Interleukin-6: a villain in the drama of pancreatic cancer development and progression

Reinhild Holmer, Freya A Goumas, Georg H Waetzig, Stefan Rose-John and Holger Kalthoff

Kiel, Germany

Interleukin-6: a villain in the drama of pancreatic cancer development and progression

Reinhild Holmer, Freya A Goumas, Georg H Waetzig, Stefan Rose-John and Holger Kalthoff

Kiel, Germany

BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a poor prognosis and little treatment options. The development and progression of the disease is fostered by inflammatory cells and cytokines. One of these cytokines is interleukin-6 (IL-6), which plays an important role in a wide range of biologic activities.

DATA SOURCES:A systematic search of PubMed was performed to identify relevant studies using key words such as interleukin-6, inflammatory cytokines, inflammation and pancreatic cancer or PDAC. Articles related to IL-6 and pancreatic cancer were systematically reviewed.

RESULTS:IL-6 is elevated in the serum of pancreatic cancer patients and correlates with cachexia, advanced tumor stage and poor survival. Its expression is enhanced by hypoxia and proteins involved in pancreatic cancer development like Kras, mesothelin or ZIP4. IL-6 in turn contributes to the generation of a pro-tumorigenic microenvironment and is probably involved in angiogenesis and metastasis. In experimental mouse models of PDAC, IL-6 was important for the development and progression of precursor lesions.

CONCLUSION:IL-6 emerges as a key player in pancreatic cancer development and progression, and hence should be considered as a new therapeutic target.

(Hepatobiliary Pancreat Dis Int 2014;13:371-380)

IL-6 signaling;

IL-6 trans-signaling;

targeted therapy;

tumor microenvironment;

tumor stroma;

pancreatic ductal adenocarcinoma;

sgp130Fc

Introduction

Pancreatic cancer is presently the fourth most common cause of cancer-related death in Europe and the only major cancer type for which no improvement in mortality rates is predicted.[1]In 2012, 103 800 Europeans were estimated to be diagnosed with pancreatic cancer and 104 500 to die from it.[2]Due to the paucity of clinical signs, late diagnosis is common, and most patients present with locally advanced or metastatic disease.[3]Thus, only a few pancreatic cancer cases are diagnosed early enough to be eligible for surgery, which offers a chance of cure. The treatment for patients with advanced disease is only palliative, focusing on managing symptoms and relieving pain and suffering. Although a number of targeted therapies have proven to be beneficial in other malignancies, most targeted therapies show no clinical benefit in pancreatic ductal adenocarcinoma (PDAC).[3-6]

One hallmark of PDAC is the presence of dense desmoplastic stroma.[7,8]It comprises various cell types, including several inflammatory cell populations that lead to an immunosuppressive milieu and, lastly, to immune privilege of the tumor.[9-12]Moreover, different inflammatory cytokines have been associated with PDAC development.[13]One of them is the multifunctional molecule interleukin-6 (IL-6). The present review is to highlight the role of IL-6 in pancreatic cancer development and progression, and to discuss the inhibition of IL-6 signaling as a new therapeutic strategy for pancreatic cancer.

Inflammatory cytokines contributing to pancreatic cancer development

PDAC: A fatal malignancy with poor prognosis

Pancreatic cancer is one of the deadliest human malignancies with incidence rates equaling mortality rates. Ninety-five percent of all pancreatic cancers are exocrine tumors of the pancreas, in particular PDAC.[14]PDAC is preceded by precursor lesions, of which pancreatic intraepithelial neoplasia (PanIN) is the most common. PanIN lesions show a high incidence of Kras mutations, and mutations of this oncogene are also a hallmark of PDAC. Kras regulates cell proliferation, survival, differentiation, migration and extracellular communication. Oncogenic Kras drives the formation and progression of pancreatic cancer precursor lesions and is required for the maintenance of invasive and metastatic disease.[15,16]

PDAC is characterized by high mortality, rapid progression, and resistance to chemo- and radiation therapy.[17]Thus, the prognosis is extremely poor with a median survival of 24.1 months for the earliest stage and 4.5 months for the most advanced stage. The mean fiveyear survival rate is only approximately 6%.[3]Radical surgical resection is considered to be the only curative option. However, only 10%-20% of all pancreatic cancer patients are candidates for resection because of extensive local disease or metastatic spread at presentation, and 80% of patients undergoing resection still develop a recurrent tumor.[18]Searching for new treatment options of PDAC therefore remains inevitable.[19]

Inflammation fostering PDAC development

The histological hallmark of PDAC is a dense stroma surrounding the malignant epithelial cells, which is referred to a desmoplastic reaction. It consists of various cell types as well as of acellular constituents. Extracellular matrix (ECM), enzymes, growth factors and cytokines compose the acellular compartment. The cellular components include fibroblasts, stellate, endothelial, endocrine, nerve and immune cells.[10,20]This microenvironment provides a milieu favoring the proliferation of malignant cells and closely resembles the fibrotic stroma seen in chronic pancreatitis.[13]Chronic pancreatitis is a well-known risk factor for PDAC. Therefore, a link between inflammation and the development of pancreatic cancer has long been recognized.[21-23]

PDAC development can be accelerated by ceruleininduced pancreatitis in genetically modified mouse models,[24,25]and inflammation promotes epithelialmesenchymal transition (EMT), invasiveness and dissemination in these models.[26]A marker of systemic inflammation, C-reactive protein (CRP), is a negative prognosticator in PDAC following resection.[11]Furthermore, activation of cyclooxygenase-2 (COX-2), nitric oxide synthetase and nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB), free radical oxygen formation and the production of the cytokines IL-1, IL-6, IL-8 and tumor necrosis factor-alpha (TNF-α) are associated with PDAC progression.[11]A COX-2 inhibitor showed a significant delay in PanIN progression in a mouse model.[27]However, a phase II study of the COX-2 inhibitor celecoxib in addition to gemcitabine and cisplatin showed no benefit over chemotherapy with gemcitabine alone.[28]

Inflammation is not only a precursor of PDAC development, but also a consequence of pancreatic cancer. Initiating Kras mutations induce the upregulation of inflammatory pathways. Furthermore, the oncogenic transcription factor c-myc, which is activated in many malignancies, remodels the tumor microenvironment via stimulation of inflammatory cells and cytokine production.[11]One pathway constitutively activated in PDAC is the NF-κB cascade. The transcription factor NF-κB contributes to the regulation of apoptosis and oncogenesis and hence facilitates tumor growth and metastasis.[13,29]Moreover, it regulates the expression of genes involved in inflammation by inducing the production of several inflammatory cytokines like IL-1β, IL-8 and TNF-α. These cytokines as well as other death ligands have been shown to increasingly enhance pro-inflammatory mechanisms resulting in invasive growth and metastases in PDAC.[17]

TNF-α acts like a double-edged sword in PDAC. On one hand, it has a tumor-promoting role. Elevated serum levels of TNF-α have been found in PDAC patients and were associated with weight loss.[13]Our group observed that treatment with TNF-α increased the invasiveness of human pancreatic cancer cellsin vitroand enhanced tumor growth as well as metastasis in mice bearing orthotopically inoculated human PDAC cells.[30]Accordingly, we found a significant reduction in tumor growth and metastasis after anti-TNF-α therapy with infliximab and etanercept.[30]Still, a recent phase I/II study using etanercept in combination with gemcitabine failed to show any significant survival improvement compared to gemcitabine alone in humans.[31]On the other hand, TNF-α has toxic effects on tumor cells in high doses. A phase I/II clinical trial showed promising results of intratumoral gene therapy with an adenoviral vector that expresses TNF-α inducible by chemotherapy and radiation.[32]Furthermore, an older phase I/II clinical study observed a beneficial outcome ofcombined TNF-α and anti-EGFR treatment in advanced pancreatic cancer patients.[33]Thus, the role of TNF-α in pancreatic cancer development is controversial, and targeted therapy using TNF-α remains challenging.

Other major pro-inflammatory cytokines involved in PDAC are IL-8 and IL-6.[13]IL-8 mainly promotes angiogenesis, but it also activates the mitogenactivated protein kinase (MAPK) pathway and fosters tumor aggressiveness and invasiveness.[34,35]IL-6 has a multifunctional role in the development and progression of pancreatic cancer by directly affecting the tumor cells as well as by modulating the tumor microenvironment.[13]Its manifold effects on pancreatic cancer development and progression are described in detail in this review.

Classic and trans-signaling of the pro-tumorigenic cytokine IL-6

IL-6 is a pleiotropic cytokine playing an important role in a wide range of biologic processes. It is involved in host immune defense as well as in the modulation of growth and differentiation in various malignancies.[36]IL-6 can be produced by a variety of cells, including lymphocytes, monocytes, macrophages, fibroblasts, endothelial cells, keratinocytes, and some tumor cells.[37]IL-6 binds to the IL-6 receptor (IL-6R), which exists in a membrane-bound (mIL-6R) and soluble form (sIL- 6R). Both require a dimer of the co-receptor gp130 for signal transduction. Signaling of IL-6 via the mIL- 6R is called classic signaling. As the mIL-6R is expressed only by a few cell types, mainly hepatocytes, neutrophils, monocytes/macrophages and some lymphocytes, classic signaling is restricted to these cells. Its action is mainly anti-inflammatory. The sIL-6R is mainly produced by protease-mediated ectodomain shedding from the cell surface and, to a minor extent, by alternative splicing. In contrast to most other soluble receptors, which are antagonists, the sIL-6R stabilizes IL-6 and, in this complex, acts as a potent agonist of gp130 signaling. gp130 is ubiquitously expressed on all cells in the body. Therefore, the IL-6/sIL-6R-complex can induce signaling also in cells lacking the IL-6R. This so-called trans-signaling mainly acts in a pro-inflammatory manner and is the preferred target of therapeutic intervention in many indications.[38-40]In analogy to other soluble cytokine receptor systems, soluble gp130 (sgp130) is the natural inhibitor of trans-signaling, and high constitutive levels of sgp130 (250-400 ng/mL) in the circulation of healthy individuals prevent global trans-signaling.[40]

IL-6 signaling activates the Janus kinases JAK1, JAK2 and TYK2 which lead to the phosphorylation of signal transducers and activators of transcription-1 and -3 (STAT1 and STAT3). STAT3 is an important regulator of a number of anti-apoptotic genes, and its activity is associated with tumor growth, survival, angiogenesis and metastatic processes.[41]In fact, dysregulation of STAT3 activation is so frequent in cancer that it is widely considered as an oncogene.[42,43]In addition to the JAK-STAT3 pathway, IL-6 activates the Ras-MAPK and phosphoinositide-3-kinase (PI3K)-Akt signaling pathways which also contribute to its anti-apoptotic and tumorigenic function.[37,44]Hence, it is not surprising that several studies revealed an association between increased serum IL-6 concentrations in patients and advanced tumor stages or short survival in various cancers like colorectal cancer, renal cell carcinoma, prostate cancer, breast cancer, multiple myeloma, nonsmall cell lung carcinoma and ovarian cancer.[36]

A key role of IL-6 in pancreatic cancer development and progression

Elevated IL-6 in the serum of PDAC patients and its correlation with a poor prognosis

It is well-established that IL-6 is elevated in the serum of pancreatic cancer patients compared with healthy controls[45-53]and those with chronic pancreatitis.[45,51,52]Microarray data comparing human PDAC tissues to matched pancreas controls showed a significant upregulation of IL-6 and its co-receptor gp130.[54]Using qPCR, Bellone et al[55]found that IL-6 was overexpressed in pancreatic cancer compared with nontumoral pancreatic tissue. In contrast, expression of the IL-6R was not significantly changed.[46,53,54]IL-6 was significantly increased in correlation with tumor stage,[45,52]size[47,51,52]and the presence of lymph node and distant metastases.[51,52]Patients with nonresectable tumors had significantly higher IL-6 serum levels than those with tumors still resectable.[52]Moreover, IL-6 serum levels correlated with worse survival of patients with pancreatic cancer[49,52,55]and a poor performance status.[49]A recent study[56]examined the impact of pro-inflammatory cytokines on the outcome of gemcitabine monotherapy in patients with advanced pancreatic cancer. Univariate and multivariate analysis for overall and progression-free survival identified high IL-6 serum levels as an independent predictor of poor survival.

Strikingly, Mroczko et al[52]reported that the measurement of IL-6 proves clinically more useful in distinguishing pancreatic cancer from healthy conditions or chronic pancreatitis than the measurementof the classic tumor markers carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) or the inflammatory molecule CRP. This is of high significance, as the diagnosis of pancreatic cancer is usually difficult and it mostly occurs too late. However, IL-6 is also elevated in a vast number of other diseases[37]and therefore not very specific in discriminating pancreatic from any other type of cancer.

Several studies[45,49,51,57,58]described higher IL-6 levels in pancreatic cancer patients suffering from cachexia. This is interesting because severe weight loss is a major side-effect of pancreatic cancer.[59,60]A polymorphism in the IL-6 gene in pancreatic cancer patients was associated with cachexia susceptibility and survival time.[61]Martignoni et al[58]found a strong IL-6 immunostaining in cancer cells from cachectic patients in contrast to tissues from patients without cachexia. Furthermore, the level of IL-6 staining in hepatocytes surrounding CD68-positive liver macrophages was significantly more intense in cachectic PDAC patients than in those without cachexia.[62]Similarly, LPS-stimulated peripheral blood mononucleated cells (PBMCs) from cachectic pancreatic cancer patients produced significantly more IL-6 than those from healthy controls.[57]Therefore, cachexia seems to be mediated by a complex interaction of different cell types in cachectic PDAC patients. These findings are in accordance with studies on other malignancies, also describing an association between IL-6 and cancer cachexia.[63-66]

While overexpression of IL-6 in pancreatic cancer tissue is well established, the literature is controversial about the cellular source of IL-6. Lesina et al[53]described macrophages as the principal IL-6 producer in an experimental mouse model of PDAC and in human tissue. In contrast, Zhang et al[67]found IL-6 expression in epithelial cells, smooth muscle actin (SMA)-positive fibroblasts and immune cells in human and murine pancreatic cancer tissues. Additionally, many pancreatic cancer cell lines express IL-6.[48,50,68]Incubation with conditioned medium from pancreatic cancer cells induced IL-6 expression in mouse primary pancreatic fibroblasts.[67]Furthermore, the IL-6 production of PBMCs isolated from cachectic patients could be stimulated by IL-6-expressing pancreatic cancer cells.[58]This argues against an exclusive IL-6 production by macrophages and rather supports the idea of a complex cross-talk between cancer cells and the tumor microenvironment. Collectively, a number of studies demonstrated the overexpression of IL-6 in pancreatic cancer patients and a correlation with cachexia, advanced tumor stage and poor survival.

IL-6 expression contributing to a pro-tumorigenic microenvironmentin vitro

Several factors influence the expression of IL-6 in PDAC cells. One of them is mesothelin. Mesothelin is a useful biomarker for pancreatic disease[69]and became well recognized when the 15-year-old Jack Andraka won both a major international science fair competition and a US Youth Award in 2012 with his idea to couple antimesothelin-antibodies to nanotubes as a dipstick test for pancreatic cancer.[70]Mesothelin expression correlates with IL-6 expression in pancreatic cancer cell lines and patient samples, and overexpression of mesothelin strongly enhances the IL-6 expression of cancer cells.[71]Interestingly, only mesothelin-overexpressing cells respond to treatment with exogenous IL-6 with enhanced proliferation and to IL-6 knockdown with decreased proliferation. This effect was not observed in cells with a normal mesothelin expression.[71]Another molecule influencing IL-6 expression is the receptor for advanced glycation endproducts (RAGE).[72]Downregulation of RAGE by shRNA significantly reduced IL-6 secretion of the human cell line Panc2.03 and the murine cell line Panc02. Furthermore, RAGE promoted the IL-6-induced phosphorylation of STAT3 and its mitochondrial localization, which occurs during autophagy. Stimulation with exogenous IL-6 increased intracellular ATP production in pancreatic cancer cells in a RAGE-dependent manner, as knockdown of RAGE by shRNA significantly diminished the ATP production.[72]Another enhancer of IL-6 expression is Kras, clearly the most important player in pancreatic tumorigenesis.[73]Furthermore, the zinc transporter ZIP4, which is overexpressed in pancreatic cancer and correlates with cancer progression, increases the expression of IL-6.[74]In addition, IL-6 expression is enhanced by hypoxia.[68,75]miR-21, a pro-tumorigenic miRNA induced by hypoxia, was found to be involved in this process, as a decreased expression of miR-21 reduced the hypoxia-induced IL-6 expression in MiaPaCa tumor sphere cells.[75]This is of interest because PDAC is a hypoxic tumor in humans.[76,77]

Treatment with exogenous IL-6 increased the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2) in some pancreatic cancer cells.[78-80]In this context, IL-6 might contribute to angiogenesis and invasion.[80]A link between IL-6 and VEGF expression was found in other malignancies.[81,82]Furthermore, IL-6 could contribute to the generation of a pro-tumorigenic environment by enhancing the expression of the Th2 cytokines IL-10 and IL-13 as well as of IL-5, IL-7 and granulocyte macrophage colony-stimulating factor (GM-CSF) inpancreatic cancer cell lines.[68]Moreover, IL-6 enhanced the expression of neuropilin-1,[68]which is associated with increased constitutive MAPK signaling, inhibition of anoikis and chemoresistance in pancreatic cancer.[83]However, treatment with exogenous IL-6 enhanced the proliferation of only some PDAC cell lines, as it is the case with the mesothelin-expressing cells.[72,80,84]

Taken together, these data show that certain protein mediators which are frequently overexpressed in pancreatic cancer, as well as hypoxia, enhance the expression of IL-6. In turn, IL-6 contributes to the generation of a pro-tumorigenic microenvironment and is probably involved in angiogenesis and metastasis. Fig. summarizes the multifaceted role of IL-6.

IL-6 favoring the development of precursor lesions and the progression to PDAC in mouse models

Studies analyzing the role of IL-6in vivowere mainly performed in the Kras mouse model. These mice carry a latent point-mutant allele of Kras (KrasG12D). Cre-mediated recombination leads to deletion of a transcriptional termination sequence and expression of the oncogenic protein. Pancreas-specific expression of Cre causes ductal lesions that recapitulate the full spectrum of human PanINs. Some of these lesions progress to invasive and metastatic adenocarcinomas.[85]Therefore, the KrasG12Dmodel is regarded as an appropriate system to study the initiation and early steps in pancreatic cancer development.

Lesina et al[53]showed that IL-6 mRNA increased over time in the pancreas of KrasG12Dmice compared with control mice. Here, IL-6 was found to be predominantly expressed by infiltrating immune cells, especially F4/80-positive macrophages, whereas acinar cells expressed only low levels of IL-6. KrasG12Dmice that do not express any IL-6 (KrasG12D; IL6-/-) developed less PanINs. However, a bone marrow transplantation of IL-6+/+cells into these mice increased the frequency of PanIN-3 lesions. Therefore, macrophage-derived IL-6 seems to be important for PanIN progression in this model. In isolated acinar cells, treatment with exogenous IL-6 induced only a weak STAT3 phosphorylation. Similarly, isolated macrophages of KrasG12Dmice were not able to stimulate STAT3 phosphorylation in these cells, even after pre-treatment with IL-6. In contrast, a fusion protein of IL-6 and the sIL-6R, termed Hyper-IL-6,[86]strongly activated STAT3 in acinar cells, suggesting a role for IL-6 trans-signaling. Moreover, KrasG12Dmice in which trans-signaling was inhibited by co-expression of an Fc fusion protein of the trans-signaling inhibitor sgp130 (KrasG12D; sgp130Fc), developed less PanINs. Thus, IL-6 trans-signaling was important for the initiation and progression of PanINs in this model.[53]However, in cell lines generated from primary tumors of the KrasG12Dmice, IL-6 alone was able to increase STAT3 phosphorylation. This suggests the occurrence of a switch towards classic IL-6 signaling at later stages in tumor development. Pancreas-specific knockout of STAT3 led to a strong reduction of PanINs. PanINs-2 and -3 were not detectable and the tumor incidence was significantly decreased.[53]A similar study published by Corcoran et al[54]in the same year confirmed the role of STAT3 in the development of the precursor lesions acinar-to-ductal metaplasias (ADMs) and PanINs.

Fig.Interleukin-6 (IL-6) is a key player in pancreatic cancer. Tumor cells and the tumor microenvironment (fibroblasts and immune cells) produce IL-6, which is enhanced by several factors. In turn, IL-6 acts on both the tumor cells and the microenvironment by upregulating several genes (in brackets) and activating many processes involved in cancer development and progression. GMCSF: granulocyte macrophage colony-stimulating factor; IL: interleukin; MMP-2: matrix metalloproteinase-2; Nrf2: nuclear factor erythroid 2-related factor 2; RAGE: receptor for advanced glycation endproducts; VEGF: vascular endothelial growth factor.

Zhang et al[67]described similar results in the elegant iKras* mouse model, in which the Kras mutation is inducible and reversible. IL-6 mRNA was elevated in iKras* pancreata with embryonic Kras activation compared to wildtype controls. iKras* IL-6-/-mice showed less ADMs and rare PanINs in contrast to iKras* mice. Interestingly, pancreatitis-driven initial PanIN formation was independent of IL-6. However, the lesions which were formed in the absence of IL-6 showed reduced activation of the MAPK, Akt and STAT3 signaling pathways and had a lower proliferation rate.[67]Strikingly, pancreatitis-induced neoplastic lesions in iKras* IL-6-/-mice regressed, whereas the lesions in iKras* mice progressed over time to high-grade PanINs.In the absence of IL-6, the stroma of PanINs was remodeled, resulting in a normal pancreatic parenchyma with some adipose tissue infiltration. PanIN elimination was due to a combination of apoptotic cell death, redifferentiation of cells toward the acinar lineage and increased proliferation of acinar cells. Furthermore, IL-6 seemed to protect cancer cells from oxidative stress by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2), a key player in the reactive oxygen species (ROS) detoxification pathway. In summary, this study showed that IL-6 switches the balance between tissuerepair and carcinogenesis in the pancreas.[67]Fukuda et al[87]also demonstrated an upregulation of IL-6 after the induction of pancreatitis. This upregulation was greatly enhanced by the Kras-mutation and diminished by STAT3 knockout. This study furthermore highlights the importance of STAT3 in PDAC development.[87]

In a subcutaneous tumor model of human pancreatic cancer cells, the effect of IL-6-knockdown by shRNA varied among different cell lines. While it caused necrosis in tumors from Capan-1 cells and retarded the growth of HPAC cells, it had no obvious effect on tumors from CFPac-1 cells.[73]However, subcutaneous models do not reflect the complex microenvironment of pancreatic cancer.[88]

Saito et al[84]suggested that IL-6 inhibits the development of liver metastasis of pancreatic cancer cells. However, the study described only a statistically significant difference between a clone with a high IL-6 production and a non-transfected control, while the frequency of liver metastases between the IL-6 high producer and a clone with no IL-6 secretion was not statistically significant. A clone that secreted low levels of IL-6 showed even more metastatic nodules than the non-producer. This questions the hypothesis that IL-6 favors metastasis. Furthermore, the study was performed in nude mice, which showed an enhanced humoral immune response against tumor cells overexpressing human IL-6. Therefore, it is difficult to distinguish which effects were due to an immune reaction against the cancer cells expressing foreign IL-6 and which effects could be attributed to a real physiological action of IL-6.[84]

In addition to the direct effects on cancer cells, IL-6 can act on the various stromal constituents of the tumor microenvironment. To our knowledge, no specific data for pancreatic cancer are available, but the general mechanisms including immune suppression and angiogenesis have recently been reviewed.[43]Conversely, some studies suggested a positive role of IL-6 trans-signaling in the mobilization of anti-tumor immunity to tumor tissues.[43]However, despite high IL-6 signaling in PDAC tissues these tumors are highly immunosuppressive and characterized by the presence of only a few tumor-specific CD8+T cells, B cells and tumor-reactive antibody producing plasma cells in the tumor mass.[10,20,89]Thus, IL-6 trans-signaling in physiologic concentrations does not seem to acutely activate the vasculature and contribute to lymphocyte trafficking in PDAC.

In summary, IL-6 was shown to play an important role in the development and progression of precursor lesions in mouse models of PDAC. Thus, IL-6 has emerged as a new target for the treatment of PDAC.[13,14]

Fighting the villain: IL-6 inhibition as a new treatment option for PDAC

As IL-6 is overexpressed in many malignancies and contributes to tumor progression, blockade of IL-6 signaling could become a new treatment option. Some clinical studies targeting IL-6 in other cancers have already been performed and were recently reviewed elsewhere.[37]The chimeric anti-IL-6 monoclonal antibody siltuximab stabilized disease in ovarian and renal cancer.[37]It furthermore led to partial or complete response in B-cell non-Hodgkin's lymphoma, multiple myeloma (MM) and Castleman's disease.[37]In castration-resistant prostate cancer, no RECIST (Response Evaluation Criteria in Solid Tumors) response was reported, but 23% of patients showed stable disease and most patients had decreased CRP plasma levels.[90]A phase II multicenter study of siltuximab, alone or in combination with dexamethasone, for patients with relapsed or refractory MM showed no responses to siltuximab monotherapy, but a 23% response rate for combination therapy.[91]Tocilizumab, a humanized anti-IL-6R antibody, suppressedin vivogrowth of human oral squamous cell carcinoma in a pre-clinical model.[92]Tocilizumab is furthermore being evaluated in current open-label phase I (USA) and II (France) trials as monotherapy in MM patients.[37]Recently, a case report described the successful use of tocilizumab for the treatment of cancer cachexia.[93]The humanized aglycosylated anti-IL-6 monoclonal antibody clazakizumab was well-tolerated in a phase IIa study in the treatment of non-small cell lung cancer-related cachexia.[94]It improved anemia and the lung symptom score, diminished weight loss and reversed fatigue.[94]

Despite the many pre-clinical studies describing the importance of IL-6 in PDAC development and progression, no clinical trials evaluating IL-6 inhibition as a treatment option in PDAC have yet been performed. Considering the devastating prognosis of PDAC patients,new therapies are urgently needed. Zhang et al[67]showed that treatment of ten-week-old KPCY mice exhibiting PanINs with an anti-IL-6 antibody reduced the number of precursor lesions. Our group recently observed that palliative and adjuvant inhibition of trans-signaling by sgp130Fc as well as inhibition of classic signaling by tocilizumab significantly reduced orthotopic tumor growth of human PDAC cells in SCID/ bg mice (manuscript in preparation). Thus, inhibiting IL-6 signaling might be a new targeted treatment option and should be evaluated in clinical studies. In this context, it will also be of particular interest whether a complete blockade of IL-6 signaling is necessary or whether selective blockade of trans-signaling is sufficient. Mostin vivomodels suggested trans-signaling as the main mechanism driving tumor growth. This inhibition could clinically be achieved by the sgp130Fc derivative FE 999301, which is so far the only specific trans-signaling inhibitor, and which is currently tested in phase I clinical trials. Blockade of trans-signaling should minimize possible side-effects of IL-6 inhibition like the risk for bacterial infections and could therefore be a superior strategy.[95,96]

As IL-6 is strongly connected to cancer cachexia, IL-6 inhibition might not only be useful in inhibiting tumor progression but also in improving the overall health status of the patient. Moreover, IL-6 has recently been linked to major depression in pancreatic cancer patients.[97]Thus, IL-6 inhibition might generally improve the quality of life in cancer patients.

Contributors:KH proposed the study. HR designed the study and, together with GFA, wrote the first draft. R-JS and WGH contributed to the critical discussion of the literature and the editing of the manuscript. KH is the guarantor.

Funding:This work was supported by grants from the Cluster of Excellence "Inflammation at Interfaces" (HR+KH+R-JS), by intramural funding from the Medical Faculty of CAU Kiel (GFA) and the DFG (SFB841, project C1; SFB877, project A1, R-JS).

Ethical approval:Not needed.

Competing interest:R-JS is a shareholder of the CONARIS Research Institute AG (Kiel, Germany), which is commercially developing sgp130Fc as a therapy for inflammatory diseases, and an inventor on gp130 patents owned by CONARIS. WGH is employed by the CONARIS Research Institute AG and an inventor on gp130 patents owned by CONARIS. All other authors declare no competing financial interests.

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Received April 1, 2014

Accepted after revision May 1, 2014

AuthorAffiliations:Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North (Holmer R and Kalthoff H) and Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery (Goumas FA), University Hospital Schleswig-Holstein, Kiel, Germany; CONARIS Research Institute AG, Kiel, Germany (Waetzig GH); and Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany (Rose-John S)

Holger Kalthoff, Professor, Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, D-24105 Kiel, Germany (Tel: +49-431-597-1938; Fax: +49-431-597-1939; Email: hkalthoff@email.uni-kiel.de)

? 2014, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(14)60259-9

Published online May 14, 2014.