Welcome international healthcare professionals

This site is no longer supported and will not be updated with new content. You are welcome to browse and download all content already included in the site. Please note you will have to register your email address to access the site.

You are here

Interleukin-6 signaling pathway in targeted therapy for cancer

Cancer Treatment Reviews, 7, 38, pages 904 - 910

Summary

Interleukin-6 (IL-6) is a multifunctional cytokine which plays an important role in a wide range of biologic activities in different types of cell including tumor cells. IL-6 is involved in the host immune defense mechanism as well as the modulation of growth and differentiation in various malignancies. These effects are mediated by several signaling pathways, in particular the signal transducer and transcription activator 3 (Stat3). There exists abundant evidence demonstrating that deregulated overexpression of IL-6 was associated with tumor progression through inhibition of cancer cell apoptosis, stimulation of angiogenesis, and drug resistance. Clinical studies have revealed that increased serum IL-6 concentrations in patients are associated with advanced tumor stages of various cancers (e.g., multiple myeloma, non-small cell lung carcinoma, colorectal cancer, renal cell carcinoma, prostate cancer, breast cancer and ovarian cancer) and short survival in patients. Therefore, blocking IL-6 signaling is a potential therapeutic strategy for cancer (i.e., anti-IL-6 therapy) characterized by pathological IL-6 overproduction. Preliminary clinical evidence has shown that antibody targeted IL-6 therapy was well tolerated in cancer patients. In this review, we detail the progress of the current understanding of IL-6 signaling pathway in cancer as well as an antibody targeted IL-6 therapy for human cancer.

Keywords: Interleukin-6, Stat3, Monoclonal antibodies, Targeted therapy, Cancer.

Introduction

Initially identified as a T-cell-derived regulating factor in B cell differentiation, Interleukin-6 (IL-6, a glycoprotein composed of 184 amino acids and of 26 kDa in molecular weight) is now known as a multi-functional cytokine.1, 2, 3, 4, and 5 Following the cloning of IL-6 DNA, it has been shown that IL-6 can be produced by various cell types, including tumor cells. IL-6 plays important roles in with a wide range of biological activities in immune regulation, hematopoiesis, and oncogenesis. IL-6 has been found to be involved in normal cell inflammatory processes, host immune defense mechanisms, and modulation of cellular growth. IL-6 is able to cross the blood–brain barrier and resulting synthesis of PGE2 in the hypothalamus, thereby changing the body’s temperature set point. 6 In normal muscle tissue, IL-6 stimulates energy mobilization which leads to increased body temperature. IL-6 can be secreted by macrophages in response to specific microbial molecules. IL-6 stimulates acute phase protein synthesis, and increases the production of neutrophils in the bone marrow. It promotes the growth of B cells and is antagonistic to regulatory T cells. Most importantly, IL-6 is involved in the proliferation and differentiation of various malignant tumor cells.7 and 8 For example, increased production of IL-6 has been implicated in a wide range of cancers, such as multiple myeloma (MM),9, 10, and 11 endometrial cancer, 12 lung cancer, 13 colorectal cancer, 14 renal cell carcinoma,15 and 16 cervical cancer, 17 breast cancer18 and 19 and ovarian carcinoma.20 and 21 Overexpression of both IL-6 and its receptors (IL-6R and sIL-6R) has been found in breast carcinoma, 18 prostate cancer 22 and oral squamous cell carcinoma (OSCC). 23 Elevated levels of IL-6 have been found in culture supernatant of multidrug resistant cell lines24, 25, 26, and 27 and the elevated IL-6 levels in the serum of cancer patient have been associated with poor clinical outcomes.28, 29, and 30 These findings suggest that blocking IL-6 may prove to be therapeutic for cancer in which IL-6 is overproduced.

Targeted chemotherapy is an area of great potential in cancer therapy. Targeted anti-IL-6 antibody therapy has been used in clinical trials and found to be well tolerated in patients of different cancers, including ovarian cancer, breast cancer, multiple myeloma, renal cell carcinoma, and B-lympho-proliferative disorders.28 and 31 Recent studies show that CNTO 328, a chimeric murine anti-human IL-6 antibody, can neutralize the function of IL-6 and reduce the incidence of cancer-related anorexia and cachexia without serious adverse effects.28 and 31

In the present review, we describe the advance in IL-6 signaling pathway and detail the progress of the current state-of-the-art methods to treat cancers by targeting the IL-6 antibody. We first present the biology of IL-6 and discuss IL-6 as a prognostic factor for cancer. Then, we summarize recent advances in the antibody targeted IL-6 therapy for cancer. Last, we discuss the current challenges and future prospects of targeting IL-6.

IL-6 signaling pathway in cancer

IL-6 signals through a cell-surface type I cytokine receptor complex consisting of the ligand-binding protein of IL-6Rα chain (also called CD126), and the signal-transducing component gp130 (also called CD130). IL-6 belongs to a cytokine family comprising IL-6, IL-11, leukaemia inhibitory factor (LIF), oncostatin M (OSM), ciliar neurotrophic factor (CNTF), cardiotrophin-1 (CT-1) and cardiotrophinlike cytokine (CLC).32 and 33 These cytokines share a common glycoprotein 130 receptor (gp130) component 34 that modulates the transcription of several liver-specific genes during acute inflammatory states. IL-6 affects cell behavior through receptor type I, which is a type of hematopoietic cytokine gp130 receptor expressed in lymphoid and nonlymphoid cells as well as malignant cells. There are two types of receptor for IL-6, i.e., cell membrane IL-6 receptor (IL-6R) with low affinity that forms a complex with gp130 after binding with IL-6 and activating the tyrosine kinase JAK, and a soluble IL-6 receptor (sIL-6R) which binds with IL-6 and then with the membrane receptor β chain – gp130, leading to the intracellular signal.35 and 36

The signal transduction of IL-6 involves the activation of janus kinase (JAK) tyrosine kinase family members, resulting in the activation of transcription factors of the signal transducers and activators of transcription 3 (Stat3).32 and 36 ( Fig. 1 ). A variety of events take place downstream of gp130 activation through the ligand, including the activation of cytoplasmic tyrosine kinases and the modification of transcription factors. Although gp130 has no intrinsic kinase domain, the JAK1, JAK2 and tyrosine kinase2 (TYK2) of the JAK family are found to be associated constitutively with gp130 and are activated in response to IL-6 family members.32, 33, and 37 The activation of these kinases, in turn, leads to tyrosine phosphorylation of the Stat3. Following phosphorylation and acetylation, Stat3 forms a dimer in which the SH2 domain of one phospho-Stat3 (pStat3) molecule binds to the phosphorylated Tyr705 of the other and vice versa. The pStat3 dimer then translocates from the cytoplasm to the nucleus. 38 Within the nucleus, pStat3 dimers recognize and bind a canonical 8–10 base pair inverted repeat DNA element with a consensus sequence 5′-TT(N4–6)AA-3′ that is commonly referred to as an interferon (IFN)-gamma activated sequence (GAS) element. The engagement of pStat3 dimers then initiates a change in the transcription of a number of genes including the apoptotic regulatory genes BcL-XL, MCL-1, XIAP, c-myc, and Fas. 39 The termination and modulation of the IL-6-Jak-Stat3 signalling pathway is mediated by the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated Stat) proteins ( Fig. 1 ). Stat3 also binds to p53 and inhibit its function as a regulator of apoptosis. Although the full spectrum of pStat3 target genes is not well defined, Stat3 has been identified as the prime transcriptional regulator mediating the IL-6 dependent cell growth, differentiation, and survival signals.33 and 40 This critical function of Stat3 is supported by experiments demonstrating that the transfection of dominant-negative Stat3 completely inhibits the anti-apoptotic effect of IL-6 in carcinoma cells. 41 In addition to Stat3 signaling pathway, IL-6 also activates Ras, MAPK, Cox-2, Wnt and PI3K/AKT pathways.42 and 43 These different pathways together contribute to the pro-tumorigenic and antiapoptotic activities of IL-6. In myeloma cells, at least two independent pathways by which IL-6 can activate PI3K and AKT, One pathway was mediated through RAS activation which was independent of p85, and a second that was mediated via p85 and a Stat3-containing complex. Additional studies in oncogenic, mutated RAS-containing myeloma cells confirmed the existence of the RAS-mediated pathway of PI3K-AKT activation. 44 In another study, IL-6 was dependent on c-Met signaling in activating both Ras and p44/42 MAPK by a mechanism involving the tyrosine phosphatase Shp2. 45

gr1

Fig. 1 IL-6-Jak-Stat signaling pathway. IL-6 binds to the IL-6R and induces a cascade of phosphorylation JAK kinase that leads to the activation of Stat3. Activated Stat3 translocates to the nucleus where it targets genes involved in apoptosis, proliferation and survival. SOCS and PIAS proteins negatively suppress IL-6-Jak-Stat pathway activity.

Potential roles of IL-6 in cancer

IL-6 is one of the most ubiquitously deregulated cytokines in cancer, with over-expression of IL-6 observed in virtually every tumor that has been studied.12, 46, 47, and 48 Several investigators have reported an aberrant IL-6 pathway activation in a variety of human cancer cell lines and solid tumors, including epithelial tumors of ovary, breast and prostate as well as multiple myelomas, leukemias and lymphomas.12, 21, 48, 49, 50, 51, and 52 IL-6 has been found to play an important role in various tumor behaviors including the development, cell migration, invasion, growth of malignancies, 53 proliferation, apoptosis, 54 progression,28 and 55 angiogenesis and differentiation of tumor cells. 56 For example, IL-6 aids tumor growth by inhibiting cancer cell apoptosis and inducting tumor angiogenesis,57 and 58 and contributes to the proliferation of colorectal cancer cells and other cancers, especially at the advanced stage of development. 59 IL-6 has also been shown to enhance endothelial cell migration, 60 a key step in angiogenesis, and dissemination of solid tumors. Furthermore, certain tumors including myeloma, AIDS associated Kaposi sarcomas, and some T and B-cell lymphomas are all stimulated by IL-6.29 and 61

The role of IL-6 has been related to other factors. For example, IL-6 regulates tumor cell proliferation through activation epithelial growth factor, hepatocyte growth factor and other factors.62, 63, 64, and 65 It stimulates angiogenesis and tumor vascularisation through regulates vascular endothelial growth factor (VEGF) synthesis. 66

In cancer stem cell studies, IL-6 has been implicated as a potential regulator of normal and tumor stem cell self renewal.67 and 68 Human primary mammospheres (MS) from node invasive breast carcinoma tissues expressed higher IL-6 levels than MS from matched non-neoplastic mammary glands did. IL-6 mRNA was detected only in basal-like breast carcinoma tissues, which is an aggressive breast carcinoma variant exhibiting stem cell features. IL-6 treatment triggered Notch-3-dependent upregulation of the Notch ligand Jagged-1 and promoted MS and MCF-7-derived spheroid growth. Moreover, IL-6 induced the Notch-3-dependent upregulation of the carbonic anhydrase IX gene and promoted a hypoxia-resistant/invasive phenotype in MCF-7 cells and MS. Finally, autocrine IL-6 signaling relied heavily upon Notch-3 activity to sustain the aggressive features of MCF-7-derived hypoxia-selected cells. 68 These studies support the hypothesis that IL-6 induces malignant features in Notch-3-expressing stem/progenitor cells from human ductal breast carcinoma and normal mammary glands. Recently, the IL-6 downstream protein Stat3 has been found to regulate cancer stem cells in brain tumors as well. 69 When Stat3 is inhibited, cancer stem cells in glioblastomas lose their stem-cell characteristics permanently, suggesting that Stat3 regulates the growth and self-renewal of stem cells within glioblastomas. Strikingly, a single, acute treatment with Stat3 inhibitors was effective, implying that a Stat3 inhibitor does in fact stop tumor formation. 69 In summary, the potential roles of IL-6-Jak-Stat signaling pathway in tumorigeneis have been reported in different tumor models, including ovarian,70 and 71 lung,72, 73, and 74 bladder,75, 76, and 77 breast,68, 78, and 79 colon, 80 prostate cancer,81 and 82 and multiple myeloma83 and 84 ( Table 1 ).

Table 1 Potential roles of IL-6 in tumorigenesis.

Cancer Related factor (s) Mechanism (s) Refs.
Multiple myeloma Myc, Stat3, FGFR Transformation, growth 83 and 84
Ovarian cancer Stat3, VEGF Growth, drug resistance 70 and 71
Lung cancer EGFR, Stat3 Transformation 72, 73, and 74
Bladder cancer NF-kappaB Transformation 75, 76, and 77
Breast cancer Notch, Ras, HER2 Transformation 68, 78, and 79
Colon cancer Stat3, c-Myc Proliferation 80
Prostate cancer IGF-1R, ErbB2 Growth 81 and 82

IL-6 has also been correlated with cancer drug resistance where modulating the IL-6 pathway directly affects the cellular resistance to drug treatments. For example, breast cancer cells that are sensitive to drug treatment do not express IL-6, but multi-drug resistant breast cancer cells produce high levels of IL-6. 51 IL-6 is found to be an autocrine and paracrine growth factor for prostate cancer cell lines and serves as a resistance factor for cisplatin-mediated cytotoxicity. 50 Treatment with combined cisplatin and an anti-IL-6 or IL-6R antibody reverses the cisplatin resistance of renal carcinoma cell lines in vitro. 85 Similarly, exogenous IL-6 treatment rendered tumor cells resistant to apoptosis induced by a number of cytotoxic agents including doxorubicin, VP-16 and cisplatin. 26 In contrast, specific blockade of IL-6 by antisense oligonucleotide sensitized the effect these drugs had on tumor cells. 26 Finally, we and others have shown that IL-6 production is increased in ovarian cancer cell lines resistant to paclitaxel as well as in serum and ascites of ovarian cancer patients.21, 24, 46, and 49 Stat3 is overexpressed in most paclitaxel-resistant ovarian cancer cells. Inhibition of Stat3 activation results in significant decreases in paclitaxel resistance and enhanced apoptosis. Drug-resistant recurrent tumors have significantly greater phosphorylated Stat3 (pStat3) expression as compared with matched primary tumors. Tumors with associated inflammatory cell infiltrates also have a higher proportion of cells staining intensely for nuclear phosphorylated Stat3 as compared with tumors without inflammatory infiltrates, consistent with paracrine activation of the Stat3 pathway by immune-mediated cytokines IL-6. 86 IL-6 is also promoting tumor cell to escape cell death induced by chemotherapy drugs. IL-6 increases the expression of several antiapoptotic proteins through Stat3. Together, these data strongly support the theory that IL-6 is a potent and clinically important regulator of anti-apoptotic gene expression and drug resistance.

Preclinical and translational findings indicate that IL-6 plays an important role in diverse malignancies and provides a biologic rationale for targeted therapeutic investigations. The success in treating certain diseases with drugs that antagonize IL-6 signaling has since provided further support for a pathological role of IL-6 in cancer. Various compounds antagonize IL-6 production, including corticosteroids, nonsteroidal anti-inflammatory agents, estrogens, and cytokines. 87 However, as expected, these drugs also have effects on tumor cells that far beyond their anti-IL-6 properties. 28 Current targeted biological therapies mainly focus on IL-6-conjugated toxins and mAbs against IL-6 and IL-6R.11 and 88 For example, the CNTO 328 antibody has been shown to be capable of neutralizing IL-6’s function in different types of human cancer including multiple myeloma 89 , ovarian cancer,18, 28, 90, 91, and 92 and prostate cancer. 93 Our study shows CNTO 328 specifically suppressed IL-6 induced Stat3 phosphorylation and Stat3 nuclear translocation. Treatment with CNTO 328 significantly decreased Stat3 downstream protein levels, including MCL-1, Bcl-XL and survivin. CNTO 328 also increased the cytotoxic effects of paclitaxel in a paclitaxel resistant ovarian cancer cell line in vitro (unpublished data). The down-regulation of IL-6 signaling using the CNTO 328 can enhance the antitumor activity of the proteasome inhibitor bortezomib in multiple myeloma by attenuating inducible chemoresistance. 90 For example, treatment of both IL-6-dependent and IL-6-independent multiple myeloma cell lines with CNTO 328 enhanced the cytotoxicity of bortezomib. CNTO 328 enhanced bortezomib-mediated activation of caspase-8 and caspase-9, and attenuated bortezomib-mediated induction of antiapoptotic hsp-70.89 and 90

Methods based on humanized anti-IL-6R mAb (rhPM-1, IgG1class) have also been developed, such as PM1 tested in patients with MM and rheumatoid arthritis. Other methods include using a mixture of anti-IL-6 or anti-IL-6R mAbs that can shorten the half-life of the IL-6/IL-6R complexes (from 4 days to less than 20 min) in vivo.94 and 95 Tocilizumab (namely MRA) is a humanized antihuman IL-6R antibody engineered by grafting the complementarily determining regions of a mouse anti-human IL-6R antibody into human IgG1κ to create a human antibody with a human IL-6R binding site. 95 Tocilizumab binds to the IL-6-binding site of human IL-6R and inhibits IL-6 signaling, leading to the neutralization of IL-6 activities. 96

More recently, a novel high-affinity fully human anti-IL-6 mAb, 1339 has been developed. 9 The mAb 1339 significantly inhibited the growth of multiple myeloma cells in the presence of bone marrow stromal cells in vitro. This is associated with the inhibition of phosphorylation of Stat3, extracellular signal-regulated kinase 1/2, and AKT. In addition, mAb 1339 enhanced the cytotoxicity induced by dexamethasone, and other drugs including bortezomib, lenalidomide, and perifosine in a synergistic fashion. More importantly, mAb 1339 significantly enhanced the growth inhibitory effects of dexamethasone in vivo in a SCID-hu mouse model of multiple myeloma. The mAb 1339 treatment also resulted in the inhibition of osteoclastogenesis in vitro and bone remodeling in SCID-hu mode. In addition, several small molecule compounds inhibit IL-6 or IL-6 downstream proteins have been developed and currently being evaluated in preclinical and clinical models of cancer. 42

IL-6 as a prognostic factor for cancer

IL-6 concentrations have been found to depend upon tumor stage, which is correlated with patient survival. For example, serum IL-6 concentration in patients is associated with the progression, histological grade, bowel wall invasion,97 and 98 as well as tumor size and shorter survival periods 99 of colorectal cancer. Serum IL-6 concentration has also been found to be correlated with the different stages of pancreatic cancer in patients with cachexia. 100 Higher serum and ascites levels of IL-6 have been found in patients with ovarian cancer, which have been shown to correlate with the extent of the disease and poor clinical outcome.41, 49, 50, 57, and 101 Existing studies report that the concentrations of IL-6 were significantly higher in patients with breast carcinoma in the advanced stage of the tumor, especially those having liver metastases. 102 In patients with high IL-6 concentrations, the response to treatment with chemotherapy and hormone therapy was worse. 102 Patients with higher IL-6 levels have a shorter survival while a reduction in the levels of IL-6 was visible in patients who responded better to therapy.101 and 102 Our recent study in ovarian cancer shows there is a trend toward greater IL-6 expression in the recurrent tumors as compared with the matched primary tumors. There is also an increase in the intensity of IL-6 expression in the recurrent metastatic lesion as compared with the primary metastasis. 103 These results suggest that IL-6 has the potential to be used as an independent prognostic factor for cancer. For example, the role of IL-6 as a prognostic factor has been found in stomach cancer104, 105, and 106 and breast carcinomas. 19

Targeting IL-6 with monoclonal antibody for cancer therapy

Most of the clinical experience in direct inhibition of IL-6 for cancer therapy has been with the use of murine or humanized monoclonal antibodies (McAbs). Several IL-6 antibodies have been developed in recent years and evaluated in clinical trials, such as anti-IL-6 chimeric McAb, CNTO 328 (Siltuximab) developed by Centocor and BE-8, developed by Diaclone.9, 28, and 31 Earlier investigations used BE-8, a murine anti-IL-6 monoclonal antibody which is, however, associated with several problems. 28 For example, BE-8 cannot efficiently block the daily production of IL-6 levels >8 mg.28 and 107 Moreover, it is difficult to suppress delayed IL-6 production without performing repeated dosing due to the short half-life of BE-8 (3–4 days). This is a challenge as murine antibodies generally are neutralized by human antimouse responses.28 and 108 On the other hand, CNTO 328 is a human-mouse chimeric antibody, constructed from a murine anti IL-6 McAb, with anti-tumor and anti-inflammatory activities.31 and 108 It contains the antigen-binding region of the human immunoglobulin G κ (IgG κ) immunoglobulin and the variable antigen-binding region of the murine anti-IL6 antibody. CNTO 328 has a long half-life (approximately 2 weeks) without significant immunogenicity and hence may be more beneficial clinically relative to BE-8. It also has a high affinity for recombinant as well as native IL-6. This feature enables it to inhibit the binding of IL-6 to the IL-6R, resulting in the blockade of the IL-6/IL-6R/gp130 signal transduction pathway and, subsequently, antitumor and anti-inflammatory activities.31, 93, and 108 CNTO 328 has been for a phase II multicenter trial in multiple myeloma. In addition to BE-8 and CNTO 328, several fully human McAb or humanized McAb to IL-6 have also been developed, including CNTO 136 and ALD518. 109 These IL-6 antibodies have been evaluated in clinical trials in patients with rheumatoid arthritis and systemic lupus erythematosus. 109

Targeted IL-6 as a potential clinical therapy for cancer

CNTO 328 also shows promise for ovarian cancer in clinical trials. 110 In this trial, the primary endpoint was response rate as assessed by combined RECIST and CA125 criteria. One patient of eighteen evaluable had a partial response, while seven others had periods of disease stabilization. In patients treated for 6 months, there was a significant decline in plasma levels of IL-6-regulated CCL2, CXCL12, and VEGF. Gene expression levels of factors that were reduced by CNTO 328 treatment in the patients significantly correlated with high IL-6 pathway gene expression and macrophage markers in microarray analyses of ovarian cancer biopsies. The investigators noted that the percentage of women who received clinical benefit from CNTO328 is an unusually high proportion for an experimental cancer drug study. Typically, only 5–20% of participants secure any benefit from taking untried treatments, according to the investigators. 110 In a phase I/II study of CNTO 328 in metastatic renal cell cancer, the results showed CNTO 328 was well tolerated overall, with no maximum tolerated dose or immune response observed. CNTO 328 stabilised disease in >50% of progressive metastatic renal cell cancer patients with one partial response was observed. 111 In a phase I study of prostate cancer patients, no adverse events related to CNTO 328 treatment were observed. Patients treated with CNTO 328 showed with higher levels of apoptosis markers. Following a single dose, serum concentrations of CNTO 328 declined in a biexponential manner. The study also showed a decrease in pStat3 and p44/p42 mitogen-activated protein kinases. In addition, gene expression analyses indicate down-regulation of genes immediately downstream of the IL-6 signaling pathway and key enzymes of the androgen signaling pathway. 112 In a trial for patients with metastatic castration-resistant prostate cancer who received prior docetaxel-based chemotherapy, treatment with CNTO 328 plus mitoxantrone/prednisone was well tolerated, although improvement in outcomes was not demonstrated. 113 In another phase II trial of CNTO328 in chemotherapy-pretreated patients with castration-resistant prostate cancer, treatment of CNTO 328 resulted in a PSA response rate of 3.8% and a RECIST stable disease rate of 23%. Despite evidence of CNTO-mediated IL-6 inhibition, elevated baseline IL-6 levels portended a poor prognosis. 114 These clinical trial results highlight the fact that the efficiency of CNTO 328 based strategy may be improved in combination with other chemotherapy agents.

Antibody targeted IL-6 therapy using BE-8 or CNTO 328 has also been applied in clinical trials in patients with lymphoma, myeloma, renal cell carcinoma, Castleman disease, and B-lympho-proliferative disorders.108 and 115 Improved performance status and amelioration of fever in patients without serious adverse effects have been observed. 108 Clinical trials using BE-8 to treat HIV-1-positive patients with immunoblastic or polymorphic large cell lymphoma showed that antitumor activity was not only limited and inconsistent but also associated with side effects of reduced platelet count. 116 A combination therapy of BE-8, DXM and high-dose melphalan, followed by autologous stem cell transplantation, has been shown to significantly inhibit IL-6 activity in advanced MM patients without toxic or allergic reactions. 107 However, side effects of increased incidence of thrombocytopenia and neutropenia were observed. 107 Clinical studies have shown that the inhibition of IL-6 signaling by Tocilizumab is therapeutically effective in rheumatoid arthritis, juvenile idiopathic arthritis, Castleman’s disease, and Crohn’s disease.117, 118, 119, 120, and 121 Therapies strictly targeting IL-6R using Tocilizumab are effective in treating oral squamous cell carcinoma through inhibiting angiogenesis. 23 However, there is yet no evidence showing whether it is a better strategy to inhibit the IL-6 ligand or block the IL-6R completely. In a phase I study in patients with Castleman’s disease, eighteen (78%) of 23 patients (95% CI, 56% to 93%) achieved clinical benefit response (CBR), and 12 patients (52%) demonstrated objective tumor response. The overall results suggest that CNTO328 is an effective treatment with favorable safety for the management of Castleman’s disease. 115 Recently, inhibitions of IL-6 signaling through different Jak inhibitors have been reported in the treatment of myeloproliferative neoplasms and psoriasis.122, 123, 124, and 125 ( Table 2 )

Table 2 Recent and on-going trials with the anti-IL-6 signaling drugs.

Agent Target Disease Refs.
CNTO 328 IL-6 Ovarian cancer

Renal cell cancer

Prostate cancer

Castleman disease
10, 111, 112, 113, 114, and 115
BE-8 IL-6 Lymphoma

Multiple myeloma
107 and 116
Tocilizumab IL-6R Arthritis

Castleman disease



Crohn’s disease

Oral cancer
23, 117, 118, 119, 120, and 121
Jak inhibitor Jak Myeloproliferative neoplasms

Psoriasis
122, 123, 124, and 125

Conclusions

The increasing knowledge regarding the molecular biology mechanisms of IL-6 and its interrelations to human cancer will lead to the development of novel antibody based therapies. New IL-6 target treatments not only target malignant tumor cells, but also target the interactions of cancer cells with their microenvironment. Extensive studies have identified IL-6 as a crucial part of tumor cell survival, proliferation, migration and drug resistance ( Fig. 1 , Table 1 ). The identification of novel IL-6 antibodies in the laboratory is followed by rationally designed clinical trials that validate these antibodies, either as a single agent or in combination with other chemotherapy drugs. During the last decade, several McAbs that inhibit IL-6 activity in preclinical models have been developed, with promising results both in cancer cell lines and animal models. Further investigations in xenograft tumor models are needed for predictions of the therapeutic efficacy of IL-6 McAbs. In addition, several of the IL-6 McAbs and IL-6 downstream protein small molecule inhibitors are now undergoing phases I and II clinical trials, which will continue to establish the therapeutic efficacy of anti-IL-6 therapy in human cancer ( Table 2 ).

Acknowledgements

Dr. Zhang is supported by the National Natural Science Foundation of China. Dr. Duan work is supported, in part, through a Grant from The National Cancer Institute, NIH (Nanotechnology Platform) and a Grant from the Ovarian Cancer Research Foundation (OCRF). Dr.Xue’s and Dr.Lu’s work is supported by the National Natural Science Foundation of China and the National 111 Project of China.

References

  • [1] T. Ara, Y.A. Declerck. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer. 2010;46:1223-1231 Crossref.
  • [2] T. Kishimoto. Interleukin-6: discovery of a pleiotropic cytokine. Arthritis Res Ther. 2006;8(Suppl. 2):S2 Crossref.
  • [3] C.A. Fielding, R.M. McLoughlin, L. McLeod, C.S. Colmont, M. Najdovska, D. Grail, et al. IL-6 regulates neutrophil trafficking during acute inflammation via STAT3. J Immunol. 2008;181:2189-2195
  • [4] J. Prieto. Inflammation, HCC and sex: IL-6 in the centre of the triangle. J Hepatol. 2008;48:380-381 Crossref.
  • [5] W. Paul. IL-6: a multifunctional regulator of immunity and inflammation. Jpn J Cancer Res. 1991;82:1458-1459
  • [6] W.A. Banks, A.J. Kastin, E.G. Gutierrez. Penetration of interleukin-6 across the murine blood–brain barrier. Neurosci lett. 1994;179:53-56 Crossref.
  • [7] E. Kastritis, A. Charidimou, A. Varkaris, M.A. Dimopoulos. Targeted therapies in multiple myeloma. Target Oncol. 2009;4:23-36 Crossref.
  • [8] Y. Adachi, N. Yoshio-Hoshino, N. Nishimoto. The blockade of IL-6 signaling in rational drug design. Curr Pharm Des. 2008;14:1217-1224 Crossref.
  • [9] M. Fulciniti, T. Hideshima, C. Vermot-Desroches, S. Pozzi, P. Nanjappa, Z. Shen, et al. A high-affinity fully human anti-IL-6 mAb, 1339, for the treatment of multiple myeloma. Clin Cancer Res. 2009;15:7144-7152 Crossref.
  • [10] Y. Shi, P.J. Frost, B.Q. Hoang, A. Benavides, S. Sharma, J.F. Gera, et al. IL-6-induced stimulation of c-myc translation in multiple myeloma cells is mediated by myc internal ribosome entry site function and the RNA-binding protein, hnRNP A1. Cancer Res. 2008;68:10215-10222 Crossref.
  • [11] V.M. Lauta. Interleukin-6 and the network of several cytokines in multiple myeloma: an overview of clinical and experimental data. Cytokine. 2001;16:79-86 Crossref.
  • [12] S. Bellone, K. Watts, S. Cane, M. Palmieri, M.J. Cannon, A. Burnett, et al. High serum levels of interleukin-6 in endometrial carcinoma are associated with uterine serous papillary histology, a highly aggressive and chemotherapy-resistant variant of endometrial cancer. Gynecol Oncol. 2005;98:92-98 Crossref.
  • [13] N. Songur, B. Kuru, F. Kalkan, C. Ozdilekcan, H. Cakmak, N. Hizel. Serum interleukin-6 levels correlate with malnutrition and survival in patients with advanced non-small cell lung cancer. Tumori. 2004;90:196-200
  • [14] C. Belluco, D. Nitti, M. Frantz, P. Toppan, D. Basso, M. Plebani, et al. Interleukin-6 blood level is associated with circulating carcinoembryonic antigen and prognosis in patients with colorectal cancer. Ann Surg Oncol. 2000;7:133-138 Crossref.
  • [15] O. Altundag, K. Altundag, E. Gunduz. Interleukin-6 and C-reactive protein in metastatic renal cell carcinoma. J Clin Oncol. 2005;23:1044 author reply-5.
  • [16] S. Negrier, D. Perol, C. Menetrier-Caux, B. Escudier, M. Pallardy, A. Ravaud, et al. Interleukin-6, interleukin-10, and vascular endothelial growth factor in metastatic renal cell carcinoma: prognostic value of interleukin-6 – from the Groupe Francais d’Immunotherapie. J Clin Oncol. 2004;22:2371-2378 Crossref.
  • [17] L.H. Wei, M.L. Kuo, C.A. Chen, C.H. Chou, K.B. Lai, C.N. Lee, et al. Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene. 2003;22:1517-1527 Crossref.
  • [18] I. Garcia-Tunon, M. Ricote, A. Ruiz, B. Fraile, R. Paniagua, M. Royuela. IL-6, its receptors and its relationship with bcl-2 and bax proteins in infiltrating and in situ human breast carcinoma. Histopathology. 2005;47:82-89 Crossref.
  • [19] R. Salgado, S. Junius, I. Benoy, P. Van Dam, P. Vermeulen, E. Van Marck, et al. Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int J Cancer. 2003;103:642-646 Crossref.
  • [20] I. Zakrzewska, J. Poznanski. Changes of serum il-6 and CRP after chemotherapy in patients with ovarian carcinoma. Pol Merkur Lekarski. 2001;11:210-213
  • [21] R.T. Penson, K. Kronish, Z. Duan, A.J. Feller, P. Stark, S.E. Cook, et al. Cytokines IL-1beta, IL-2, IL-6, IL-8, MCP-1, GM-CSF and TNFalpha in patients with epithelial ovarian cancer and their relationship to treatment with paclitaxel. Int J Gynecol Cancer. 2000;10:33-41 Crossref.
  • [22] Z. Culig, H. Steiner, G. Bartsch, A. Hobisch. Interleukin-6 regulation of prostate cancer cell growth. J Cell Biochem. 2005;95:497-505 Crossref.
  • [23] S. Shinriki, H. Jono, K. Ota, M. Ueda, M. Kudo, T. Ota, et al. Humanized anti-interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral squamous cell carcinoma. Clin Cancer Res. 2009;15:5426-5434 Crossref.
  • [24] Z. Duan, A.J. Feller, R.T. Penson, B.A. Chabner, M.V. Seiden. Discovery of differentially expressed genes associated with paclitaxel resistance using cDNA array technology: analysis of interleukin (IL) 6, IL-8, and monocyte chemotactic protein 1 in the paclitaxel-resistant phenotype. Clin Cancer Res. 1999;5:3445-3453
  • [25] Z. Duan, D.E. Lamendola, R.T. Penson, K.M. Kronish, M.V. Seiden. Overexpression of IL-6 but not IL-8 increases paclitaxel resistance of U-2OS human osteosarcoma cells. Cytokine. 2002;17:234-242 Crossref.
  • [26] Y.S. Pu, T.C. Hour, S.E. Chuang, A.L. Cheng, M.K. Lai, M.L. Kuo. Interleukin-6 is responsible for drug resistance and anti-apoptotic effects in prostatic cancer cells. Prostate. 2004;60:120-129 Crossref.
  • [27] Y. Wang, X.L. Niu, Y. Qu, J. Wu, Y.Q. Zhu, W.J. Sun, et al. Autocrine production of interleukin-6 confers cisplatin and paclitaxel resistance in ovarian cancer cells. Cancer Lett. 2010;295:110-123 Crossref.
  • [28] M. Trikha, R. Corringham, B. Klein, J.F. Rossi. Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res. 2003;9:4653-4665
  • [29] D.S. Hong, L.S. Angelo, R. Kurzrock. Interleukin-6 and its receptor in cancer: implications for Translational Therapeutics. Cancer. 2007;110:1911-1928 Crossref.
  • [30] Z. Chen, P.S. Malhotra, G.R. Thomas, F.G. Ondrey, D.C. Duffey, C.W. Smith, et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res. 1999;5:1369-1379
  • [31] T. Puchalski, U. Prabhakar, Q. Jiao, B. Berns, H.M. Davis. 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 Crossref.
  • [32] P.C. Heinrich, I. Behrmann, S. Haan, H.M. Hermanns, G. Muller-Newen, F. Schaper. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. 2003;374:1-20 Crossref.
  • [33] P.C. Heinrich, I. Behrmann, G. Muller-Newen, F. Schaper, L. Graeve. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J. 1998;334(Pt 2):297-314
  • [34] V.M. Lauta. A review of the cytokine network in multiple myeloma: diagnostic, prognostic, and therapeutic implications. Cancer. 2003;97:2440-2452 Crossref.
  • [35] J. Scheller, N. Ohnesorge, S. Rose-John. Interleukin-6 trans-signalling in chronic inflammation and cancer. Scand J Immunol. 2006;63:321-329 Crossref.
  • [36] K. Imada, W.J. Leonard. The Jak-STAT pathway. Mol Immunol. 2000;37:1-11 Crossref.
  • [37] V. Calo, M. Migliavacca, V. Bazan, M. Macaluso, M. Buscemi, N. Gebbia, et al. STAT proteins: from normal control of cellular events to tumorigenesis. J Cell Physiol. 2003;197:157-168 Crossref.
  • [38] D.E. Levy, C.K. Lee. What does Stat3 do?. J Clin Invest. 2002;109:1143-1148
  • [39] J.E. Darnell Jr. STATs and gene regulation. Science. 1997;277:1630-1635
  • [40] H. Yu, R. Jove. The STATs of cancer – new molecular targets come of age. Nat Rev Cancer. 2004;4:97-105 Crossref.
  • [41] C.M. Leu, F.H. Wong, C. Chang, S.F. Huang, C.P. Hu. Interleukin-6 acts as an antiapoptotic factor in human esophageal carcinoma cells through the activation of both STAT3 and mitogen-activated protein kinase pathways. Oncogene. 2003;22:7809-7818 Crossref.
  • [42] T. Ara, Y.A. Declerck. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer. 2010;46:1223-1231 Crossref.
  • [43] S.H. Jee, C.Y. Chu, H.C. Chiu, Y.L. Huang, W.L. Tsai, Y.H. Liao, et al. Interleukin-6 induced basic fibroblast growth factor-dependent angiogenesis in basal cell carcinoma cell line via JAK/STAT3 and PI3-kinase/Akt pathways. J Invest Dermatol. 2004;123:1169-1175 Crossref.
  • [44] J.H. Hsu, Y. Shi, P. Frost, H. Yan, B. Hoang, S. Sharma, et al. Interleukin-6 activates phosphoinositol-3’ kinase in multiple myeloma tumor cells by signaling through RAS-dependent and, separately, through p85-dependent pathways. Oncogene. 2004;23:3368-3375 Crossref.
  • [45] H. Hov, E. Tian, T. Holien, R.U. Holt, T.K. Vatsveen, U.M. Fagerli, et al. C-Met signaling promotes IL-6-induced myeloma cell proliferation. Eur J of Haematol. 2009;82:277-287 Crossref.
  • [46] G. Scambia, U. Testa. Benedetti Panici P, Foti E, Martucci R, Gadducci A, et al. Prognostic significance of interleukin 6 serum levels in patients with ovarian cancer. Br J Cancer. 1995;71:354-356
  • [47] D.J. George, S. Halabi, T.F. Shepard, B. Sanford, N.J. Vogelzang, E.J. Small, et al. The prognostic significance of plasma interleukin-6 levels in patients with metastatic hormone-refractory prostate cancer: results from cancer and leukemia group B 9480. Clin Cancer Res. 2005;11:1815-1820 Crossref.
  • [48] M.G. Alexandrakis, F.H. Passam, D.S. Kyriakou, A.V. Christophoridou, K. Perisinakis, A. Hatzivasili, et al. Serum level of interleukin-16 in multiple myeloma patients and its relationship to disease activity. Am J Hematol. 2004;75:101-106 Crossref.
  • [49] J.S. Berek, C. Chung, K. Kaldi, J.M. Watson, R.M. Knox, O. Martinez-Maza. Serum interleukin-6 levels correlate with disease status in patients with epithelial ovarian cancer. Am J Obstet Gynecol. 1991;164:1038-1042 discussion 42-3
  • [50] N. Borsellino, A. Belldegrun, B. Bonavida. Endogenous interleukin 6 is a resistance factor for cis-diamminedichloroplatinum and etoposide-mediated cytotoxicity of human prostate carcinoma cell lines. Cancer Res. 1995;55:4633-4639
  • [51] D. Conze, L. Weiss, P.S. Regen, A. Bhushan, D. Weaver, P. Johnson, et al. Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells. Cancer Res. 2001;61:8851-8858
  • [52] W. Cozen, P.S. Gill, S.A. Ingles, R. Masood, O. Martinez-Maza, M.G. Cockburn, et al. IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma. Blood. 2004;103:3216-3221 Crossref.
  • [53] F.R. Santer, K. Malinowska, Z. Culig, I.T. Cavarretta. Interleukin-6 trans-signalling differentially regulates proliferation, migration, adhesion and maspin expression in human prostate cancer cells. Endocr-relat cancer. 2010;17:241-253 Crossref.
  • [54] K. Suchi, H. Fujiwara, S. Okamura, H. Okamura, S. Umehara, M. Todo, et al. Overexpression of Interleukin-6 suppresses cisplatin-induced cytotoxicity in esophageal squamous cell carcinoma cells. Anticancer Res. 2011;31:67-75
  • [55] E.T. Keller, J. Wanagat, W.B. Ershler. Molecular and cellular biology of interleukin-6 and its receptor. Front Biosci. 1996;1:d340-d357
  • [56] S. Akira, T. Taga, T. Kishimoto. Interleukin-6 in biology and medicine. Adv Immunol. 1993;54:1-78 Crossref.
  • [57] M.B. Nilsson, R.R. Langley, I.J. Fidler. Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res. 2005;65:10794-10800
  • [58] A. Saidi, M. Hagedorn, N. Allain, C. Verpelli, C. Sala, L. Bello, et al. Combined targeting of interleukin-6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness. Int j cancer J Int du cancer. 2009;125:1054-1064 Crossref.
  • [59] W. Brozek, G. Bises, T. Girsch, H.S. Cross, H.E. Kaiser, M. Peterlik. Differentiation-dependent expression and mitogenic action of interleukin-6 in human colon carcinoma cells: relevance for tumour progression. Eur J Cancer. 2005;41:2347-2354 Crossref.
  • [60] J.S. Yao, W. Zhai, W.L. Young, G.Y. Yang. Interleukin-6 triggers human cerebral endothelial cells proliferation and migration: the role for KDR and MMP-9. Biochem Biophys Res Commun. 2006;342:1396-1404 Crossref.
  • [61] L. Fassone, G. Gaidano, C. Ariatti, D. Vivenza, D. Capello, A. Gloghini, et al. The role of cytokines in the pathogenesis and management of AIDS-related lymphomas. Leuk Lymphoma. 2000;38:481-488 Crossref.
  • [62] R. Sun, B. Jaruga, S. Kulkarni, H. Sun, B. Gao. IL-6 modulates hepatocyte proliferation via induction of HGF/p21cip1: regulation by SOCS3. Biochem Biophys Res Commun. 2005;338:1943-1949 Crossref.
  • [63] S.L. Grant, A. Hammacher, A.M. Douglas, G.A. Goss, R.K. Mansfield, J.K. Heath, et al. An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells. Oncogene. 2002;21:460-474 Crossref.
  • [64] A. Badache, N.E. Hynes. Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells. Cancer Res. 2001;61:383-391
  • [65] Y.D. Wang, J. De Vos, M. Jourdan, G. Couderc, Z.-Y. Lu, J.-F. Rossi, et al. Cooperation between heparin-binding EGF-like growth factor and interleukin-6 in promoting the growth of human myeloma cells. Oncogene. 2002;21:2584-2592 Crossref.
  • [66] B. Dankbar, T. Padro, R. Leo, B. Feldmann, M. Kropff, R.M. Mesters, et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood. 2000;95:2630-2636
  • [67] Z.T. Schafer, J.S. Brugge. IL-6 involvement in epithelial cancers. J Clin Invest. 2007;117:3660-3663 Crossref.
  • [68] P. Sansone, G. Storci, S. Tavolari, T. Guarnieri, C. Giovannini, M. Taffurelli, 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 Crossref.
  • [69] M.M. Sherry, A. Reeves, J.K. Wu, B.H. Cochran. STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem cells. 2009;27:2383-2392 Crossref.
  • [70] D.G. Rosen, I. Mercado-Uribe, G. Yang, R.C. Bast Jr., H.M. Amin, R. Lai, et al. The role of constitutively active signal transducer and activator of transcription 3 in ovarian tumorigenesis and prognosis. Cancer. 2006;107:2730-2740 Crossref.
  • [71] M. Huang, C. Page, R.K. Reynolds, J. Lin. Constitutive activation of stat 3 oncogene product in human ovarian carcinoma cells. Gynecol Oncol. 2000;79:67-73 Crossref.
  • [72] S.P. Gao, K.G. Mark, K. Leslie, W. Pao, N. Motoi, W.L. Gerald, 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 Crossref.
  • [73] K.M. Quesnelle, A.L. Boehm, J.R. Grandis. STAT-mediated EGFR signaling in cancer. J Cellular Biochem. 2007;102:311-319 Crossref.
  • [74] S. Grivennikov, M. Karin. Autocrine IL-6 signaling: a key event in tumorigenesis?. Cancer Cell. 2008;13:7-9 Crossref.
  • [75] M. Okamoto, H. Kawamata, K. Kawai, R. Oyasu. Enhancement of transformation in vitro of a nontumorigenic rat urothelial cell line by interleukin 6. Cancer Res. 1995;55:4581-4585
  • [76] M. Okamoto, R. Oyasu. Effect of transfected interleukin-6 in non-tumorigenic and tumorigenic rat urothelial cell lines. Int J Cancer J Int du cancer. 1996;68:616-621 Crossref.
  • [77] A.G. Eliopoulos, M. Stack, C.W. Dawson, K.M. Kaye, L. Hodgkin, S. Sihota, et al. Epstein-Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-kappaB pathway involving TNF receptor-associated factors. Oncogene. 1997;14:2899-2916 Crossref.
  • [78] K. Leslie, S.P. Gao, M. Berishaj, K. Podsypanina, H. Ho, L. Ivashkiv, et al. Differential interleukin-6/Stat3 signaling as a function of cellular context mediates Ras-induced transformation. Breast cancer research: BCR. 2010;12:R80 Crossref.
  • [79] Z.C. Hartman, X.Y. Yang, O. Glass, G. Lei, T. Osada, S.S. Dave, et al. HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis. Cancer Res. 2011;71:4380-4391 Crossref.
  • [80] E. Foran, M.M. Garrity-Park, C. Mureau, J. Newell, T.C. Smyrk, P.J. Limburg, et al. Upregulation of DNA methyltransferase-mediated gene silencing, anchorage-independent growth, and migration of colon cancer cells by interleukin-6. Molecular cancer research: MCR. 2010;8:471-481 Crossref.
  • [81] A. Rojas, G. Liu, I. Coleman, P.S. Nelson, M. Zhang, R. Dash, et al. IL-6 promotes prostate tumorigenesis and progression through autocrine cross-activation of IGF-IR. Oncogene. 2011;30:2345-2355 Crossref.
  • [82] Y. Qiu, L. Ravi, H.J. Kung. Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells. Nature. 1998;393:83-85
  • [83] S. Rutsch, V.T. Neppalli, D.M. Shin, W. DuBois, H.C. Morse 3rd, H. Goldschmidt, et al. IL-6 and MYC collaborate in plasma cell tumor formation in mice. Blood. 2010;115:1746-1754 Crossref.
  • [84] H. Ishikawa, N. Tsuyama, S. Liu, S. Abroun, F.J. Li, K. Otsuyama, et al. Accelerated proliferation of myeloma cells by interleukin-6 cooperating with fibroblast growth factor receptor 3-mediated signals. Oncogene. 2005;24:6328-6332 Crossref.
  • [85] Y. Mizutani, B. Bonavida, Y. Koishihara, K. Akamatsu, Y. Ohsugi, O. Yoshida. Sensitization of human renal cell carcinoma cells to cis-diamminedichloroplatinum(II) by anti-interleukin 6 monoclonal antibody or anti-interleukin 6 receptor monoclonal antibody. Cancer Res. 1995;55:590-596
  • [86] Z. Duan, R. Foster, D. Bell, J. Mahoney, K. Wolak, A. Vaidya, et al. Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer. Clin Cancer Res. 2006;:12
  • [87] M.L. Varterasian. Advances in the biology and treatment of multiple myeloma. Curr Opin Oncol. 1999;11:3-8 Crossref.
  • [88] G. Mantovani, A. Maccio, P. Lai, M. Ghiani, E. Turnu, G.S. Del Giacco. Membrane-bound/soluble IL-2 receptor (IL-2R) and levels of IL-1 alpha, IL-2, and IL-6 in the serum and in the PBMC culture supernatants from 17 patients with hematological malignancies. Cell Biophys. 1995;27:1-14
  • [89] P.M. Voorhees, Q. Chen, D.J. Kuhn, G.W. Small, S.A. Hunsucker, J.S. Strader, et al. Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clin Cancer Res. 2007;13:6469-6478 Crossref.
  • [90] P.M. Voorhees, Q. Chen, G.W. Small, D.J. Kuhn, S.A. Hunsucker, J.A. Nemeth, et al. Targeted inhibition of interleukin-6 with CNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone-mediated cell death. Br J Haematol. 2009;145:481-490 Crossref.
  • [91] A. Tomillero, M.A. Moral. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009;31:47-57
  • [92] I.T. Cavarretta, H. Neuwirt, G. Untergasser, P.L. Moser, M.H. Zaki, H. Steiner, et al. The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1. Oncogene. 2007;26:2822-2832 Crossref.
  • [93] L. Wallner, J. Dai, J. Escara-Wilke, J. Zhang, Z. Yao, Y. Lu, 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 Crossref.
  • [94] R. Savino, L. Ciapponi, A. Lahm, A. Demartis, A. Cabibbo, C. Toniatti, et al. Rational design of a receptor super-antagonist of human interleukin-6. EMBO J. 1994;13:5863-5870
  • [95] K. Sato, M. Tsuchiya, J. Saldanha, Y. Koishihara, Y. Ohsugi, T. Kishimoto, et al. Reshaping a human antibody to inhibit the interleukin 6-dependent tumor cell growth. Cancer Res. 1993;53:851-856
  • [96] M. Mihara, K. Kasutani, M. Okazaki, A. Nakamura, S. Kawai, M. Sugimoto, et al. Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. Int Immunopharmacol. 2005;5:1731-1740 Crossref.
  • [97] J. Kaminska, M.P. Nowacki, M. Kowalska, A. Rysinska, M. Chwalinski, M. Fuksiewicz, et al. Clinical significance of serum cytokine measurements in untreated colorectal cancer patients: soluble tumor necrosis factor receptor type I–an independent prognostic factor. Tumour Biol. 2005;26:186-194 Crossref.
  • [98] F. Esfandi, S. Mohammadzadeh Ghobadloo, G. Basati. Interleukin-6 level in patients with colorectal cancer. Cancer Lett. 2006;244:76-78 Crossref.
  • [99] N.I. Nikiteas, N. Tzanakis, M. Gazouli, G. Rallis, K. Daniilidis, G. Theodoropoulos, et al. Serum IL-6, TNFalpha and CRP levels in Greek colorectal cancer patients: prognostic implications. World J Gastroenterol. 2005;11:1639-1643
  • [100] S. Okada, T. Okusaka, H. Ishii, A. Kyogoku, M. Yoshimori, N. Kajimura, et al. Elevated serum interleukin-6 levels in patients with pancreatic cancer. Jpn J Clin Oncol. 1998;28:12-15 Crossref.
  • [101] M. Plante, S.C. Rubin, G.Y. Wong, M.G. Federici, C.L. Finstad, G.A. Gastl. Interleukin-6 level in serum and ascites as a prognostic factor in patients with epithelial ovarian cancer. Cancer. 1994;73:1882-1888 Crossref.
  • [102] G.J. Zhang, I. Adachi. Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma. Anticancer Res. 1999;19:1427-1432
  • [103] Y. Guo, J. Nemeth, C. O’Brien, M. Susa, X. Liu, Z. Zhang, et al. Effects of siltuximab on the IL-6-induced signaling pathway in ovarian cancer. Clin Cancer Res. 2010;16:5759-5769 Crossref.
  • [104] T. Ashizawa, R. Okada, Y. Suzuki, M. Takagi, T. Yamazaki, T. Sumi, et al. Clinical significance of interleukin-6 (IL-6) in the spread of gastric cancer: role of IL-6 as a prognostic factor. Gastric Cancer. 2005;8:124-131 Crossref.
  • [105] S.P. Huang, M.S. Wu, C.T. Shun, H.P. Wang, M.T. Lin, M.L. Kuo, et al. Interleukin-6 increases vascular endothelial growth factor and angiogenesis in gastric carcinoma. J Biomed Sci. 2004;11:517-527
  • [106] C.W. Wu, S.R. Wang, M.F. Chao, T.C. Wu, W.Y. Lui. K, et al. Serum interleukin-6 levels reflect disease status of gastric cancer. Am J Gastroenterol. 1996;91:1417-1422
  • [107] P. Moreau, J.L. Harousseau, J. Wijdenes, N. Morineau, N. Milpied, R. Bataille. A combination of anti-interleukin 6 murine monoclonal antibody with dexamethasone and high-dose melphalan induces high complete response rates in advanced multiple myeloma. Br J Haematol. 2000;109:661-664 Crossref.
  • [108] B. Ahmed, J.A. Tschen, P.R. Cohen, M.H. Zaki, P.L. Rady, S.K. Tyring, et al. Cutaneous castleman’s disease responds to anti interleukin-6 treatment. Mol Cancer Ther. 2007;6:2386-2390 Crossref.
  • [109] N. Nishimoto. Interleukin-6 as a therapeutic target in candidate inflammatory diseases. Clin Pharmacol Ther. 2010;87:483-487
  • [110] J. Coward, H. Kulbe, P. Chakravarty, D. Leader, V. Vassileva, D.A. Leinster, et al. Interleukin-6 as a therapeutic target in human ovarian cancer. Clin Cancer Res. 2011;17:6083-6096 Crossref.
  • [111] J.F. Rossi, S. Negrier, N.D. James, I. Kocak, R. Hawkins, H. Davis, et al. A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer. Br J Cancer. 2010;103:1154-1162 Crossref.
  • [112] J. Karkera, H. Steiner, W. Li, V. Skradski, P.L. Moser, S. Riethdorf, et al. The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study. Prostate. 2011;71:1455-1465 Crossref.
  • [113] K. Fizazi, J.S. De Bono, A. Flechon, A. Heidenreich, E. Voog, N.B. Davis, et al. Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer. Eur J Cancer. 2012;48:85-93
  • [114] T.B. Dorff, B. Goldman, J.K. Pinski, P.C. Mack, P.N. Lara Jr., P.J. Van Veldhuizen, 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 Crossref.
  • [115] F. van Rhee, L. Fayad, P. Voorhees, R. Furman, S. Lonial, H. Borghaei, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease. J Clin Oncol: Official J Am Soc Clin Oncol. 2010;28:3701-3708 Crossref.
  • [116] D. Emilie, J. Wijdenes, C. Gisselbrecht, B. Jarrousse, E. Billaud, J.Y. Blay, et al. Administration of an anti-interleukin-6 monoclonal antibody to patients with acquired immunodeficiency syndrome and lymphoma: effect on lymphoma growth and on B clinical symptoms. Blood. 1994;84:2472-2479
  • [117] N. Nishimoto, K. Yoshizaki, N. Miyasaka, K. Yamamoto, S. Kawai, T. Takeuchi, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;50:1761-1769 Crossref.
  • [118] M. Mihara, N. Nishimoto, Y. Ohsugi. The therapy of autoimmune diseases by anti-interleukin-6 receptor antibody. Expert Opin Biol Ther. 2005;5:683-690 Crossref.
  • [119] M.B. Nilsson, R.R. Langley, I.J. Fidler. Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res. 2005;65:10794-10800
  • [120] S. Yokota, T. Imagawa, M. Mori, T. Miyamae, N. Nishimoto, T. Kishimoto. Phase II trial of anti-IL-6 receptor antibody (MRA) for systemic-onset juvenile idiopathic arthritis. Autoimmunity Rev.. 2004;3:599-600 Crossref.
  • [121] M. Plante, S.C. Rubin, G.Y. Wong, M.G. Federici, C.L. Finstad, G.A. Gastl. Interleukin-6 level in serum and ascites as a prognostic factor in patients with epithelial ovarian cancer. Cancer. 1994;73:1882-1888 Crossref.
  • [122] R.A. Mesa. Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis. IDrugs: The Inves Drugs J.. 2010;13:394-403
  • [123] M.A. Dawson, J.E. Curry, K. Barber, P.A. Beer, B. Graham, J.F. Lyons, et al. AT9283, a potent inhibitor of the Aurora kinases and Jak2, has therapeutic potential in myeloproliferative disorders. Br J Haematol. 2010;150:46-57
  • [124] A. Pardanani, A.M. Vannucchi, F. Passamonti, F. Cervantes, T. Barbui, A. Tefferi. JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations. Leukemia: (Official J Leukemia Soc Am, Leukemia Res Fund, UK). 2011;25:218-225 Crossref.
  • [125] A.D. William, A.C. Lee, S. Blanchard, A. Poulsen, E.L. Teo, H. Nagaraj, et al. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1. 1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med Chem. 2011;54:4638-4658 Crossref.

Footnotes

a The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China

b Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, USA

c The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, PR China

d Biomedical Engineering and Biomechanics Center, Xi’an Jiaotong University, Xi’an, PR China

lowast Corresponding author. Address: Department of Obstetrics and Gynecology, Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China. Tel.: +11 86 371 66991970; fax: +11 86 371 66991971.