in 1935 , rous and beard were the first to describe the progression of virus - induced papillomas to carcinomas in rabbits 1 . during subsequent decades , it has been widely accepted that the development of human cancer follows a multi - stage process involving tumor initiation , promotion and progression 2 . these stages are paralleled by an accumulation of several mutations in genes regulating critical cellular pathways , which provide a growth advantage for individual tumor cells . in this regard , only a few genetic modifications enable the clonal expansion of normal cells during tumor initiation . additional mutations further support tumor growth during promotion , and tumor cells finally develop a malignant phenotype including invasive growth and metastasis during progression 3 , 4 . concerning colorectal cancer ( crc ) , it has been known for several decades that carcinomas mostly develop from adenomas . in 1988 , vogelstein et al . described four specific mutations that accumulate during the progression of adenomas to carcinomas 5 . these mutations have subsequently been shown to involve so - called care- and gatekeeper genes , which enable genetic or epigenetic instability and support tumor growth respectively . although several other mutations involved in crc development have been added during recent years , most sporadic crcs are believed to develop as a consequence of the mutations initially described by vogelstein et al . various factors have been shown to be responsible for the accumulation of mutations in crc including inheritance and environmental factors ( e.g. composition of diet , obesity , diabetes mellitus , smoking , alcohol consumption ) 6 . of note , also chronic inflammation is regarded as an important risk factor for the development of cancer . this is especially apparent in patients with inflammatory bowel diseases ( ibd ) , which have an increased risk for the development of colitis - associated crc depending on the duration and severity of intestinal inflammation 7 . whereas the contribution of chronic inflammation to tumor development has been widely attributed to its ability to induce mutations ( e.g. through reactive oxygen or nitrogen species ) 8 , recent data propose a direct effect of inflammation on tumor growth . several pro - inflammatory cytokines released by innate and adaptive immune cells have been shown to regulate cancer cell growth and thereby contribute to tumor promotion and progression . among these , interleukin-6 ( il-6 ) seems to take a center stage in human cancer development . an increased expression of il-6 has been detected and associated with an unfavourable prognosis in patients with various types of cancer including both sporadic and colitis - associated crc . experimental studies found an activation of important oncogenic pathways in cancer cells through il-6 . in this article , we review the role of il-6 during sporadic and inflammation - associated crc development . besides data from human crc , molecular mechanisms of il-6 signaling in experimental models of crc will be discussed with an outlook on future therapeutic implications . following its initial description as a b cell differentiation factor in 1986 9 , a versatile role has been attributed to il-6 for the regulation of innate and adaptive immunity . in fact , il-6 is involved in the regulation of the acute phase response through the induction of acute phase proteins in hepatocytes , the differentiation of monocytes to macrophages , the proliferation and resistance against apoptosis of t cells and th2 cytokine production 9 - 11 . importantly , recent data suggest a critical role for il-6 during chronic inflammation , since il-6 is required for the induction of effector th17 cells and inhibits the differentiation of regulatory t cells . il-6 is produced by various cell types including monocytes , macrophages , fibroblasts , keratinocytes , endothelial cells , b cells , t cells , and also several tumor cells 12 . however , monocytes and macrophages seem to be the predominant producers of il-6 during acute and t cells during chronic inflammation 13 . in these cells , il-6 expression is regulated through the activation of several transcription factors such as nf - kb , c / ebpbeta ( caat / enhancer - binding protein beta ) or ap-1 ( activator protein 1 ) . the regulation of il-6 expression through these transcription factors enables a rather unspecific upregulation of this cytokine during nearly every type of inflammation . il-6 binds to the membrane - bound il-6 receptor alpha ( mil-6r , cd126 ) subunit of the il-6 receptor on target cells . this complex then associates with a homodimer of the second receptor subunit , glycoprotein 130 ( gp130 , cd130 ) , and thereby enables the activation of subsequent downstream signaling . this so - called  classic signaling  is restricted to cells expressing both the mil-6r subunit and gp130 . although gp130 is widely expressed , mil-6r expression is limited to hepatocytes and some leukocytes 14 . importantly , a soluble form of il-6r ( sil-6r ) enables il-6 signaling in cells that do not express mil-6r through  trans - signaling  . sil-6r is either produced by limited proteolysis of mil-6r through the metalloproteinase adam17 or translation from a splice variant of il-6r mrna 14 . sil-6r binds il-6 with a similar affinity as mil-6r and the complex of sil-6r and il-6 can interact with gp130 on target cells that do n't express mil-6r . as signal transduction during both classic and trans - signaling these include the activation of janus kinases ( jaks ) with a subsequent activation of the transcription factor signal transducer and activator of transcription 3 ( stat3 ) through phosphorylation . stat3 activation has been shown to be an important step for promotion and progression through the induction of various target genes . these target genes are involved in tumor cell survival ( e.g. bcl-2 , survivin , mcl-1 ) , proliferation ( e.g. c - myc , cyclin d1 , cyclin b ) , angiogenesis ( e.g. hif1alpha , vegf ) , metastasis ( e.g. mmp2 , mmp9 ) , cell adhesion ( e.g. icam-1 , twist1 ) , inflammation ( e.g. il-6 , il-17 , il-23 , cox2 ) and others ( for review see 15 , 16 ) . among these , suppressor of cytokine signaling 3 ( socs3 ) is a direct inhibitor of stat3 signaling . although the influence of these pathways on immune cells has been known for several years , only recent data provide a molecular insight on the importance of il-6 signaling during tumor development . concerning the role of il-6 in b cell differentiation , it 's not surprising that multiple myeloma was among the first types of cancer that have been shown to be influenced by il-6 . in fact , il-6 acts as an auto- and paracrine growth factor for myeloma cells and antibodies against il-6 inhibit myeloma cell growth in vitro and in vivo 17 . today , il-6 is regarded as an important tumor promoting factor in various types of human cancer including glioma , lymphoma , melanoma as well as breast , ovarian , pancreatic , prostate , renal and , of course , colorectal cancer . various studies have found an increased expression of il-6 in patients with crc , where il-6 levels are elevated in the serum of patients and in tumor tissue itself 18 - 20 . according to a review article by knpfer and preiss , il-6 expression can be associated with tumor stage , size , metastasis and survival of patients with crc 21 . although data on il-6 expression in sporadic crc are well proven , there is an on - going debate about the source of il-6 expression in non - inflammation - associated cancer . for instance , belluco et al . described an association of a polymorphism of the il-6 promoter with serum levels of this cytokine in patients with crc 22 . an additional mechanism could be an amplification of the il-6 gene , as reported in patients with glioblastoma , although this mechanism has not been shown for crc so far 23 . another explanation for increased il-6 levels could be an infiltration of tumors with il-6 secreting inflammatory cells as seen in colitis - associated cancer ( cac ) . as mentioned above , patients with inflammatory bowel diseases such as crohn 's disease ( cd ) and ulcerative colitis ( uc ) have an increased risk for the development of cac . for instance , the cumulative risk for the development of crc in patients with uc is about 17.8% after 30 years of disease 24 . in patients with large bowel involvement of cd , there is a 8.3% risk for crc over a period of 30 years 25 . in fact , various studies have shown that il-6 is an important regulator of ibd pathogenesis , mainly through its effect on immune cell function 11 . for instance , il-6 trans - signaling has been shown to activate t cells in the lamina propria of patients with ibd and induces resistance of these cells against apoptosis through upregulation of anti - apoptotic factors such as bcl-2 and bcl - xl 27 . due to the correlation of il-6 expression with crc prognosis and the increased expression of il-6 in patients with ibd , il-6 is thought to act as a link between chronic inflammation and tumor development . importantly , corvinus et al . could show an increased phosphorylation of stat3 in crc cells , but not in normal intestinal epithelial cells 28 . these data propose a functional relevance for il-6 directly acting on tumor cells in sporadic crc . this direct effect of il-6 on colorectal cancer cells is likely mediated through trans - signaling , as intestinal epithelial cells usually do not express mil-6r 14 . in fact , evidence for this hypothesis comes from various experimental studies in mouse models of colitis - associated cancer . in 1992 , lahm et al . were among the first to describe a growth - promoting effect of il-6 on colorectal cancer cell lines in vitro 29 . however , it was not until 2004 that becker et al . were able to show that il-6 , secreted by lamina propria t cells and macrophages , is also important for the development of cac in vivo 30 . in the widely used aom+dss mouse model of cac , the authors found an il-6 dependent growth of intestinal tumors that was dependent on il-6 trans - signaling in intestinal epithelial cells , possibly with downstream activation of stat3 . the tumor promoting effect of il-6 could be inhibited through treatment with anti - il-6r antibodies or sgp130fc , a designer variant of soluble gp130 that specifically blocks trans - signaling . similarly , grivennikov et al . found reduced tumor development in il-6 -/- mice exposed to the aom+dss model 31 . in this work , the authors underlined the importance of an il-6 dependent stat3 in tumor cells as critical for proliferation and the inhibition of apoptosis . these data were complemented by bollrath et al . showing increased cac development following aom+dss treatment in gp130y757f mice , which have stat3 hyperactivation , and attenuated tumor development in conditional knockout mice with a specific deletion of stat3 in intestinal epithelial cells 32 . the effect of stat3 on tumor cells was mediated through the expression of various regulators of g1/s and g2/m cell cycle progression . interestingly , in both studies defective il-6/stat3 signaling was impairing intestinal inflammation in aom+dss treated animals . in this regards , il-6 and stat3 were proposed as important regulators of intestinal homeostasis . in addition to il-6 and stat3 , in a study by rigby et al . the specific deletion of socs3 in intestinal epithelial cells of mice treated with aom+dss was associated with increased tumor development 33 . in contrast , overexpression of socs3 in vitro was able to reduce proliferation of crc cell lines . whereas most effects of stat3 have been attributed to a direct regulation of cell cycle progression through this transcription factor , , we were able to show that il-6 induces the expression of vegfr2 ( vascular endothelial growth factor receptor 2 ) in intestinal epithelial cells and enables an auto-/paracrine feedback loop , which promotes proliferation of tumor cells in the aom+dss model of cac through vegfr2-dependent stat3 activation 34 . despite substantial progress of crc treatment during recent years , crc still belongs to the leading causes of cancer related death in industrialized countries . therefore , new therapeutics , especially for patients with advanced disease , are desperately required . according to the growing evidence supporting a critical role for il-6/stat3 signaling during various aspects of both sporadic and inflammation - associated crc development , therapeutics targeting this pathway could be promising options for affected patients . in fact , several therapeutics inhibiting the il-6/stat3 pathway have been developed for the treatment of human disease . these include anti - il-6 or anti - il-6r antibodies , soluble gp130fc ( sgp130fc ) and selective small molecule jak inhibitors 35 ( table 1 ) . anti - il-6 antibodies were among the first therapeutics targeting the il-6/stat3 pathway to be used in clinical studies on human cancer during the 1990s . these include the treatment of multiple myeloma or aids - associated kaposi 's sarcoma 36 , 37 . however , these treatments only produced a limited response , and , as the antibody used ( be-8 ) was from murine origin , an immune response against this therapeutic was induced in treated patients 38 . as a consequence , the chimeric , murine - human monoclonal anti - il-6 antibody siltuximab was generated during subsequent years . although there are currently no data on the use of siltuximab in patients with crc , a study analyzing the effect of siltuximab in various types of solid cancer including crc has just been finished and the results are awaited eagerly ( clinicaltrials.gov identifier : nct00841191 ) . however , initial clinical studies using siltuximab in patients with metastatic renal cancer , ovarian cancer or prostate cancer provided mixed results 39 - 41 . a possible explanation might come from the fact that antibody - associated il-6 is not cleared from the circulation and thus increases systemic il-6 concentrations 35 . so far , several clinical studies have shown a promising effect of tocilizumab in chronic inflammatory diseases and led to the approval of this antibody for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis by the fda 43 . although there are preclinical data on a therapeutic effect of tocilizumab in cancer , clinical trials in human cancer are missing so far . another strategy to inhibit il-6/stat3 for instance , the small molecule jak1 and 2 inhibitor ruxolitinib has shown promising results in a clinical trial in patients with post myeloproliferative neoplasms and acute myeloid leukemia 44 . currently , there are no clinical data on the use of ruxolitinib in crc . however , cep-33779 , another jak inhibitor , could successfully reduce tumor growth in experimental cac 45 all of the treatments mentioned above inhibit both classical and trans - signaling , and therefore also block physiological functions of il-6 . in contrast , a specific inhibition of trans - signaling could be achieved by sgp130fc . sgp130fc is a designer cytokine that specifically binds il-6/sil-6r complexes and therefore only blocks trans - signaling . in fact , sgp130fc has been shown to be effective for the treatment of experimental cac in the study by becker et al . the substance will soon enter clinical development and it will be interesting to see its effect on human cancer 46 . il-6 has been shown to be an important tumor promoting cytokine that enforces proliferation and anti - apoptotic effects in tumor cells . clinical and experimental data strongly propose a contribution of il-6 signaling to the development of both sporadic and colitis - associated colorectal cancer development . in this regard , several components of the il-6 signaling pathway such as il-6 , il-6r , jak have been proposed a promising targets for crc therapy . as initial clinical studies using anti - il-6 therapy are on their way , it will be interesting to see , if preclinical data will live up to their promise .
growing evidence proposes an important role for pro - inflammatory cytokines during tumor development . 
 several experimental and clinical studies have linked the pleiotropic cytokine interleukin-6 ( il-6 ) to the pathogenesis of sporadic and inflammation - associated colorectal cancer ( crc ) . increased il-6 expression has been related to advanced stage of disease and decreased survival in crc patients . according to experimental studies , these effects are mediated through il-6 trans - signaling promoting tumor cell proliferation and inhibiting apoptosis through gp130 activation on tumor cells with subsequent signaling through janus kinases ( jaks ) and signal transducer and activator of transcription 3 ( stat3).during recent years , several therapeutics targeting the il-6/stat3 pathway have been developed and pose a promising strategy for the treatment of crc . 
 this review discusses the molecular mechanisms and possible therapeutic targets involved in il-6 signaling in crc .