis or the anti-tumor immune response. Here, we separately review what is known about the actions of these two factors in oncogenesis and finally discuss the existence of reciprocal cross-regulation mechanisms that can exert an influence on both physiological and pathological responses

STAT1 in Tumorigenesis

STAT1 plays a critical role in tumorigenesis by controlling a complex array of activities and functions. In many types of tumors STAT1 induces anti-proliferative and pro-apoptotic genes that directly hamper tumor growth. Other STAT1-dependent antitumor effects are due to the induction of genes that block cell cycle progression or inhibit angiogenesis. In addition, STAT1 activation is pivotal for tumor immunosurveillance as it drives induction of MHC Class I molecules, required for efficient display of antigens to effector T-lymphocytes and thus to elicit anti-tumor immune responses. Despite all this, under specific conditions STAT1 can instead favour carcinogenesis and tumor survival, confirming the complexity of this biological system. This section will briefly survey what is known of STAT1 activities related to tumorigenesis, as summarized in Table 1.

Table 1. Effects of STAT1 on tumorigenesis.

Table 1

Effects of STAT1 on tumorigenesis.

Direct Effects of STAT1 Activity on Tumor Growth Inhibition

STAT1 plays a pivotal role in controlling the expansion of different neoplastic cell types as its activation induces many pro-apoptotic and anti-proliferative genes. Interferon regulatory factor-1 (IRF-1), a member of the IRF family of transcription factors that plays critical roles in interferon signaling in a wide range of malignancies, is typically induced following STAT1 activation and mediates many of its downstream effects.23 IRF-1 is involved in IFNγ/STAT1 dependent apoptosis of hematopoietic malignancies,7 , 24 cervical carcinoma25 and Ewing tumor26 cells. In Ewing tumor, neuroblastoma or medulloblastoma the activation of IFNγ/STAT1/IRF-1 pathway induces caspase-8, thus reinstating their susceptibility to apoptosis induced by TRAIL, APO1, TNFα or cytotoxic drugs.27 STAT1 can however also act independently of IRF-1, inducing for example the Interferon consensus for example Interferon consensus sequence-binding protein (ICSBP)/IRF-8, another member of the IRF transcription factors that together with IRF-1 causes regression of epithelial cell carcinoma.28 Interferon-induced transmembrane protein 1 (IFITM1) also plays a key role in mediating the anti-proliferative action of IFNγ its knock down by RNA interference confers tumorigenicity to non tumor hepatic cells in SCID mice.29

In addition, activated STAT1 specifically recognizes the conserved GAS elements in the cyclin-dependent kinase (CDK) inhibitor p21 WAF1/CIP1 promoter, thus regulating p21 mRNA induction.30 Indeed, STAT1 negatively regulates the cell cycle by inducing p21 WAF1/CIP1 in ovarian cancer.31 In myeloid cells, the treatment with all-trans retinoic acid (ATRA) induces STAT1 phosphorylation, which in turn up-regulates the expression of the CDK inhibitor p27Kip1 and ultimately triggers G0/G1 arrest.32 Conversely, ATRA-dependent STAT1 activation inhibits the expression of c-Myc and of cyclin A, B, D2, D3 and E,32 in keeping with data suggesting the existence of an IFNγ/STAT1 dependent pathway of c-Myc negative regulation.33 In promyelocytic leukemia cells, both ATRA and IFNα induce a cytoplasmic protein, RIG-G, which is a direct target of STAT1 and triggers cell cycle arrest through down regulation of c-Myc.34 Finally, in some prostatic cancers the suppressive effect of IFNγ is due to STAT1-dependent down-regulation of the human epidermal growth factor receptor (HER)-2/neu oncogene.35

Besides cell cycle arrest, STAT1 promotes apoptosis in tumors by inducing the expression of surface cell death receptors and their ligands. IFNγ-dependent STAT1 activation induces the expression of Fas and Fas ligand (FasL) in hematopoietic and colon carcinoma cells24 , 36 , 37 and of TNF-Related Apoptosis Inducer Ligand (TRAIL) and its receptor KILLER/DR5 in myeloma and melanoma cells,38 , 39 while IFNβ-dependent STAT1 activation induces TRAIL expression in fibrosarcoma40 and colorectal cancer.41 Moreover, STAT1 promotes induction or activation of different caspase family members of executor of cell death. Both EGF and IFNγ induce caspase-1 in a STAT1-dependent manner in breast cancer, epithelial carcinoma, T-cell lymphoma and, together with caspase-3 and -7, in renal cell carcinoma.24 , 27 , 28 , 42 STAT1/IRF-1-dependent activation of caspase-7 and -8 is triggered by IFNβ in Ewing sarcoma26 and by IFNγ in Ewing sarcoma, neuroblastoma and medulloblastoma.27 The ability of IFNβ to induce STAT1 dependent apoptosis in many tumor cells is linked to the induction of novel tumor suppressor genes such as XIAP-associated factor 1 (XAF1).43 In addition, STAT1 is required for optimal DNA damage-induced apoptosis by negatively regulating the p53-inhibitor Mdm2 and acting as a p53 co-activator. It can also directly interact with p53 and this association is enhanced following DNA damage.44 , 46 STAT1-dependent apoptosis is also promoted in hepatoma cells by exposure to nitric oxide (NO),47 which favors IFNγ-dependent apoptosis of neoplastic T-cells48 and IFNγ/TNFα-dependent G1 arrest followed by apoptosis in pancreatic carcinoma cell lines.49 On the other hand, treatment with IFNγ induces NO production in a STAT1-dependent manner, correlating with Bcl-2 down-regulation and apoptotic cell death in melanoma cells.50 In turn, NO endorses the activation of caspases via Fas/FasL in different neoplastic lymphoid cell lines51 , 52 and induces nuclear accumulation of p53 and upregulation of p21 WAF1/CIP1 in different cancer cell lines.53

STAT1 Is an Inhibitor of Angiogenesis

STAT1 is known to play a key role in the inhibition of angiogenesis, acting on both endothelial and tumor cells. Activation of IFNγ/STAT1 signaling inhibits growth and tube formation in human umbilical vein endothelial cells (HUVECs)54 and suppresses the biological activity of vascular endothelial growth factor (VEGF) through inhibition of genes required for the VEGF response, including angiopoietin-2, urokinase plasminogen activator, tissue inhibitor of matrix metalloproteinase (MMP)-1, cyclooxygenase-2 and VEGF receptor 2.54 In addition, intratumoral delivery of the murine IL-12 gene ows its efficacy to the STAT1 dependent induction of the interferon-inducible protein IP10 (CXCL10), a known anti-angiogenic gene.55 STAT1 can also suppress tumor and metastasis formation by sarcoma cells in nude mice by inhibiting the expression of the pro-angiogenic molecules fibroblast growth factor (FGF)-β, MMP-2 and MMP-956 and decreasing microvessel density. Thus, STAT1 acts as a negative regulator of tumor angiogenesis and, hence, tumor growth and metastasis.

STAT1 Is an Important Player in Immunosurveillance

Tumors often undergo loss of sensitivity to the IFNγ/STAT1 pathway through mutations/silencing of genes coding different components of its signaling machinery (IFNGR1, IFNGR2, JAK1, JAK2, STAT1). This mechanism is thought to contribute to tumor escape from immunosurveillance as tumors became resistant to the direct anti-proliferative/pro-apoptotic effect of IFNγ released by T and Natural Killer (NK) cells and fail to up-regulate MHC class I expression in response to IFNγ, thus becoming unable to display tumor associated antigens to effector CD8+ T-cells.57 In renal cell carcinoma, the lack of MHC class I antigen presentation has been attributed to the down-regulation of genes normally induced by IFNγ and needed for antigen processing, such as the antigen processing-associated transporters TAP1 and TAP2 and the proteasomal components low molecular weight proteins LMP2 and LMP7.58 Indeed, transcription of both LMP and TAP genes requires the activity of STAT1/IRF-1 transcription factors.59 , 62 Finally, defective class I MHC inducibility was correlated to defective STAT1 phosphorylation in melanoma cells.63.

IFNγ also induces STAT1-dependent expression of the MHC class II transactivator CIITA, a transcriptional coactivator essential for MHC class II expression, in multiple myeloma64 and in melanoma.65 , 66 CIITA transcription is epigenetically silenced in uveal melanoma,67 and is reduced or absent in B-cell lymphoma68 and in neuroblastoma.69 Of interest, down-regulation of the interferon signaling pathway in T-lymphocytes from patients with metastatic melanoma has been reported,70 suggesting that tumors can adopt this strategy to escape immunosurveillance. Thus, defects in IFNγ/ STAT1 signaling represent novel, dominant mechanisms of immune dysfunction in cancer. These findings might be exploited to design therapies to improve cancer immunotherapy.

In Vivo Models to Study the Effects of STAT1 in the Promotion of Carcinogenesis

Although the most evident defect of STAT1 mutant mice is the high susceptibility to microbial infections,71 - 73 it was expected that loss of STAT1 would lead to increased incidence of tumors due to an impairment of the negative control pathways described above. Indeed, similar to IFNγR-/- mice, STAT1-/- mice display increased susceptibility to the development of methylcholanthrene (MCA)-induced tumors. Moreover, STAT1-/- × p53-/- double mutant mice earlier tumor onset. These data the existence of an IFNγ/STAT1-mediated tumor surveillance system that controls the development of both chemically induced and spontaneously arising tumors.57 Interestingly, RAG2-/- × STAT 1-/- mice show increased incidence of both MCA-induced sarcomas and spontaneous epithelial carcinomas, thus demonstrating that anti-tumor STAT1 activities are not limited to lymphocytes.74 In the absence of STAT1, mice failed to reject immunogenic tumors and did not support regression of poorly immunogenic tumors when treated with an IL-12-based vaccine. T-cells from immunized STAT1-/- mice display impaired IFNγ production and defective cytolitic activity, suggesting that IFNγ/STAT1 signaling in host cells is required for the development of antitumor lytic effector cells.75 Lack of STAT1 not only affects the adaptive but also the innate response to tumors but also the innate response, as shown by the observation that the NK-mediated anti-melanoma effect of IFNα is abrogated in STAT1-/- mice.76 All these data clearly support the idea that STAT1 acts as a tumor suppressor.

However, inappropriate activation of STAT1 has also been observed in a variety of malignant cells from breast cancer, head and neck squamous carcinoma, melanoma, lymphoma and leukemia, suggesting that STAT1 may under specific conditions contribute to rather than inhibit malignant transformation.77 Kovacic and collaborators demonstrated that STAT 1-/- mice are partially protected from v-abl-induced leukemia development78 and that v-Abl-transformed STAT1-/- cells induce leukemia with increased latency in both immunodeficient and immunocompetent mice. NK-mediated immunosurveillance is enhanced in STAT1-/- mice due to the low MHC class I expression levels. Interestingly, the transformed STAT1-/- cells that eventually give rise to tumors display an edited phenotype, i.e., acquire higher levels of MHC class I molecules. Additionally, ectopic expression of IFNγ and persistent activation of STAT1, mediating high expression of the Sonic HedgeHog gene, have been implicated in the development of cerebellar tumors.79 STAT1 activation can also enhance tumor formation by interfering with the anti-tumor immune responses at different levels. STAT1 activation in tumor associated macrophages (TAM) induces the expression of arginase and the production of NO, which in turn suppresses T-cell-mediated immune responses and induces T-cell apoptosis, respectively.80 Furthermore, STAT1 plays a key role in inducing the expression of the gene encoding IDO, an immuno-regulatory enzyme over-expressed in many cancers. IDO enhances tryptophan catabolism thus blocking T-cells activation.81 - 83 In vitro, constitutive over-expression of STAT1 renders squamous cell carcinoma cells resistant to the apoptosis induced by ionizing radiation84 and induces high expression of anti-apoptotic genes (IAP-1, IAP-2, Bcl-XL, Bfl1 and TRAF1) that protects Hodgkin Lymphoma cells from apoptosis.85 Finally, STAT1 activation suppresses anti-tumor CTL activity mediated by IL-12 administration.86.

In conclusion, despite the numerous indications that STAT1 plays a pivotal role in the suppression of tumor growth in many models, there are also several examples of STAT1 tumor-promoting activities, often restricted to particular tissues or resulting from the cooperation with other signaling pathways. As STAT1 plays a critical role in the control of T-cell homeostatis,87 it is conceivable that the suppressive/promoting role of STAT1 in tumorigenesis will be influenced by environmental signals that might favor STAT1 activation in tumor cells or in host immune cells, respectively, with opposite consequences on tumor development. Further studies devoted to gather information on the regulation of this equilibrium will help to clarify the paradoxical actions observed for STAT1 in the control of tumorigenesis.

STAT3 in Tumorigenesis

Among all STAT family members, STAT3 is most often correlated to tumorigenesis, and is considered as an oncogene. Indeed, this factor is the point of convergence of many signaling pathways triggered by cytokines, growth factors and oncogenes and is accordingly found to be constitutively active in a wide range of tumors and transformed cell lines. In particular, STAT3 constitutive activity has been reported in nearly 70% of solid and hematological tumors, including multiple myeloma, several lymphomas and leukemias, breast cancer, head and neck cancer, prostate cancer, ovarian carcinoma, melanoma, renal carcinoma, colorectal carcinoma and thymic epithelial tumors.19 Interfering with its activity in these tumor systems almost invariably affects tumor growth and survival, hitting STAT3-driven proliferation, angiogenesis and immune-escape, but also impairs tumor invasivity and metastatic potential. The wide variety of different tumors where STAT3 activity is essential suggests that this factor may play multiple roles in tumorigenesis, not all of which have been so far completely understood. Thus, a growing number of studies are being performed to address unanswered questions about STAT3 and its potential value as a therapeutic target to fight cancer. In this section we review what is known about the different ways of action of STAT3 in tumorigenesis, summarized in Figure 1. These can be classified into cell-autonomous functions, directly affecting specifc features of cancer cells such as proliferation and survival, and indirect effects, exerted through the regulation of tumor angiogenesis or tumor immunosurveillance.

Figure 1. Milestones defining STAT3 role in cancer.

Figure 1

Milestones defining STAT3 role in cancer. The crucial findings identifying the multiple functions of STAT3 in oncogenesis are illustrated along a timeline. ST3, STAT3; ST3C, STAT3C; FA, focal adhesions.

Prosurvival and Proproliferative Roles of STAT3

STAT3 direct pro-oncogenic activities were first suggested by the observation that an over-expressed constitutively active mutant form, STAT3C, could transform fibroblasts and other non-malignant cell types, such as breast and prostate epithelial cells.20 - 22 Initially, STAT3 was thought to contribute to the tumorigenic process mainly by triggering pro-survival and pro-proliferative signaling into the cells. Indeed, several genes known to be crucial for tumor growth and tumor cell survival are direct STAT3 target genes and are down-regulated as a consequence of STAT3 inhibition, correlating with growth arrest and apoptosis (reviewed in 88). Among these are anti-apoptotic proteins, such as survivin and members of the Bcl family (e.g., Bcl-XL, Bcl-2 and Mcl1—myeloid cell leukemia sequence 1) and proteins involved in proliferation and cell cycle progression such as cyclin D1, c-Myc and pim-1/2.89 , 90 STAT3 can also inhibit the extrinsic apoptotic pathway by directly binding to the Fas promoter and suppressing its transcription.91 Moreover, STAT3 was shown to transcriptionally repress murine p53 expression, thus impacting on p53-mediated apoptosis and contributing to cell survival.92 Interestingly, not all of the above genes are expressed in a STAT3-dependent manner in all tumors analyzed. Rather, STAT3 controls distinct subsets of them in different tumors.88

STAT3 and Drug-Resistance

Related to STAT3 anti-apoptotic effects is the ability of this factor to confer resistance to chemotherapeutic drugs in several tumors, with important implications for cancer therapy. For example, doxorubicin activates STAT3 in a metastatic subline of breast cancer cells, suggesting that STAT3-mediated anti-apoptotic activities may represent one of the protection mechanisms activated in response to chemotherapeutic drugs.93 Indeed, treatment of a metastatic breast cancer cell line with a STAT3 dominant-negative form sensitizes cells to taxol or adriamycine treatment, inhibiting STAT3-mediated Bcl-2 induction.94 An inverse correlation among STAT3 activity, survivin expression and response to docetaxel and doxorubicin treatment was observed during a phase II neoadjuvant chemotherapy trial. Additionally, interference with STAT3 activity by different means increases doxorubicin-induced apoptosis in highly metastatic breast cancer cell lines.93 Finally, combined administration of cisplatin with YC1, a novel anti-cancer agent shown to downregulate active STAT3, suppresses tumor growth in a hepatocellular carcinoma xenograft model.96 Thus, STAT3 inhibition coupled to chemotherapeutic treatment might be a valid approach to cancer therapy.

STAT3 Oncogenic Functions not Directly Related to Survival/Growth

Besides the well accepted effects of STAT3 on tumor cell survival and growth reported above, an involvement of STAT3 in many other aspects of tumor progression is strongly emerging, as depicted in Figure 1. This suggests that STAT3 contributes to multiple cancer cells features, in keeping with the wide variety of tumor types where its activity is crucial. For example, STAT3 has been linked to important steps of tumor progression such as tumor cell invasion, metastasis and angiogenesis. Invasion and metastasis are multi-step processes involving proteolytic degradation of the basal membrane and the extracellular matrix by enzymes such as MMPs, altered adhesion properties and the acquisition of a motile, mesenchymal-like phenotype. In addition, both tumor invasion and growth need to be supported by de novo angiogenesis. As summarized below, STAT3 can directly contribute to each of these steps with both canonical (i.e., transcriptional) and noncanonical activities. In addition, STAT3 is also emerging as an important negative modulator of tumor immunosurveillance.

STAT3 and Matrix-Metalloproteinases

Among STAT3 target genes are several members of the MMP family, known to contribute to tumor invasion, angiogenesis and metastasis. Indeed, STAT3C-mediated transformation of immortalized human mammary epithelial cells requires the activity of MMP-9 and this correlates with STAT3 activation and enhanced MMP-9 levels in human breast oncogenesis.21 STAT3 can activate the MMP-9 promoter in breast cancer cell lines.97 In melanoma cells, STAT3 can directly regulate the expression of another MMP family member, MMP-2, thus increasing invasive and metastatic potential.98 Finally, STAT3 interaction with c-Jun is required for the induction of MMP-1 in bladder cancer cells in response to EGF and is crucial for EGF-induced migration, invasion and tumor formation in xenografted nude mice.99 A correlation between STAT3 and MMP-1 in colon carcinomas was also reported.100

STAT3 and Angiogenesis

The first evidence of an involvement of STAT3 in angiogenesis was the demonstration that STAT3C could directly induce the production of VEGF if overexpressed in fibroblasts or B16 melanoma cells101 and in human pancreatic and cervical cancer cells.102 , 103 STAT3 can also indirectly regulate VEGF by inducing the expression of hypoxia-inducible factor 1α (HIF-1α), which drives VEGF transcription upon hypoxic stimulation.104 This was also indirectly confirmed by STAT3 inhibition in human renal carcinoma cells.105 In addition, STAT3 was also proposed to be involved in VEGF signaling.106 , 107

STAT3 and Epithelial-Mesenchymal Transition

Epithelial-mesenchymal transition (EMT) has been linked to the progression of epithelial tumors.108 It is a general process required for embryonic development, tissue remodelling and wound repair, during which epithelial cells lose cell-cell adherence, remodel their cytoskeleton and acquire mesenchymal properties, becoming able to migrate, invade and form metastasis. The first step of this process is thought to be the down-regulation of some epithelial surface markers, in particular E-cadherin, by transcription factors such as Snail and Twist. E-cadherin is required to form the adherence junctions characteristic of epithelial cells.

STAT3 involvement in EMT was first suggested by the work of T. Hirano and coworkers in zebrafish, reporting that STAT3 activity is required for cell movements during gastrulation.109 STAT3 acts through the regulation of the breast-cancer-associated zinc transporter LIV1, which in turn is essential for the nuclear localization of Snail. These observations link STAT3 with Snail and EMT through LIV1.110 More recent data suggest a direct link between STAT3 and EMT. On one side, the expression of dominant negative STAT3 inhibits TGF-β-induced apoptosis and EMT in hepatocytes.111 On the other side, EGF was shown to induce EMT in EGFR-expressing cancer cells via STAT3-mediated induction of Twist gene expression. Accordingly, STAT3 was shown to directly bind to and transactivate Twist promoter.112 , 113

STAT3 and Cell Migration

Many indications suggest a role for STAT3 in regulating cell movement, mainly by contributing to cytoskeleton reorganization and controlling cell adhesion properties. The first demonstration of a central role played by STAT3 in cell migration was the observation that STAT3 conditional disruption in keratinocytes resulted in impaired wound healing due to compromised migration, both in vivo and in vitro, in response to cytokines and growth factors such as EGF, TGF-α, HGF and IL-6.114 STAT3 was also shown to contribute to disrupt epithelial adhesion and polarity downstream of ErbB2-Integrin β4 signaling, leading to promotion of mammary tumorigenesis.115 Moreover, the introduction of STAT3C in prostate epithelial cells enhances cell migration and tumor formation by inducing the expression of Integrin β6 and its ligands.22 The target genes involved in the above-described functions have not yet been identified.

STAT3-mediated regulation of cell motility might depend not only on its canonical transcriptional activity but also on recently proposed nonnuclear functions. For example, DJ. Montell and co-authors showed a correlation between STAT3 activity, cell motility and aggressiveness of ovarian carcinoma cells. Interestingly, in these cells phosphorylated STAT3 localized to focal adhesions where it directly interacted with active focal adhesion kinase and paxillin, thus potentially playing a role in their signaling.116 Moreover, the group of X. Cao recently showed that nonphosphorylated STAT3 in the cytoplasm interacts with the microtubule-destabilizing protein stathmin, inhibiting its microtubule depolymerizing function and resulting in enhanced microtubules polymerization and cell migration.117

STAT3 Immune-Mediated Effects on Tumors

STAT3 has also been recently shown to enable tumors to evade immune system control. STAT3 activity in antigen presenting cells (APC), including dendritic cells (DC) and macrophages, was shown to inhibit their maturation, thus impairing DC-mediated induction of T-cell responses.118 Y. Nefedova and co-authors suggested that STAT3 activity impaired APC differentiation by maintaining cells in a proliferative stage.119 Interestingly, inhibition of APC maturation can be indirectly triggered by the frequently detected constitutive activity of STAT3 in the tumor cells themselves, which in turn induces the production of soluble anergyzing factors such as VEGF and IL-10, while at the same time downregulating the secretion of pro-infammatory mediators.120 In a xenograft melanoma system, even incomplete STAT3 blockade increased the production of chemoattractants inducing the migration of lymphocytes, NK cells, neutrophils and macrophages, resulting in macrophage-mediated cytostatic activity against tumor cells.121 STAT3 could also contribute to the oncogenic activity of the PAX3-Forkhead fusion protein in rhabdomyosarcoma cells by inhibiting local inflammatory and immune responses.122 Accordingly, inhibition of STAT3 in macrophages could induce an anti-tumor immune response in a rat model of breast cancer123 and in vivo deletion of STAT3 in hematopoietic precursor cells resulted in enhanced anti-tumor activity triggered by DC, T-cell, NK cells and neutrophils, correlating with a reduction of regulatory T-cells.124

In Vivo Models of STAT3 in Tumorigenesis

Numerous in vivo studies with STAT3 conditional mutant mice or mice over-expressing the constitutively active STAT3C mutant form have contributed to the understanding of the role of STAT3 in tumorigenesis. The first evidence that STAT3 activation was required for tumor progression in vivo was the observation that its specific ablation in keratinocytes completely abrogated skin tumor development in the two-stage chemical carcinogenesis model.125 STAT3-deficient keratinocytes were more sensitive to apoptosis and STAT3 inhibition with an oligonucleotide decoy injected into primary skin papillomas led to significant reduction of tumor volume.

A non-redundant role for STAT3 in a lymphoma mouse model mediated by the oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) was subsequently demonstrated both in vitro and in vivo.126 Despite the fact that NPM-ALK-dependent tumors could develop also in the absence of STAT3, STAT3 activity was required for survival and sof agar growth of T-cell lymphoma cell lines derived from NPM-ALK transgenic mice. Moreover, treatment of mice bearing xenografted NPM-ALK-dependent T-cell lymphomas with STAT3 antisense oligonucleotides (ASO) significantly impaired tumor growth in vivo. These data suggest that tumor cells developing in the presence of STAT3 may become STAT3-addicted, supporting the idea that STAT3 targeting may be a promising strategy for cancer therapy. Additionally, the enhanced anti-tumor activity of STAT3-deficient hematopoietic cells mentioned in the above section underlines a central role for STAT3 in orchestrating tumor escape from the immune system in vivo.124

However, can STAT3 be considered a bona fide oncogene, able to induce tumorigenesis in vivo as suggested by in vitro over-expression experiments?20 - 22Only recently have in vivo oncogenic properties of STAT3 been demonstrated.

Keratin 5 promoter-driven STAT3C (K5.STAT3C) transgenic mice, overexpressing the constitutively active form of STAT3C in keratinocytes, developed skin tumors with a shorter latency and in greater number compared to nontransgenic mice in a two-stage chemical carcinogenesis model.127 Additionally, inducible STAT3C overexpression in alveolar type II epithelial cells induced lung bronchoalveolar adenocarcinomas preceded by remarkable infiltration of inflammatory cells.128 Tumor development correlated with enhanced secretion of pro-inflammatory molecules and with reactivation of genes critical for epithelial cell growth during embryonic lung development in STAT3C-overexpressing alveolar cells, similar to what was observed in human bronchoalveolar adenocarcinomas. Finally, unpublished data from our laboratory suggest that STAT3C can cooperate with the HER-2/neu oncogene in mammary carcinogenesis (Barbieri et al, manuscript in preparation).

Although most published data are in agreement with a pro-oncogenic role of STAT3, there is one recent report suggesting that STAT3 can be either tumor-suppressive or tumor-promoting in glioblastoma, depending on the tumor genetic background.129 Indeed, while STAT3 could cooperate with EGFRvIII, an oncogenic mutant form of the EGFR, to mediate transformation, STAT3 inhibition accelerated the disease in glioblastoma induced by PTEN-loss, suggesting tumor suppressor activity under these conditions.

Inhibiting STAT3 for Terapeutic Intervention

In keeping with the wide involvement of STAT3 in tumorigenesis discussed above, STAT3 constitutive activation in cancer often correlates with poor prognosis and metastasis, as it was well established for example in renal carcinoma, melanoma, thymic carcinoma and colorectal adenocarcinoma.15 , 18 , 130 - 132 Accordingly, efforts aimed at targeting STAT3 for cancer therapy are steadily increasing.

In the past few years several new molecules inhibiting STAT3 were generated and tested both in vitro and in vivo, including nucleic-acid-based molecules such as small interfering RNAs (siRNA), ASO and decoy oligonucleotides, peptides and a range of small molecule inhibitors.

siRNA-mediated STAT3 silencing in vitro was first reported in astrocytoma cell lines,133 where it inhibited tumor cells growth in vitro, but also in many other systems. Among the few examples of in vivo RNA interference approaches, most representative is the work of the groups of DQ. Xu and XJ. Zhao, who could obtain significant reduction of tumor size by directly injecting a vector-based siRNA into human xenografted prostate and laryngeal tumors.134 , 135

Another strategy used with surprising high efficiency in vivo is based on the use of STAT3 ASO. ASO injection in vivo was successfully used to reduce tumor volume in mice carrying xenografted NPM-ALK anaplastic large cell lymphoma (see previous section)126 or hepatocellular carcinomas.136

Appreciable results were also obtained using decoy oligonucleotides to block STAT3 DNA binding activity. STAT3 decoys could successfully induce growth arrest of head and neck cancer cells in vitro.137 Recently, STAT3 decoys were used to inhibit the growth of a human nonsmall-cell lung cancer line in xenografted nude mice.138 Another molecule proposed as STAT3 inhibitor is a G-quartet oligonucleotide, which impairs STAT3 dimer stability and DNA binding activity and dramatically reduces the growth of prostate and breast tumors139 and of head and neck squamous cell carcinomas140 in nude mice xenografts.

In addition to nucleic acid-based inhibitory molecules, a phosphopeptide carrying the sequence of the STAT3 phosphotyrosine domain and interacting with its SH2 domain has also been widely used to inhibit STAT3 activity.141 Both this phosphotyrosyl peptide and a peptidomimetic compound could inhibit STAT3 transcriptional activity, induce apoptosis and suppress soft agar growth of v-Src-transformed fibroblasts as well as proliferation in human breast carcinoma cells.142

A number of small molecules and/or natural compounds inhibiting STAT3 have also been described.143 The platinum-containing compound CPA-7 is able to displace STAT3 from DNA and to induce regression of colon tumors in the mouse.144 Cucurbitacin I, also called JSI-124, suppresses STAT3 phosphorylation and was shown to improve the efficacy of a p53-expressing adenoviral vector used to transduce DC in tumor-bearing mice.145 Cucurbitacin I has also been used incapsulated in polymeric micelles to increase its solubilization and delivery, thus successfully inhibiting tumor growth in B16 melanoma tumor-bearing mice.146 Also galiellalactone, a fungal metabolite, probably interfering with DNA binding, could inhibit the growth of prostate cancer in mice.147 Finally, the chemical probe S3I-201, which inhibits STAT3 dimerization and DNA-binding, induces regression of human breast tumor xenografts.148 More inhibitors showed promising activities in vitro but have not yet been tested in vivo, including peptidomimetics142 and low-molecular weight compounds.149

Alterations in Control Mechanisms of STAT1 and STAT3 Activation

Despite the wide range of tumors where STAT3 is constitutively active, no activating genetic mutations have so far been described in tumors, suggesting that abnormal STAT3 activity in neoplastic cells must be triggered by unbalanced upstream activating events or defective negative feedback regulation.

As already mentioned, many oncogenes and growth factor receptors known to be abnormally activated/amplified in tumors can lead to STAT3 phosphorylation (among others, EGFR, ErbB2, PDGFR, HGFR, v-Src, Ros, v-Eyk, v-Abl, Lck, TEL-JAK, Middle T antigen). In addition, unbalanced/uncontrolled production of STAT activating cytokines and growth factors can often occur in the tumor microenvironment, triggering prolonged, abnormal STAT activation.150

Other components known to be involved in aberrant STAT activation in tumors are members of the JAK family of cytokine receptor-associated protein kinases. The most frequently involved is JAK2, which participates in the signaling of many cytokines and growth factors. Several JAK2-activating mutations have been described in a number of myeloproliferative neoplasms (MPNs). The best characterized is the JAK2V617F mutation, occurring in a high percentage of patients affected by polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF),151 , 154 as well as in acute and chronic myeloid malignancies.155 , 156 This mutation results in increased kinase activity and hyper-responsiveness to cytokines151 and mainly affects STAT5 signaling. However, enhanced STAT3 activation appears to be specifically involved in JAK2V617F-positive myelofibrosis with myeloid metaplasia and ET157 , 158 A number of different JAK2 and also JAK3 gain of function mutations have been described in rare cases of myeloproliferative diseases (recently reviewed in 159). Three different fusion proteins generated by chromosomal translocation and involving JAK2 are known (TEL-JAK2, BCR-JAK2 and PCM1-JAK2). These are relatively rare and give rise to different tumors, all characterized by constitutive kinase activity.160 Finally, rare JAK1 mutations have been described in T-cell acute lymphoblastic leukemia patients161 and in uterine leiomyosarcoma.162

Another event that can determine STATs constitutive phosphorylation is defective activity of their negative regulators, in particular the suppressors of cytokine signaling (SOCS) family of proteins. These are cytokine target genes that in turn down-regulate the same cytokine-activated JAK-STAT signaling pathway, acting as an essential physiological self-limiting mechanism for cytokine responses.163 In particular, SOCS1 is strongly involved in the IFNγ signaling and can associate with all known JAKs directly inhibiting their catalytic activity. SOCS3 in contrast cannot directly interact with JAK kinases but needs to be recruited to phosphotyrosine residues of activated receptors, in particular gp130, leptin, growth hormone and erythropoietin receptors. In addition to specific inhibition of JAKs kinase activity, all SOCS members are thought to act as E3 ubiquitin ligases and to mediate proteasomal degradation of associated proteins.

Growing evidence suggests a tumor suppressor role for SOCS1 in both hematological and solid neoplasms. SOCS1-/- fibroblasts display increased susceptibility to either spontaneous or oncogene-induced transformation.164 Moreover, ectopic SOCS1 expression blocks in vitro proliferation of Ba/F3 cells transformed by different hematopoietic-specific oncogenes and partially hampers metastasis formation by BCR-ABL transformed cells.164 Accordingly, SOCS1 activity is frequently defective in hematological tumors, either by posttranslational modifications (for example, v-Abl-induced SOCS1 phosphorylation alters its function165 , 166) or, more frequently, by direct silencing of the SOCS1 locus due to hypermethylation.166-169 Particularly sensitive to SOCS1 silencing are tumors where cytokine activation and JAK/STAT signaling play a pathogenic role. This is the case of multiple myeloma, where SOCS1 silencing favors IL-6 signaling thus promoting STAT3-dependent survival and proliferation.167 SOCS1 silencing has also been reported in acute myeloid leukemia (AML) and in a small percentage of BCR-ABL negative myeloproliferative disorders (MPD).168 , 170 SOCS1 activity can be impaired in tumors also by genetic mutations, as in the case of MedB-1 mediastinal lymphoma cells and of Hodgkin lymphomas, where it apparently mainly interferes with the activation of STAT5.171

SOCS1 silencing may play a role also in the onset and growth of solid tumors, as suggested by the observation that SOCS1+/- mice are more susceptible to carcinogen-mediated hepatocellular carcinoma development.172 Indeed, hypermethylation and silencing have also been detected in cell lines from hepatocellular,173 ovarian, pancreatic and breast carcinoma,174 , 175 Barrett's adenocarcinoma,176 head and neck squamous cell carcinoma (HSCC),177 glioblastoma multiforme178 and human gastric carcinoma,179 often correlating with altered STAT3 and/or STAT1 activity.

Many reports suggest that also silencing of SOCS3, which is the main negative-feedback regulator of STAT3 signaling, may be a common mechanism to constitutively activate STAT3 in tumors. Indeed, SOCS3 promoter is frequently hypermethylated in malignant melanomas, Barrett's adenocarcinomas, head and neck squamous cell carcinomas, hepatocellular and lung carcinomas.176 , 180 - 183 In many of these systems, SOCS3 silencing correlates with increased STAT3 activity and restoring its expression triggers a reduction of STAT3 phosphorylation correlating with apoptosis and growth suppression.181 , 183 In agreement with this idea, mice where SOCS3 is conditionally inactivated in the liver display increased susceptibility to chemically-induced hepatocarcinogenesis correlating with enhanced STAT3 phosphorylation184 and increased expression of STAT3 target genes Bcl-XL, Bcl-2, c-Myc, cyclin D1 and VEGF.185

Probably as a consequence of STAT3 constitutive activity, SOCS3 expression can also be enhanced in tumors, where it could act by regulating STAT1 activity. For example,SOCS3 was shown to determine resistance to IFNα-induced apoptosis by inhibiting STAT1 signaling in chronic myelogenous leukemia cells and in cutaneous T-cell lymphoma.

STAT1:STAT3 Cross-Regulation

As detailed above, STAT1 and STAT3 often play opposing roles in proliferation, apoptotic death, inflammatory and anti-tumor immune responses. In addition, studies on STAT-deficient cells have revealed the existence of reciprocal STAT1:STAT3 regulatory mechanisms.188 - 191 For example, in STAT3-deficient murine embryonic fibroblasts (MEFs) IL-6 triggers prolonged activation of STAT1 correlating with an IFNγ-like response, including up-regulation of multiple IFNγ-inducible genes, expression of Class II MHC antigens and induction of an anti-viral state. Accordingly, increased and prolonged phosphorylation of STAT1 in response to gp130 cytokines occurs in several systems upon STAT3 gene inactivation.192 - 194 These data suggest that in normal cells one of the functions of STAT3 in response to IL-6 is to down-regulate STAT1 activity, thus preventing IFNγ-like responses and allowing IL-6-specific signaling. To what extent this may be true also in tumor cells has not yet been investigated. Similarly, studies on STAT1-deficient bone-marrow-derived macrophages or MEFs indicate that in the absence of STAT1 IFNγ loses its pro-apoptotic activity and can even induce proliferative responses correlating with predominant activation of STAT3 and STAT3-mediated transcription.190 , 195 , 196 In addition, IFNα treatment can enhance rather than inhibit cell proliferation and survival in STAT1-/- T-lymphocytes,189 , 191 although contrasting data attribute this effect either to skewed STAT3 activation189 or to the action of other, non STAT-mediated, pathways.191 These observations suggest that the relative abundance of STAT3 or STAT1 may play a role in determining their relative activation levels and biological effects in response to activating stimuli. In turn, this may be relevant for the development and growth of tumors in the presence of specific tumor microenvironments, where different cytokine/ growth factor combinations can modulate the relative levels of STAT1 and STAT3, resulting in their differential activation. Indeed, the intensity and duration of inflammatory responses is known to influence the development of a favorable microenvironment for neoplastic transformation and growth.197 , 198 STAT1 activation, mainly mediated by IFNs, acts as a pro-infammatory factor both indirectly, by triggering cell apoptosis196 and directly, by inducing pro-inflammatory genes and promoting antigen presentation. In contrast, STAT3 is the main mediator of the functions of IL-10, a major anti-inflammatory cytokine. Of note, IL-10 can directly inhibit IFN-induced gene transcription at least partly by down-regulating STAT1 activation.199 The already reported ability of STAT3 to promote the escape of tumors from cell-mediated immunity correlates with STAT3-dependent induction of anti-inflammatory mediators such as IL-10 or VEGF, acting as DC inhibitors. At the same time, the production of pro-inflammatory, DC-activating, mediators is down-regulated.120 This observation could explain the acquired ability of many tumors to secrete IL-10.200 Interestingly, many of the inflammatory mediators produced by cancer cells upon STAT3 inactivation are typical STAT1 targets (e.g., CXCL10, CCL5, ICAM1), suggesting that reciprocal regulation between STAT3 and STAT1 may take place also in tumor cells and that STAT1:STAT3 unbalanced expression/activation and cross-regulation could play a role in tumor biology.

It is thus tempting to speculate that interfering with the activation of either factor in tumors may result in activation or re-activation of the other, which in turn would mediate some of the observed effects through the induction of specific target genes. Very little data is available on this subject. Grandis and coworkers showed that the therapeutic mechanism of STAT3 blockade by means of an oligonucleotide decoy is independent of STAT1 activation in cell lines derived from squamous cell carcinomas of the head and neck.201 In contrast, we have observed that STAT3 blockade by RNA interference in human T-cell lymphoma cell lines enables IL-6 to reinstate STAT1 activation, normally defective, and to induce apoptosis (Regis et al, manuscript in preparation).

Until more studies are available to establish if re-activation of either STAT in response to interference with the other one is a general mechanism and to which extent this may contribute to the observed biological outcome, care should be taken to plan therapeutic intervention using compounds that could unbalance finely tuned equilibria between STAT1 and STAT3 mediated actions. At the same time, the possibility to activate a specific STAT pathway by interfering with the other may under specific conditions provide unique therapeutic opportunities. For example, normal resting and neoplastic T-lymphocytes can become resistant to IFNγ antiproliferative effects or even proliferate in response to it, often due to down-regulation of the IFNγR chains and consequent failure to activate STAT1.202 Insensitivity to IFNγ, correlating with defective STAT1 activation, has also been observed in lymphoid and non-lymphoid tumor cell lines which constitutively express high levels of both receptor chains.24 , 203 - 206 These observations suggest the involvement of mechanisms acting both upstream and downstream from the interaction between IFNγ and its receptor.

Therefore, the balance between activated STAT1 and STAT3 may play a role in the phenomenon of IFNγ resistance downstream of the IFNγ/IFNγR interaction. In addition, the specific responses to gp130 cytokines and/or to IFNs could be redirected by manipulating STAT1:STAT3 balance, even in the presence of defective IFNγR signaling. Indeed, we have recently observed that interference with STAT3 activity in IFNγ-resistant human T-lymphoma cells enhances pro-apoptotic responses to IFNγ and makes cells sensitive to IL-6, which under these conditions triggers prolonged activation of STAT1, apoptosis and impaired in vivo growth (Regis et al, manuscript in preparation). This strategy might be as well suitable in other conditions characterized by impaired STAT1 activation.


We wish to thank Drs. F. Bazzoni for discussions inspiring this work and I. Barbieri for sharing his unpublished results. Work in the author’s laboratories was supported by the Italian Ministry of Research (MIUR PRIN) and by the Italian Association for Cancer Research (AIRC). G. Regis was the recipient of a “Young Researchers Contract” supported by FIRB (Fondo per gli Investimenti della Ricerca di Base).


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