In the present study, we demonstrated that IL6 expression in TB had significant effects on OS. Recently, it has been shown that CAFs, which account for the majority of the tumor stroma, have an important role in producing factors involved in invasion and metastasis. In CRC, CAFs are known to be involved in prognostic factors such as invasion and metastasis  , and there are some reports of IL6 expression in CAFs  . Hugo et al. reported that cancer cells cause an inflammatory response in fibroblasts and promote IL6 expression . In our study, no association was found between IL6 and inflammation expressed as TILs, possibly because of the method of evaluation and the number of cases. However, there are no reports of IL6 expression in CAFs in CRC. Nonetheless, there are reports of IL6 expression from CAFs in several other carcinomas  . Qiao et al. reported that IL6 expression from CAFs is associated with poor prognosis in esophageal squamous cell carcinoma . This is the first report on IL6 expression from CAFs in the TB region, and indicates that IL6 expression is a poor prognostic factor.
TB grade was previously reported to be associated with prognosis . In our study, TB grade was not related to prognosis, possibly because of the small number of samples. The TB region strongly affects metastasis and invasion. Although the mechanism of TB involvement in prognosis is unclear, the involvement of EMT has been reported in recent years . TB in CRC has been shown to upregulate mesenchymal markers and known inducers of EMT, such as the transcription factors ZEB1 and ZEB2 . However, another report revealed that TB shows downregulation of E-cadherin but does not share other regulatory changes common to EMT, suggesting that TB formation may occur by other mechanisms  . Yamada et al. reported that ZEB1, an EMT protein, is highly expressed in stroma near TB . Our study demonstrates that IL6 expression is correlated with TB grade. As mentioned above, its involvement of TB and EMT is speculated . EMT and IL6 expression in the cancer stroma are known to be involved in miR-34A suppression . This fact proves an indirect link between TB and IL6. However, IL6-affected TB may be directly involved in EMT IL6-affected TB may be directly involved in EMT.
There are several studies of IL6 in CRC, but these mostly focused on IL6 expression in cancer cells  . Although many reports indicate that IL6 expression in cancer cells is associated with poor prognosis  , one report demonstrated that IL6 expression at other sites confers a favorable prognosis . Meanwhile, Nagasaki et al. reported that IL6 expression is higher in CAFs than in cancer cells when comparing cancer cells and CAFs isolated from human CRC . In our study, IL6 expression has been largely identified in the stroma corresponding to CAFs, and IL6 expression in cancer cells is negligible. Therefore, although IL6 produced by CAFs seems to have a strong effect on prognosis, further investigation is necessary. Many reports have examined IL6 expression by immunostaining   , but there may be many nonspecific reactions. Thus, RNA in situ measurement may provide more accurate information.
There are several limitations of our study. An increased number of cases would enable more accurate information to be obtained. In addition, expression analysis of IL6 receptor in cancer cells in the TB area should be performed.
Taken together, inhibition of IL6 expression may be a potential therapeutic strategy for the treatment of cancers in which IL6 from CAFs may have important effects.