Logo of jcoHomeThis ArticleSearchSubmitASCO JCO Homepage
J Clin Oncol. Mar 20, 2012; 30(9): 1005–1014.
Published online Feb 21, 2012. doi:  10.1200/JCO.2010.31.8907
PMCID: PMC3341105

Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies

Abstract

The Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway was discovered 20 years ago as a mediator of cytokine signaling. Since this time, more than 2,500 articles have been published demonstrating the importance of this pathway in virtually all malignancies. Although there are dozens of cytokines and cytokine receptors, four Jaks, and seven Stats, it seems that interleukin-6–mediated activation of Stat3 is a principal pathway implicated in promoting tumorigenesis. This transcription factor regulates the expression of numerous critical mediators of tumor formation and metastatic progression. This review will examine the relative importance and function of this pathway in nonmalignant conditions as well as malignancies (including tumor intrinsic and extrinsic), the influence of other Stats, the development of inhibitors to this pathway, and the potential role of inhibitors in controlling or eradicating cancers.

INTRODUCTION

The Janus kinase/signal transducer and activator of transcription (Jak/Stat) signaling pathway was first discovered in a study of interferon signaling, identifying how a growth factor leads to the activation of a transcription factor.13 Jaks (tyrosine kinases) engage with cytokine receptors and mediate tyrosine phosphorylation of their associated receptors and recruited proteins, including Stats.

Tyrosine phosphorylated Stats are released from the receptors and form homodimers, which translocate to the nucleus where they bind canonical sequences and modulate transcription.4 In addition to tyrosine phosphorylation, Stats are serine phosphorylated within their transcriptional activation domain, influencing their transcriptional activation function, stability, and noncanonical functions.511 Stats are also acetylated, methylated, sumoylated, and ubiquitylated, which alters their stability, dimerization, nuclear localization, transcriptional activation function, and association with histone acetyltransferases and histone deacetylases.1222 Importantly, Jak/Stat activation is tightly regulated through the expression of positive (cytokines, receptors, tyrosine kinases) and negative regulators (tyrosine phosphatases, protein inhibitors of activated Stat, suppressor of cytokine signaling [SOCS] proteins).2331

The function of the Jaks and Stats in normal cells were determined principally through the analysis of mice or tissues deficient for each of these molecules.32,33 For example, Jak1-deficient mice die perinatally; it is required for leukemia inhibitory factor, interleukin-6 (IL-6), IL-10, interferon (IFN), and IL-2 signaling. Jak2 deficiency leads to profound anemia and mice die E12.5.3335 Jak2 plays a critical role in signaling through the single-chain (erythropoietin, growth hormone, and prolactin receptors), IL-3 (IL-3, IL-5, and granulocyte macrophage colony-stimulating factor [GM-CSF] receptors), and IFN-γ receptor families and embryonic stem-cell maintenance.3638 Interestingly, Jak2 can directly modify chromatin through tyrosine phosphorylation of histone H3 tyrosine 41 and histone arginine methyltransferase.3638

Stat1 is the principal transcriptional mediator of IFN signaling and plays a central role in the regulation of innate and adaptive immune responses. Additionally, many other cytokines (eg, IL-6 family) can lead to its phosphorylation in conjunction with other Stats (notably Stat3 and Stat5). Stat1 is a positive regulator of Th1 differentiation and a negative regulator of regulatory T cells (Tregs).39,40 Gain of function Stat1 alleles was discovered in patients with chronic mucocutaneous candidiasis, which leads to enhanced production of IFNs and IL-27 and an imbalance between Stat1 and Stat3 activation in IL-17–producing T cells, resulting in impaired IL-17–dependent immunity.41

Stat3 is activated in response to the IL-6 and IL-10 family of cytokines, G-CSF, leptin, IL-21, and IL-27 as well as to receptor tyrosine kinases (MET and epidermal growth factor receptor [EGFR]) and non–receptor tyrosine kinases (Abl, Src, Syk).4252 Stat3 deficiency is embryonic lethal (E6.5), underscoring its role in early development, whereas tissue-specific loss of Stat3 demonstrates its importance in regulating inflammation (Th17 cells, myeloid cells, Bregs, dendritic cells).33,5360 IL-6, IL-23, and IL-21 through Jak-mediated phosphorylation of Stat3 are required for Th17-cell generation, essential for protective immunity against fungi, and participate in autoimmune diseases.61 The most significant negative regulator of immune-mediated inflammation is the IL-10 cytokine, which also signals through Jak1/Jak2/Tyk2 and Stat3. Ablation of the IL-10 receptor or Stat3 in Treg cells leads to fatal Th17-mediated colitis. The ability of different Stat3-activating cytokines (IL-6, IL-23, IL-10) to regulate Th17-cell functions (both activate and inhibit) remains an unanswered question, but possible/likely mechanisms involve the levels of cytokines, their corresponding receptors, the degree of Stat3 phosphorylation, SOCS3-dependent inhibition of glycoprotein 130 (gp130), and the interplay between Tregs and Th17 cells.6265 Stat3 also plays a critical role in the development and function of myeloid cells. Mice deficient for Stat3 in myeloid cells develop chronic colitis (in a lymphocyte-dependent manner), phenocopying mice deficient for IL-10.66,67 Furthermore, macrophage-derived IL-10 is a critical regulator of Treg suppressive functions in models of colitis.68 Stat3 has been shown to transcriptionally repress IL-12 and IL-23 through IL-10 signaling in myeloid cells.69 Thus, Stat3 activation in different cell types through different receptors (IL-6 or IL-10 receptors) can regulate immune effector cells, leading to controlled inflammatory responses. Stat3 is required for G-CSF–mediated expansion of both immature and mature granulocytes.70 The specific roles Stat3 plays in hepatic inflammation/damage/regeneration through its activation in myeloid cells and in hepatocytes are essential to prevent liver failure by attenuating a strong innate (Stat1-dependent) inflammatory response.71 Stat3 also plays a critical role in generating effector B cells from naive precursors in humans.72 Mutations in the DNA-binding domain of Stat3 (dominant negative) were shown to be a cause of hyperimmunoglobulin E syndrome, which is a primary immunodeficiency leading to recurrent infections (bacterial and fungal), elevated levels of immunoglobulin E through defective production of Th17 cells, and impaired generation of tolerogenic dendritic cells.7377 Interestingly, these patients are predisposed to the development of B-cell lymphomas, which highlights the complexities of globally suppressing Stat3 activity.78

Constitutive Activation of Jaks/Stats in Cancer

In contrast to normal cells, in which Stat tyrosine phosphorylation occurs transiently, it has been determined that Stats 1, 3, and 5 are persistently tyrosine phosphorylated in most malignancies (particularly Stat3).7981 The mechanisms by which Stat3 is persistently or constitutively tyrosine phosphorylated in cancers include increased production of cytokines and cytokine receptors, which occurs in both an autocrine and paracrine manner (from the tumor microenvironment), a decrease in the expression of the SOCS proteins through promoter methylation, and loss of tyrosine phosphatases.52,8286 A few genetic abnormalities have recently been discovered in malignancies, which lead to increased Stat3 or Stat5 tyrosine phosphorylation. For example, a subset of myeloproliferative disorders harbor a somatic activating mutation in the Jak2 kinase (V617F and exon 12) or in the thrombopoietin receptor (MPL), resulting in hyperactivation of Jak2 or thrombopoietin signaling (both Stat5 and Stat3 phosphorylation).8791 Somatic in-frame deletions in the gp130 receptor can lead to hyperactivation of the receptor and activation of Stat3 and the development of inflammatory hepatocellular adenomas in mice.92 The receptor protein tyrosine phosphatase delta is frequently inactivated in glioblastoma (GBM) multiforme, head and neck, and lung cancers and has been shown to dephosphorylate Stat3.29 LNK is a regulator of hematpoiesis through direct binding and inhibition of Jak2.93 In one report, myeloproliferative disorders expressing mutations in the LNK gene led to enhanced Jak2/Stat3/5 activation and myeloproliferative neoplasms.94 Sphingosine-1-phosphate receptor-1 upregulates Jak2 activity, leading to enhanced Stat3 phosphorylation.95 Stat3 transcriptionally regulates itself, sphingosine-1-phosphate receptor-1, and the IL-6 gene, leading to a positive feed-forward loop in a number of epithelial tumors.9597 Aberrant EGFR and Ras signaling can lead to increased cytokine production, resulting in enhanced Stat3 phosphorylation, demonstrating both redundancies and crosstalk between seemingly parallel pathways.82,98100

Dependence on Jak/Stat3 Signaling in Malignancies

Numerous studies have revealed Stats (particularly Stat3) to be required in many aspects of tumorigenesis, including differentiation, proliferation, apoptosis, increased sensitivity to cytotoxic agents, angiogenesis, recruitment of immune cells, and metastasis.3,81,101 To explore the specific functions of each signaling component and to determine their mechanisms of action, a number of tools and approaches have been used, including murine knockout and knock-in models, shRNA knockdown approaches, introduction of dominant-negative forms (lacking specific residues or domains), inhibitors of tyrosine kinases (natural products or designed), inhibitors of Stat3-DNA binding (platin derivatives), molecular inhibitors of Stat3 dimerization (SH2 [Src homology 2] –domain mimetics), decoys (optimal DNA binding sites), and blocking antibodies to receptors.3,102104

For example, mice deficient for Stat3 in specific cell types do not develop oncogene- or mutagen-induced cancers and/or develop less aggressive cancers.57,105109 Conversely, the generation of mice expressing mutant forms of the gp130 receptor can lead to hyperactivation of Stat3, resulting in gastric adenomas and lymphopoiesis.110112 Inducible expression of a constitutively activated form of Stat3 in the lung leads to chronic inflammatory changes and increased cytokine production, eventually resulting in de novo tumorigenesis.113 Introduction of sh/siRNA to Stat3 in cancer-derived cell lines leads to a marginal effect on in vitro growth but results in a significant effect on in vivo tumor growth, principally through decreased angiogenesis and invasion, possibly through a reduction in the Stat3-mediated production of tumor-secreted pro-inflammatory and angiogenic factors (IL-8, IL-6, hypoxia-inducible factor 1 alpha, vascular endothelial growth factor [VEGF]).114,115

Stat3 Activation in Tumor-Associated Cells

Stat3 activation in nontumor cells plays a significant role in tumor progression, particularly in those tumor subtypes associated with chronic inflammation (eg, colitis-associated colorectal cancers, hepatocellular carcionoma, and pancreatic cancer).57,116121 Activation of Stat3 by VEGF, platelet-derived growth factor, IL-6, or IL-10 is responsible for various immunosuppressive activities, such as the blockade of dendritic-cell maturation and the release of IL-10, which inhibits T-cell and macrophage activation and downregulated HLA expression in cancer cells. The association between angiogenesis and immunosuppression may be the result of hypoxia, which induces production of hypoxia-inducible factor 1 and VEGF in a Stat3-dependent manner, which also leads to the recruitment and differentiation of Tregs and myeloid-derived suppressor cells (MDSCs).122 Analysis of circulating myeloid cells in patients with metastatic melanoma revealed high levels of phosphorylated Stat3 (pStat3) in MDSCs (as defined by suppression of CD8 T cells), which was abrogated by pretreatment with a Jak inhibitor.123 Deletion of Stat3 in myeloid cells or in vivo targeting of Stat3 in toll-like receptor 9–positive cells (eg, tumor-associated dendritic cells, MDSCs, and B cells) by synthetically linking a Stat3 siRNA to a CpG oligonucleotide agonist of toll-like receptor 9 targets resulted in enhanced CD8 T-cell responses and activation of tumor-associated dendritic cells and monocytes, leading to an antitumor immune response.59,124 Conversely, Stat3 activation in myeloid cells led to increased IL-6 expression and IL-6 trans-signaling in models of pancreatic cancer, which mediates Stat3 activation in epithelial cells promoting tumorigenesis.118 Thus, silencing or inhibition of Stat3 activity may be a strategy to overcome MDSC function and enhance the immune response to cancer.

Heterogeneous Stat3 Activation in Cancers

Immunohistochemical approaches on tumor microarrays are the most common manner by which to examine the relative levels of Stat proteins. Although this approach is preferable to most other methods, a number of important limitations should be mentioned. First, a majority of tumor samples express variable levels of pStats in terms of signal intensity, distribution, and cell types involved (Figs 1A, A,1B).1B). Specifically, we have determined that levels of pStat3 are highest on the leading edge of tumors in association with stromal, immune, and endothelial cells. This is not surprising given the evidence that paracrine sources of IL-6 (eg, from cancer-associated fibroblasts or myeloid cells) can induce autocrine production of IL-6 and pStat3 expression in tumor cells, leading to heterogeneous levels of pStat3.51,57,100,125,126 Thus, a proper examination of tumor samples should include the complete tumor section, including the leading edge, because the cores obtained for tumor microarrays are typically centrally located.

Fig 1.
Heterogeneity in phosphorylated signal transducer and activator of transcription 3 (pStat3) expression. (A) Immunohistochemical analysis of pStat3 levels in a primary invasive ductal carcinoma. Nuclear pStat3 is detected in stromal (blue arrow) and endothelial ...

In addition to the individual roles each Stat may play in promoting or inhibiting tumorigenesis, the relative roles that individual Stats play when coactivated in cancers are only beginning to be explored. For example, Stats 1, 3, and 5 are simultaneously tyrosine phosphorylated in a number of human cancers including breast, lung, and head and neck tumors. The presence of pStat5 (in addition to pStat3) in head and neck tumors can enhance tumor growth and invasion and may contribute to resistance to EGFR inhibitors and chemotherapy.127129 Interestingly, in these squamous cell carcinomas, erythropoietin is felt to be mediating Stat5 phosphorylation, in contrast to breast cancers, whereby prolactin is the likely ligand. Of note, both of these growth factors lead to Jak2 activation. The functional interplay between activated Stat3 and Stat5 has also been described in breast cancers. Activated Stat3 and IL-6 are preferentially found in triple-negative breast cancers or in high-grade tumors and are associated with poor response to chemotherapy.100,130133 In human tumors, the presence of pStat5 is found predominantly in well-differentiated estrogen receptor (ER) –positive tumors and is associated with favorable prognosis.134 Furthermore, the presence of pStat5 is a predictive factor for endocrine therapy response and strong prognostic molecular marker in ER-positive breast cancer.135 A recent study examined the consequences of simultaneous activation of Stat3 and Stat5 and determined that compared with tumors only expressing Stat3, tumors expressing both were more likely to be ER positive and human epidermal growth factor receptor 2 negative and of a lower stage.136 Furthermore, Stat5 activation affects the transcriptional profile of tumors expressing activated Stat3. For example, prolactin-mediated Stat5 activation in breast cancers can lead to the transcriptional repression of B-cell lymphoma 6 (regardless of pStat3 status), overexpression of which is associated with high grade and metastatic disease.136,137 These studies suggest that examination of the levels of multiple Stats in a tumor sample may be required before determining the optimal treatment regimen. Understanding the relationship between the Jak/Stat pathway and other aberrantly regulated signaling pathways and the roles they play in tumors, as well as how this relates to responsiveness to therapies, is an active area of clinical investigation in the attempt to personalize treatments.

IL-6/Jak/Stat Signaling in Tumorigenesis: Inhibiting the Pathway

IL-6 Blockade

IL-6 was determined to have pleiotropic functions activating numerous cell types expressing the gp130 receptor and the membrane-bound IL-6 receptor (classical IL-6 signaling). In addition, a soluble form of the IL-6 receptor (sIL-6 receptor) binds to IL-6 and interacts with gp130. This so-called IL-6 trans-signaling represents an alternative to classical IL-6 signaling and permits IL-6 to modulate a broad spectrum of target cells including epithelial cells, neutrophils, macrophages, and T cells.138 Given the importance of aberrant IL-6 signaling in driving Stat3 activation in cancers, IL-6 blockade using IL-6 ligand-binding antibodies and IL-6R blocking antibodies have been tested preclinically, demonstrating tumor growth inhibition either alone or in combination with cytotoxic chemotherapies. Clinically, an IL-6 ligand-blocking antibody (CNTO-328) is being tested in a number of phase I/II clinical trials in transplant-refractory myeloma and castrate-resistant prostate cancer.139141 An IL-6R blocking antibody (tocilizumab) was recently approved for Castelman's disease and rheumatoid arthritis and will likely be tested in cancers (Table 1; Fig 2).142,143

Table 1.
IL-6/Stat3 Inhibitors
Fig 2.
Signal transducer and activator of transcription 3 (Stat3) signaling. Canonical: Stat3 is tyrosine phosphorylated by Janus kinase (Jak) kinases in response to cytokine/growth factor activation of cell surface receptors (eg, receptor tyrosine kinases [RTKs], ...

Jak Inhibitors

The study of Jak inhibitors for targeting cancers began in 1996 with the use of the pan-Jak inhibitor AG490, which led to inhibition of both in vitro and in vivo growth of relapsed B-cell leukemias.144 Since then, a number of natural products (eg, curcumin, resveratrol, flavopiridol, and piceatannol) have been tested preclinically and demonstrated to inhibit a myriad of pathways involved in inflammation, including inhibition of Stat3 phosphorylation, principally through a decrease in cytokine production or as a direct inhibitor of the Jaks.104,145 In addition, more potent and orally bioavailable Jak inhibitors have been developed by many pharmaceutical companies since the discovery of the Jak2 mutation in myeloproliferative disorders. Preclinically, these inhibitors are extremely effective in abrogating disease in myeloproliferative models, which has led to their clinical testing.91,146148 The best studied is the Jak1/2 inhibitor INCB018424 (Incyte, Wilmington, DE), which is in phase III clinical trials and has shown significant clinical improvements (reduction in splenomegaly, fatigue, discomfort, night sweats), correlating with a decrease in circulating pro-inflammatory cytokines.148 However, only partial reductions in the mutant Jak2 allele burden were observed. Perhaps this is because of inadequate inhibition of the mutant Jak2 kinase or because another driver is responsible for the disease. Similar observations have been made with the other Jak inhibitors (CEP-701, XL019, TG101348), although they have their unique sets of adverse effects including thrombocytopenia, anemia, neutropenia, transaminitis, GI intolerance, and neurotoxicity.148 These Jak inhibitors differ in their specificity (Jak1/2 v Jak2), potency, and half-life, which may be the reason for differences in adverse effects. Importantly, Jak1/2 is required for normal hematopoiesis, and therefore, these drugs will lead to anemia and thrombocytopenia unless different dosing schedules or lower doses are administered. The role of Jak inhibition in solid tumors was examined preclinically in models of IL-6–driven breast, ovarian, and prostate cancers using the Jak1/2 inhibitor AZD1480, which led to the suppression of tumor growth (Table 2).114 These compounds are now being tested in phase I clinical trials for solid tumors.

Table 2.
Jak Inhibitors

Stat3 Inhibitors

To target Stat3 as a DNA-binding protein, an optimal Stat3-binding site (double-stranded DNA) was synthesized and administered to cells in culture, injected intravenously or intratumorally, leading to sequestration of dimeric Stat3 away from its endogenous targets and onto this decoy.149153 Preclinically, the Stat3 decoy was tested in head and neck squamous cell carcinomas expressing high levels of tyrosine phosphorylated Stat3, which led to apoptosis of cancer cells, resulting in decreased tumor growth. Synergy between the decoy and other therapies was also demonstrated. Clinically, the Stat3 decoy is presently being tested in patients with head and neck cancer, because this disease is locally invasive and readily accessible to local injection (Table 1).

Attempts to find direct inhibitors of Stat3 has focused on developing agents that target the SH2 domain, preventing either Stat3 phosphorylation and/or dimerization. These include peptidomimetics and designed small molecules. Results from an in vitro DNA-binding assay would suggest that possible modes of inhibition by peptidomimetics in vivo include disruption/dissociation of preexisting constitutively active Stat3:Stat3 dimers.154 Additionally, peptidomimetics might associate with nonphosphorylated Stat3 monomer proteins through pY-SH2 interactions (the peptide or mimetic contains the pY motif, and the Stat3 monomer has an SH2 domain) to form a heterocomplex. This in turn would decrease the levels of free nonphosphorylated Stat3 monomers available for de novo phosphorylation and activation. A number of these agents have been shown to inhibit cancer growth in multiple preclinical cancer models.154156 Although these compounds have shown reasonable specificity to disrupting Stat3 function, they have not been developed clinically in part because of the high concentrations required to impart their effects.104

Using a chemical library of clinically established and well-tolerated compounds in a luciferase cell–based assay led to the identification of inhibitors of Stat3- and Stat5-dependent transcription.157159 For example, nifuroxazide, a drug used for the treatment of diarrhea, could inhibit Jak2, and Tyk2 effectively reduced pStat3 levels in multiple myeloma.160 Pyrimethamine, an antimalarial compound, was identified as an inhibitor of Stat3 and myeloma growth and is presently in clinical trials for the treatment of chronic lymphocytic leukemia and small lymphocytic leukemia.158

Introduction of mutant (dominant-negative forms) Stats has allowed for delineation of the specific function of domains or residues and has led to the discovery of novel or noncanonical functions for the Stats as mediators of tumorigenesis.161,162 Interestingly, both canonical and noncanonical roles of individual Stats have been determined to play a critical role in mediating both tumor initiation and promotion. The canonical pathway is defined as tyrosine phosphorylated Stats functioning as transcription factors. The noncanonical pathway includes the many roles of nontyrosine phosphorylated Stats, Stats as mediators of DNA methylation, Stats activating focal adhesions, and Stats as regulators of mitochondrial function.96,163169 Examples of the noncanonical pathway include nontyrosine phosphorylated Stat3 activating transcription in conjunction with nuclear factor κB or CD44, localizing to the mitochondria and regulating ATP synthesis, and interacting with the microtubule-associated protein stathmin modulating the motility of cells.12,96,168170 Interestingly, microtubule-targeting agents (eg, paclitaxel) can disrupt Stat3 tubulin interactions.171 Furthermore, serine phosphorylated but nontyrosine phosphorylated Stat3 can regulate transcription in chronic lymphoid leukemia cells.172 The roles of Stat acetylation, ubiqutylation, and sumoylation are presently being explored in regulating tumor formation and metastatic progression. Thus, both nontyrosine and tyrosine phosphorylated Stat3 play important functions in cancer cells, which should be taken into consideration in the choice of inhibitory agents to be used in preclinical and clinical settings (Fig 2).

Dependency on Jak/Stat Signaling for Tumorigenesis

A number of important questions arise when we consider how to predict whether a particular tumor will be dependent on the Jak/Stat signaling pathway. Will tumors with the highest, most homogeneous expression of tyrosine phosphorylated Stat be predictive of dependence on this signaling protein? Alternatively, will tyrosine phosphorylated Stats in the microenvironment determine response to anti-Stat therapies? What is the contribution of the other Stats in determining responsiveness to targeted therapy? For example, if we use Jak inhibitors in the treatment of breast cancer, we will inhibit Stat5 phosphorylation, which may thwart the benefits of inhibiting Stat3.

Perhaps the most significant effect of inhibiting IL-6/Jaks and Stat3 will be on its role in modulating the tumor-associated immune microenvironment. The complex relationship between tumor-associated Tregs and Th17 cells (both dependent on Stat3), dendritic cells, Th1, Th2, Bregs, MDSCs, neutrophils, and activated macrophages may result in unexpected findings on inhibition of this pathway. For example, Stat3 has been shown to enhance the expression of IL-23 (leading to the expansion of Tregs) while conversely suppressing the expression of IL-12 within the tumor milieu.173 In the context of colitis, IL-10 signaling in Tregs can suppress pathogenic Th17 responses.65 Tumor-evoked Bregs express activated Stat3 and induce transforming growth factor–beta conversion of Tregs from resting T cells.174 Thus, depending on what agent is used to block, these signaling molecules are likely to give rise to markedly different effects. For example, inhibition of Jak2 during encounters between human T cells and allogeneic monocyte–derived dendritic cells induced T-cell tolerance, preserving Treg numbers and impairing expansion of Th1 and Th17 cells.175 In contrast, IL-6 receptor blockade had no effect on dendritic-cell maturation, T-cell proliferation, Treg expansion, or Th1/Th17 responses in vitro.176 Inhibition of Jak1/2 was shown to decrease CD11b/Gr1-positive cells in a murine model of breast cancer, and although effects on T-cell subsets/activity were not reported, it seems likely that they would have a significant impact.177 These few examples are meant to highlight the importance of examining these critical immune cell types while inhibiting these pathways in the hopes of correlating clinical responses to changes in the immunophenotype of the tumor.

Will nontyrosine phosphorylated Stats play a critical role in promoting tumorigenesis? If so, inhibiting phosphorylation of the protein may prove to be ineffective. Attention to the biology of the cancer should be considered when choosing a particular regimen. For example, prostate cancers (androgen receptor [AR] positive) are usually responsive to androgen blockade. However, when castration-resistant disease develops, tumors often express higher levels of the AR, possibly through activated Stat3, which can transcriptionally regulate AR.178181 Thus, we may consider combining antiandrogens with anti-Stat3 drugs rather than with chemotherapy in hormone-refractory metastatic prostate cancer. It is also important to recognize that Stats may act as tumor suppressors in certain tumor contexts. For example, Stat3 can inhibit tumorigenesis in phosphatase and tensin homolog–null GBMs. While in EGFRvIII expressing GBMs Stat3 is required for tumorigenesis182,183 There are conflicting data in murine APC models of intestinal cancer where one publication demonstrated that Stat3 was required for tumorigenesis while another suggested that Stat3 loss promoted tumor progression and invasion of intestinal tumors.57,107,109

Inhibitors of Jaks, Stat3, or IL-6 signaling induce growth arrest, inhibit angiogenesis, and block recruitment of immune cells to the tumor but rarely lead to complete abrogation or regression of tumor formation. Although many in vitro studies have demonstrated that concomitant inhibition of the IL-6/Jak/Stat3 pathway with cytotoxic chemotherapies can promote apoptosis in a variety of cancer-derived cell lines, few in vivo studies have been performed to confirm or support these in vitro findings. Identifying appropriate Jak/Stat inhibition–containing regimens preclinically is essential for optimizing the sequence in which combination therapies should be administered. Furthermore, with the development of small-molecule inhibitors of tyrosine kinases with relatively short half-lives, we may wish to consider developing and testing regimens using pulsatile high doses, which may result in more effective targeting, fewer adverse effects, and less acquired resistance.184,185 Importantly, what is difficult and lacking in many clinical trials are the means of determining whether our targeted therapies are indeed hitting the appropriate targets. Thus, determination of the optimal correlative studies is essential. These questions and examples are meant to point out that when we design clinical trials to test inhibitors of the Jak/Stat pathways, we are fully cognizant of the potential pitfalls and difficulties in interpreting the outcomes of these trials. Nevertheless, we are extremely optimistic that inhibition of this pathway will prove to be beneficial in the treatment of a number of malignancies. We hope that an awareness of the complexities of this pathway will lead to informed and careful clinical trial design, resulting in an understanding of how these therapies induce tumor regression and cures.

Footnotes

Supported by National Institutes of Health Grant No. R01 CA87637, AstraZeneca, the Sussman Family Fund, the Charles and Marjorie Holloway Foundation, the Breast Cancer Alliance, and the Lerner Award.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Jacqueline Bromberg, AstraZeneca Research Funding: Jacqueline Bromberg, AstraZeneca Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Financial support: Jacqueline Bromberg

Manuscript writing: All authors

Final approval of manuscript: All authors

REFERENCES

1. Darnell JE., Jr STATs and gene regulation. Science. 1997;277:1630–1635. [PubMed]
2. Darnell JE., Jr Transcription factors as targets for cancer therapy. Nat Rev Cancer. 2002;2:740–749. [PubMed]
3. Jove R. Preface: Stat signaling. Oncogene. 2000;19:2466–2467. [PubMed]
4. Mertens C, Darnell JE., Jr SnapShot: JAK-STAT signaling. Cell. 2007;131:612. [PubMed]
5. Kramer OH, Heinzel T. Phosphorylation-acetylation switch in the regulation of STAT1 signaling. Mol Cell Endocrinol. 2010;315:40–48. [PubMed]
6. Maiti NR, Sharma P, Harbor PC, et al. Serine phosphorylation of Stat6 negatively controls its DNA-binding function. J Interferon Cytokine Res. 2005;25:553–563. [PubMed]
7. Morinobu A, Gadina M, Strober W, et al. STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proc Natl Acad Sci U S A. 2002;99:12281–12286. [PMC free article] [PubMed]
8. Xue HH, Fink DW, Jr, Zhang X, et al. Serine phosphorylation of Stat5 proteins in lymphocytes stimulated with IL-2. Int Immunol. 2002;14:1263–1271. [PubMed]
9. Vanhatupa S, Ungureanu D, Paakkunainen M, et al. MAPK-induced Ser727 phosphorylation promotes SUMOylation of STAT1. Biochem J. 2008;409:179–185. [PubMed]
10. Friedbichler K, Kerenyi MA, Kovacic B, et al. Stat5a serine 725 and 779 phosphorylation is a prerequisite for hematopoietic transformation. Blood. 2010;116:1548–1558. [PMC free article] [PubMed]
11. Decker T, Kovarik P. Serine phosphorylation of STATs. Oncogene. 2000;19:2628–2637. [PubMed]
12. Lee JL, Wang MJ, Chen JY. Acetylation and activation of STAT3 mediated by nuclear translocation of CD44. J Cell Biol. 2009;185:949–957. [PMC free article] [PubMed]
13. Sun Y, Chin YE, Weisiger E, et al. Cutting edge: Negative regulation of dendritic cells through acetylation of the nonhistone protein STAT-3. J Immunol. 2009;182:5899–5903. [PubMed]
14. Ray S, Lee C, Hou T, et al. Requirement of histone deacetylase1 (HDAC1) in signal transducer and activator of transcription 3 (STAT3) nucleocytoplasmic distribution. Nucleic Acids Res. 2008;36:4510–4520. [PMC free article] [PubMed]
15. Yuan ZL, Guan YJ, Chatterjee D, et al. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science. 2005;307:269–273. [PubMed]
16. O'Shea JJ, Kanno Y, Chen X, et al. Cell signaling: Stat acetylation—A key facet of cytokine signaling? Science. 2005;307:217–218. [PubMed]
17. Kramer OH, Baus D, Knauer SK, et al. Acetylation of Stat1 modulates NF-kappaB activity. Genes Dev. 2006;20:473–485. [PMC free article] [PubMed]
18. Komyod W, Bauer UM, Heinrich PC, et al. Are STATS arginine-methylated? J Biol Chem. 2005;280:21700–21705. [PubMed]
19. Lee H, Herrmann A, Deng JH, et al. Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell. 2009;15:283–293. [PMC free article] [PubMed]
20. Hou T, Ray S, Lee C, et al. The STAT3 NH2-terminal domain stabilizes enhanceosome assembly by interacting with the p300 bromodomain. J Biol Chem. 2008;283:30725–30734. [PMC free article] [PubMed]
21. Sun W, Snyder M, Levy DE, et al. Regulation of Stat3 transcriptional activity by the conserved LPMSP motif for OSM and IL-6 signaling. FEBS Lett. 2006;580:5880–5884. [PubMed]
22. Ulane CM, Rodriguez JJ, Parisien JP, et al. STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling. J Virol. 2003;77:6385–6393. [PMC free article] [PubMed]
23. Alexander WS, Hilton DJ. The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annu Rev Immunol. 2004;22:503–529. [PubMed]
24. Kishimoto T. Interleukin-6: From basic science to medicine—40 years in immunology. Annu Rev Immunol. 2005;23:1–21. [PubMed]
25. Nishimoto N, Kishimoto T. Interleukin 6: From bench to bedside. Nat Clin Pract Rheumatol. 2006;2:619–626. [PubMed]
26. Xu D, Qu CK. Protein tyrosine phosphatases in the JAK/STAT pathway. Front Biosci. 2008;13:4925–4932. [PMC free article] [PubMed]
27. Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol. 2003;3:900–911. [PubMed]
28. ten Hoeve J, de Jesus Ibarra-Sanchez M, Fu Y, et al. Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol Cell Biol. 2002;22:5662–5668. [PMC free article] [PubMed]
29. Veeriah S, Brennan C, Meng S, et al. The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers. Proc Natl Acad Sci U S A. 2009;106:9435–9440. [PMC free article] [PubMed]
30. Shuai K, Liu B. Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol. 2005;5:593–605. [PubMed]
31. Chung CD, Liao J, Liu B, et al. Specific inhibition of Stat3 signal transduction by PIAS3. Science. 1997;278:1803–1805. [PubMed]
32. Levy DE. Physiological significance of STAT proteins: Investigations through gene disruption in vivo. Cell Mol Life Sci. 1999;55:1559–1567. [PubMed]
33. Schindler C, Levy DE, Decker T. JAK-STAT signaling: From interferons to cytokines. J Biol Chem. 2007;282:20059–20063. [PubMed]
34. Decker T, Muller M, Stockinger S. The yin and yang of type I interferon activity in bacterial infection. Nat Rev Immunol. 2005;5:675–687. [PubMed]
35. Levy DE, Darnell JE., Jr Stats: Transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3:651–662. [PubMed]
36. Griffiths DS, Li J, Dawson MA, et al. LIF-independent JAK signalling to chromatin in embryonic stem cells uncovered from an adult stem cell disease. Nat Cell Biol. 2010;13:13–21. [PMC free article] [PubMed]
37. Rui L, Emre NC, Kruhlak MJ, et al. Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell. 2010;18:590–605. [PMC free article] [PubMed]
38. Liu F, Zhao X, Perna F, et al. JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation. Cancer Cell. 2011;19:283–294. [PubMed]
39. Caretto D, Katzman SD, Villarino AV, et al. Cutting edge: The Th1 response inhibits the generation of peripheral regulatory T cells. J Immunol. 2010;184:30–34. [PMC free article] [PubMed]
40. Ma H, Lu C, Ziegler J, et al. Absence of Stat1 in donor CD4+ T cells promotes the expansion of Tregs and reduces graft-versus-host disease in mice. J Clin Invest. 2011;121:2554–2569. [PMC free article] [PubMed]
41. Liu L, Okada S, Kong XF, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med. 2011;208:1635–1648. [PMC free article] [PubMed]
42. Shao H, Cheng HY, Cook RG, et al. Identification and characterization of signal transducer and activator of transcription 3 recruitment sites within the epidermal growth factor receptor. Cancer Res. 2003;63:3923–3930. [PubMed]
43. Zhang T, Ma J, Cao X. Grb2 regulates Stat3 activation negatively in epidermal growth factor signalling. Biochem J. 2003;376:457–464. [PMC free article] [PubMed]
44. Xia L, Wang L, Chung AS, et al. Identification of both positive and negative domains within the epidermal growth factor receptor COOH-terminal region for signal transducer and activator of transcription (STAT) activation. J Biol Chem. 2002;277:30716–30723. [PubMed]
45. Boccaccio C, Andò M, Tamagnone L, et al. Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature. 1998;391:285–288. [PubMed]
46. Kermorgant S, Parker PJ. Receptor trafficking controls weak signal delivery: A strategy used by c-Met for STAT3 nuclear accumulation. J Cell Biol. 2008;182:855–863. [PMC free article] [PubMed]
47. Carlesso N, Frank DA, Griffin JD. Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl. J Exp Med. 1996;183:811–820. [PMC free article] [PubMed]
48. Ilaria RL, Jr, Van Etten RA. P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J Biol Chem. 1996;271:31704–31710. [PubMed]
49. Shuai K, Halpern J, ten Hoeve J, et al. Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. Oncogene. 1996;13:247–254. [PubMed]
50. Yu CL, Meyer DJ, Campbell GS, et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science. 1995;269:81–83. [PubMed]
51. Bromberg J, Wang TC. Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell. 2009;15:79–80. [PMC free article] [PubMed]
52. Grivennikov S, Karin M. Autocrine IL-6 signaling: A key event in tumorigenesis? Cancer Cell. 2008;13:7–9. [PubMed]
53. Kato T. Stat3-driven cancer-related inflammation as a key therapeutic target for cancer immunotherapy. Immunotherapy. 2010;3:587–590. [PubMed]
54. Chen Z, O'Shea JJ. Th17 cells: A new fate for differentiating helper T cells. Immunol Res. 2008;41:87–102. [PubMed]
55. Korn T, Bettelli E, Oukka M, et al. IL-17 and Th17 cells. Annu Rev Immunol. 2009;27:485–517. [PubMed]
56. Kujawski M, Zhang C, Herrmann A, et al. Targeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects. Cancer Res. 2010;70:9599–9610. [PMC free article] [PubMed]
57. Grivennikov S, Karin E, Terzic J, et al. IL-6 and stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009;15:103–113. [PMC free article] [PubMed]
58. Kortylewski M, Kujawski M, Herrmann A, et al. Toll-like receptor 9 activation of signal transducer and activator of transcription 3 constrains its agonist-based immunotherapy. Cancer Res. 2009;69:2497–2505. [PMC free article] [PubMed]
59. Kortylewski M, Swiderski P, Herrmann A, et al. In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat Biotechnol. 2009;27:925–932. [PMC free article] [PubMed]
60. Zhang M, Liu Q, Mi S, et al. Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. J Immunol. 2011;186:4716–4724. [PubMed]
61. Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and restraining inflammation. Cell. 2010;140:845–858. [PubMed]
62. Stewart CA, Trinchieri G. At 17, in-10's passion need not inflame. Immunity. 2011;34:460–462. [PubMed]
63. Stewart CA, Trinchieri G. Reinforcing suppression using regulators: A new link between STAT3, IL-23, and Tregs in tumor immunosuppression. Cancer Cell. 2009;15:81–83. [PubMed]
64. Huber S, Gagliani N, Esplugues E, et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3 and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity. 2011;34:554–565. [PMC free article] [PubMed]
65. Chaudhry A, Samstein RM, Treuting P, et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity. 2011;34:566–578. [PMC free article] [PubMed]
66. Reindl W, Weiss S, Lehr HA, et al. Essential crosstalk between myeloid and lymphoid cells for development of chronic colitis in myeloid-specific signal transducer and activator of transcription 3-deficient mice. Immunology. 2007;120:19–27. [PMC free article] [PubMed]
67. Takeda K, Clausen BE, Kaisho T, et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity. 1999;10:39–49. [PubMed]
68. Murai M, Turovskaya O, Kim G, et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol. 2009;10:1178–1184. [PMC free article] [PubMed]
69. Smith AM, Qualls JE, O'Brien K, et al. A distal enhancer in Il12b is the target of transcriptional repression by the STAT3 pathway and requires the B-ZIP protein NFIL-3. J Biol Chem. 2011;286:23582–23590. [PMC free article] [PubMed]
70. Zhang H, Nguyen-Jackson H, Panopoulos AD, et al. STAT3 controls myeloid progenitor growth during emergency granulopoiesis. Blood. 2010;116:2462–2471. [PMC free article] [PubMed]
71. Horiguchi N, Lafdil F, Miller AM, et al. Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell-specific signal transducer and activator of transcription 3 gene knockout mice. Hepatology. 2010;51:1724–1734. [PMC free article] [PubMed]
72. Avery DT, Deenick EK, Ma CS, et al. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J Exp Med. 2010;207:155–171. [PMC free article] [PubMed]
73. Minegishi Y. Hyper-IgE syndrome. Curr Opin Immunol. 2009;21:487–492. [PubMed]
74. Saito M, Nagasawa M, Takada H, et al. Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells. J Exp Med. 2011;208:235–249. [PMC free article] [PubMed]
75. Milner JD, Brenchley JM, Laurence A, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008;452:773–776. [PMC free article] [PubMed]
76. Holland SM, DeLeo FR, Elloumi HZ, et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007;357:1608–1619. [PubMed]
77. Minegishi Y, Saito M, Tsuchiya S, et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007;448:1058–1062. [PubMed]
78. Kumanovics A, Perkins SL, Gilbert H, et al. Diffuse large B cell lymphoma in hyper-IgE syndrome due to STAT3 mutation. J Clin Immunol. 2010;30:886–893. [PubMed]
79. Bowman T, Garcia R, Turkson J, et al. STATs in oncogenesis. Oncogene. 2000;19:2474–2488. [PubMed]
80. Calò V, Migliavacca M, Bazan V, et al. STAT proteins: From normal control of cellular events to tumorigenesis. J Cell Physiol. 2003;197:157–168. [PubMed]
81. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: A leading role for STAT3. Nat Rev Cancer. 2009;9:798–809. [PubMed]
82. Sriuranpong V, Park JI, Amornphimoltham P, et al. Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system. Cancer Res. 2003;63:2948–2956. [PubMed]
83. Levine RL, Gilliland DG. Myeloproliferative disorders. Blood. 2008;112:2190–2198. [PMC free article] [PubMed]
84. Yoshikawa H, Matsubara K, Qian GS, et al. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth- suppression activity. Nat Genet. 2001;28:29–35. [PubMed]
85. He B, You L, Uematsu K, et al. SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci U S A. 2003;100:14133–14138. [PMC free article] [PubMed]
86. Meenhuis A, Irandoust M, Wölfler A, et al. Janus kinases promote cell-surface expression and provoke autonomous signalling from routing-defective G-CSF receptors. Biochem J. 2009;417:737–746. [PubMed]
87. Scott LM. The JAK2 exon 12 mutations: A comprehensive review. Am J Hematol. 2011;86:668–676. [PubMed]
88. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779–1790. [PubMed]
89. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387–397. [PubMed]
90. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3:e270. [PMC free article] [PubMed]
91. Koppikar P, Abdel-Wahab O, Hedvat C, et al. Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis. Blood. 2010;115:2919–2927. [PMC free article] [PubMed]
92. Rebouissou S, Amessou M, Couchy G, et al. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature. 2009;457:200–204. [PMC free article] [PubMed]
93. Bersenev A, Wu C, Balcerek J, et al. Lnk constrains myeloproliferative diseases in mice. J Clin Invest. 2010;120:2058–2069. [PMC free article] [PubMed]
94. Oh ST, Simonds EF, Jones C, et al. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood. 2010;116:988–992. [PMC free article] [PubMed]
95. Lee H, Deng J, Kujawski M, et al. STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nat Med. 2010;16:1421–1428. [PMC free article] [PubMed]
96. Yang J, Liao X, Agarwal MK, et al. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev. 2007;21:1396–1408. [PMC free article] [PubMed]
97. Ichiba M, Nakajima K, Yamanaka Y, et al. Autoregulation of the Stat3 gene through cooperation with a cAMP-responsive element-binding protein. J Biol Chem. 1998;273:6132–6138. [PubMed]
98. Ancrile B, Lim KH, Counter CM. Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev. 2007;21:1714–1719. [PMC free article] [PubMed]
99. Gao SP, Mark KG, Leslie K, et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest. 2007;117:3846–3856. [PMC free article] [PubMed]
100. Sansone P, Storci G, Tavolari S, et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest. 2007;117:3988–4002. [PMC free article] [PubMed]
101. Levy DE, Inghirami G. STAT3: A multifaceted oncogene. Proc Natl Acad Sci U S A. 2006;103:10151–10152. [PMC free article] [PubMed]
102. Ara T, Declerck YA. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer. 2010;46:1223–1231. [PMC free article] [PubMed]
103. Kortylewski M, Yu H. Stat3 as a potential target for cancer immunotherapy. J Immunother. 2007;30:131–139. [PubMed]
104. Fletcher S, Drewry JA, Shahani VM, et al. Molecular disruption of oncogenic signal transducer and activator of transcription 3 (STAT3) protein. Biochem Cell Biol. 2009;87:825–833. [PubMed]
105. Chan KS, Sano S, Kiguchi K, et al. Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. J Clin Invest. 2004;114:720–728. [PMC free article] [PubMed]
106. Chiarle R, Simmons WJ, Cai H, et al. Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Nat Med. 2005;11:623–629. [PubMed]
107. Bollrath J, Phesse TJ, von Burstin VA, et al. Gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell. 2009;15:91–102. [PubMed]
108. Ranger JJ, Levy DE, Shahalizadeh S, et al. Identification of a Stat3-dependent transcription regulatory network involved in metastatic progression. Cancer Res. 2009;69:6823–6830. [PMC free article] [PubMed]
109. Musteanu M, Blaas L, Mair M, et al. Stat3 is a negative regulator of intestinal tumor progression in Apc(Min) mice. Gastroenterology. 2010;138:1003–1011. e1–e5. [PubMed]
110. Jenkins BJ, Grail D, Nheu T, et al. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Nat Med. 2005;11:845–852. [PubMed]
111. Jenkins BJ, Roberts AW, Greenhill CJ, et al. Pathological consequences of STAT3 hyper-activation by IL-6 and IL-11 during hematopoiesis and lymphopoiesis. Blood. 2006;109:2380–2388. [PubMed]
112. Judd LM, Bredin K, Kalantzis A, et al. STAT3 activation regulates growth, inflammation, and vascularization in a mouse model of gastric tumorigenesis. Gastroenterology. 2006;131:1073–1085. [PubMed]
113. Li Y, Du H, Qin Y, et al. Activation of the signal transducers and activators of the transcription 3 pathway in alveolar epithelial cells induces inflammation and adenocarcinomas in mouse lung. Cancer Res. 2007;67:8494–8503. [PubMed]
114. Hedvat M, Huszar D, Herrmann A, et al. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell. 2009;16:487–497. [PMC free article] [PubMed]
115. Ling X, Arlinghaus RB. Knockdown of STAT3 expression by RNA interference inhibits the induction of breast tumors in immunocompetent mice. Cancer Res. 2005;65:2532–2536. [PubMed]
116. Corcoran RB, Contino G, Deshpande V, et al. STAT3 Plays a Critical Role in KRAS-Induced Pancreatic Tumorigenesis. Cancer Res. 2011;71:5020–5029. [PMC free article] [PubMed]
117. Fukuda A, Wang SC, Morris JP, 4th, et al. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell. 2011;19:441–455. [PMC free article] [PubMed]
118. Lesina M, Kurkowski MU, Ludes K, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell. 2011;19:456–469. [PubMed]
119. He G, Karin M. NF-kappaB and STAT3: Key players in liver inflammation and cancer. Cell Res. 2011;21:159–168. [PMC free article] [PubMed]
120. Li N, Grivennikov SI, Karin M. The unholy trinity: Inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell. 2011;19:429–431. [PMC free article] [PubMed]
121. Park EJ, Lee JH, Yu GY, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140:197–208. [PMC free article] [PubMed]
122. Tartour E, Pere H, Maillere B, et al. Angiogenesis and immunity: A bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev. 2011;30:83–95. [PubMed]
123. Poschke I, Mougiakakos D, Hansson J, et al. Immature immunosuppressive CD14+HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Res. 2010;70:4335–4345. [PubMed]
124. Herrmann A, Kortylewski M, Kujawski M, et al. Targeting Stat3 in the myeloid compartment drastically improves the in vivo antitumor functions of adoptively transferred T cells. Cancer Res. 2010;70:7455–7464. [PMC free article] [PubMed]
125. Studebaker AW, Storci G, Werbeck JL, et al. Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner. Cancer Res. 2008;68:9087–9095. [PubMed]
126. Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449:557–563. [PubMed]
127. Koppikar P, Lui VW, Man D, et al. Constitutive activation of signal transducer and activator of transcription 5 contributes to tumor growth, epithelial-mesenchymal transition, and resistance to epidermal growth factor receptor targeting. Clin Cancer Res. 2008;14:7682–7690. [PMC free article] [PubMed]
128. Lai SY, Childs EE, Xi S, et al. Erythropoietin-mediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma. Oncogene. 2005;24:4442–4449. [PubMed]
129. Xi S, Zhang Q, Gooding WE, et al. Constitutive activation of Stat5b contributes to carcinogenesis in vivo. Cancer Res. 2003;63:6763–6771. [PubMed]
130. Dolled-Filhart M, Camp RL, Kowalski DP, et al. Tissue microarray analysis of signal transducers and activators of transcription 3 (Stat3) and phospho-Stat3 (Tyr705) in node-negative breast cancer shows nuclear localization is associated with a better prognosis. Clin Cancer Res. 2003;9:594–600. [PubMed]
131. Diaz N, Minton S, Cox C, et al. Activation of stat3 in primary tumors from high-risk breast cancer patients is associated with elevated levels of activated SRC and survivin expression. Clin Cancer Res. 2006;12:20–28. [PubMed]
132. Berishaj M, Gao SP, Ahmed S, et al. Stat3 is tyrosine-phosphorylated through the interleukin-6/glycoprotein 130/Janus kinase pathway in breast cancer. Breast Cancer Res. 2007;9:R32. [PMC free article] [PubMed]
133. Marotta LL, Almendro V, Marusyk A, et al. The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24− stem cell-like breast cancer cells in human tumors. J Clin Invest. 2011;121:2723–2735. [PMC free article] [PubMed]
134. Nevalainen MT, Xie J, Torhorst J, et al. Signal transducer and activator of transcription-5 activation and breast cancer prognosis. J Clin Oncol. 2004;22:2053–2060. [PubMed]
135. Yamashita H, Nishio M, Ando Y, et al. Stat5 expression predicts response to endocrine therapy and improves survival in estrogen receptor-positive breast cancer. Endocr Relat Cancer. 2006;13:885–893. [PubMed]
136. Walker SR, Nelson EA, Zou L, et al. Reciprocal effects of STAT5 and STAT3 in breast cancer. Mol Cancer Res. 2009;7:966–976. [PubMed]
137. Tran TH, Utama FE, Lin J, et al. Prolactin inhibits BCL6 expression in breast cancer through a Stat5a-dependent mechanism. Cancer Res. 2010;70:1711–1721. [PMC free article] [PubMed]
138. Culig Z. Cytokine disbalance in common human cancers. Biochim Biochim Biophys Acta. 2011;1813:308–314. [PubMed]
139. Wallner L, Dai J, Escara-Wilke J, et al. Inhibition of interleukin-6 with CNTO328, an anti-interleukin-6 monoclonal antibody, inhibits conversion of androgen-dependent prostate cancer to an androgen-independent phenotype in orchiectomized mice. Cancer Res. 2006;66:3087–3095. [PubMed]
140. Dorff TB, Goldman B, Pinski JK, et al. Clinical and correlative results of SWOG S0354: a phase II trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotherapy-pretreated patients with castration-resistant prostate cancer. Clin Cancer Res. 2010;16:3028–3034. [PMC free article] [PubMed]
141. Puchalski T, Prabhakar U, Jiao Q, et al. Pharmacokinetic and pharmacodynamic modeling of an anti-interleukin-6 chimeric monoclonal antibody (siltuximab) in patients with metastatic renal cell carcinoma. Clin Cancer Res. 2010;16:1652–1661. [PubMed]
142. Nakashima Y, Kondo M, Harada H, et al. Clinical evaluation of tocilizumab for patients with active rheumatoid arthritis refractory to anti-TNF biologics: Tocilizumab in combination with methotrexate. Mod Rheumatol. 2010;20:343–352. [PubMed]
143. Garnero P, Thompson E, Woodworth T, et al. Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: Results from a substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone. Arthritis Rheum. 2010;62:33–43. [PubMed]
144. Meydan N, Grunberger T, Dadi H, et al. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature. 1996;379:645–648. [PubMed]
145. Aggarwal BB, Kunnumakkara AB, Harikumar KB, et al. Signal transducer and activator of transcription-3, inflammation, and cancer: How intimate is the relationship? Ann N Y Acad Sci. 2009;1171:59–76. [PMC free article] [PubMed]
146. Wernig G, Kharas MG, Okabe R, et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell. 2008;13:311–320. [PubMed]
147. Quintás-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: Therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115:3109–3117. [PMC free article] [PubMed]
148. Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program. 2009:636–642. [PubMed]
149. Sen M, Tosca PJ, Zwayer C, et al. Lack of toxicity of a STAT3 decoy oligonucleotide. Cancer Chemother Pharmacol. 2009;63:983–995. [PMC free article] [PubMed]
150. Boehm AL, Sen M, Seethala R, et al. Combined targeting of epidermal growth factor receptor, signal transducer and activator of transcription-3, and Bcl-X(L) enhances antitumor effects in squamous cell carcinoma of the head and neck. Mol Pharmacol. 2008;73:1632–1642. [PMC free article] [PubMed]
151. Lui VW, Boehm AL, Koppikar P, et al. Antiproliferative mechanisms of a transcription factor decoy targeting signal transducer and activator of transcription (STAT) 3: The role of STAT1. Mol Pharmacol. 2007;71:1435–1443. [PubMed]
152. Xi S, Gooding WE, Grandis JR. In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: Implications for cancer therapy. Oncogene. 2005;24:970–979. [PubMed]
153. Leong PL, Andrews GA, Johnson DE, et al. Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proc Natl Acad Sci U S A. 2003;100:4138–4143. [PMC free article] [PubMed]
154. Zhao W, Jaganathan S, Turkson J. A cell-permeable Stat3 SH2 domain mimetic inhibits Stat3 activation and induces antitumor cell effects in vitro. J Biol Chem. 2010;285:35855–35865. [PMC free article] [PubMed]
155. Zhang X, Yue P, Fletcher S, et al. A novel small-molecule disrupts Stat3 SH2 domain-phosphotyrosine interactions and Stat3-dependent tumor processes. Biochem Pharmacol. 2010;79:1398–1409. [PMC free article] [PubMed]
156. Redell MS, Ruiz MJ, Alonzo TA, et al. Stat3 signaling in acute myeloid leukemia: Ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood. 2011;117:5701–5709. [PMC free article] [PubMed]
157. Madoux F, Koenig M, Sessions H, et al. Bethesda, MD: National Center for Biotechnology Information; 2011. Modulators of STAT transcription factors for the targeted therapy of cancer (STAT3 inhibitors)
158. Nelson EA, Sharma SV, Settleman J, et al. A chemical biology approach to developing STAT inhibitors: Molecular strategies for accelerating clinical translation. Oncotarget. 2011;2:518–524. [PMC free article] [PubMed]
159. Nelson EA, Walker SR, Weisberg E, et al. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood. 2011;117:3421–3429. [PMC free article] [PubMed]
160. Nelson EA, Walker SR, Kepich A, et al. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. Blood. 2008;112:5095–5102. [PMC free article] [PubMed]
161. Li WX. Canonical and non-canonical JAK-STAT signaling. Trends Cell Biol. 2008;18:545–551. [PMC free article] [PubMed]
162. Regis G, Pensa S, Boselli D, et al. Ups and downs: The STAT1:STAT3 seesaw of interferon and gp130 receptor signalling. Semin Cell Dev Biol. 2008;19:351–359. [PubMed]
163. Yang J, Chatterjee-Kishore M, Staugaitis SM, et al. Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer Res. 2005;65:939–947. [PubMed]
164. Kumar A, Commane M, Flickinger TW, et al. Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science. 1997;278:1630–1632. [PubMed]
165. Zhang Q, Wang HY, Marzec M, et al. STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Proc Natl Acad Sci U S A. 2005;102:6948–6953. [PMC free article] [PubMed]
166. Zhang Q, Wang HY, Liu X, et al. STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression. Nat Med. 2007;13:1341–1348. [PubMed]
167. Silver DL, Naora H, Liu J, et al. Activated signal transducer and activator of transcription (STAT) 3: Localization in focal adhesions and function in ovarian cancer cell motility. Cancer Res. 2004;64:3550–3558. [PubMed]
168. Gough DJ, Corlett A, Schlessinger K, et al. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science. 2009;324:1713–1716. [PMC free article] [PubMed]
169. Reich NC. STAT3 revs up the powerhouse. Sci Signal. 2009;2:pe61. [PubMed]
170. Ng DC, Lin BH, Lim CP, et al. Stat3 regulates microtubules by antagonizing the depolymerization activity of stathmin. J Cell Biol. 2006;172:245–257. [PMC free article] [PubMed]
171. Walker SR, Chaudhury M, Nelson EA, et al. Microtubule-targeted chemotherapeutic agents inhibit signal transducer and activator of transcription 3 (STAT3) signaling. Mol Pharmacol. 2010;78:903–908. [PubMed]
172. Hazan-Halevy I, Harris D, Liu Z, et al. STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells. Blood. 2010;115:2852–2863. [PMC free article] [PubMed]
173. Kortylewski M, Xin H, Kujawski M, et al. Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell. 2009;15:114–123. [PMC free article] [PubMed]
174. Olkhanud PB, Damdinsuren B, Bodogai M, et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4 T cells to T-regulatory cells. Cancer Res. 2011;71:3505–3515. [PMC free article] [PubMed]
175. Betts BC, Abdel-Wahab O, Curran SA, et al. Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell-stimulated T cells, yet preserves immunity to recall antigen. Blood. 2011;118:5330–5339. [PMC free article] [PubMed]
176. Betts BC, St Angelo ET, Kennedy M, et al. Anti-IL-6 receptor alpha (tocilizumab) does not inhibit human monocyte-derived dendritic cell maturation or alloreactive T-cell responses. Blood. 2011;118:5340–5343. [PMC free article] [PubMed]
177. Xin H, Herrmann A, Reckamp K, et al. Anti-angiogenic and anti-metastatic activity of JAK inhibitor AZD1480. Cancer Res. 2011;71:6601–6610. [PMC free article] [PubMed]
178. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33–39. [PubMed]
179. De Miguel F, Lee SO, Onate SA, et al. Stat3 enhances transactivation of steroid hormone receptors. Nucl Recept. 2003;1:3. [PMC free article] [PubMed]
180. Barton BE, Karras JG, Murphy TF, et al. Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: Direct STAT3 inhibition induces apoptosis in prostate cancer lines. Mol Cancer Ther. 2004;3:11–20. [PubMed]
181. Aaronson DS, Muller M, Neves SR, et al. An androgen-IL-6-Stat3 autocrine loop re-routes EGF signal in prostate cancer cells. Mol Cell Endocrinol. 2007;270:50–56. [PubMed]
182. de la Iglesia N, Konopka G, Lim KL, et al. Deregulation of a STAT3-interleukin 8 signaling pathway promotes human glioblastoma cell proliferation and invasiveness. J Neurosci. 2008;28:5870–5878. [PMC free article] [PubMed]
183. de la Iglesia N, Konopka G, Puram SV, et al. Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Genes Dev. 2008;22:449–462. [PMC free article] [PubMed]
184. Morris PG, McArthur HL, Hudis C, et al. Dose-dense chemotherapy for breast cancer: What does the future hold? Future Oncol. 2010;6:951–965. [PubMed]
185. Clarke JL, Pao W, Wu N, et al. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol. 2010;99:283–286. [PMC free article] [PubMed]

Articles from Journal of Clinical Oncology are provided here courtesy of American Society of Clinical Oncology
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...