It is clear that chronic inflammation is recognized as a promoting factor in tumor initiation and development including colorectal cancer[2]. The patients suffering from IBD have an increased risk of developing to colorectal cancer, in which the longstanding of colonic inflammation may play a pathogenic role in malignant transformation [6]. Although the etiology and pathology of IBD have not been defined completely, which has been recently ascribed to impaired barrier function and immune disorder resulting from the complexity genetic background and various defined or undefined environmental factors [28, 29]. It is well-established that blocking cytokines-mediated inflammatory pathways can reduce tumorigenesis of CAC, supported by several discoveries. For example, blocking TNFα pathway and IL-6 deficiency reduced tumor formation in mice treated by AOM and DSS [22, 30]. TcES treatment inhibited AOM/DSS-induced tumorigenesis by regulating both STAT3 and NF-κB signaling pathways [20]. The application of GCs in therapy of IBD has not diminished, despite of the toxicity and increased risk of infection, due to long-term administration [6, 11]. A growing number of studies have investigated the role of GCs in tumor development and revealed their distinct mechanisms that promote or inhibit cancer progression in different types of cancer, indicating that their activity was not limited to anti-inflammation [31–35]. Thus, it is impending to explore the effect and underlying mechanism of GCs in colitis-associated cancer.
In this study, DEX was administered after the second or the third cycle of DSS drinking, which simulated the fact that GCs were given to induce rapid remission after the symptoms of IBD were observed. We concluded that DEX played an anti-inflammatory role in experimental colitis in mice, evidenced by decreased histological score, releasing of TNFα, and infiltration of mature macrophagocytes. We also observed that DEX aggravated body weight loss, rectal bleeding and elevated DAI score throughout of the experiment. As supported, a previous study revealed that budesonide had both protective and deleterious effects in DSS-induced colitis, and demonstrated that budesonide impaired wound healing and weakened mucosal barrier function by inhibiting epithelial proliferation, evidenced by decreased expression of claudin-2, PCNA, cyclin D1, cytokeratin 5/8 and claudin-4 in budesonide treated mice [27]. Similarly, another study analyzed and compared the efficiency of key compounds used in the treatment of IBD, implying that budesonide, one of the synthetic glucocorticoids, had limited activity in preventing DSS-induced colitis due to its severe side effects [36]. This will mask its inhibitory effect on local inflammation and induce unfavorable outcome.
The immune cells and inflammatory mediators in the tumor microenvironment play a crucial role in tumor promotion [37]. Inflammatory response and tumorigenesis are frequently associated with dysregulation of MAPK pathways, including JNK, which is activated by pro-inflammatory cytokines [38], and has been demonstrated to take part in the survival and proliferation of tumor cells [25]. Of them, TNFα plays a critical role in inflammatory response and tumor progression by targeting both immune and tumor cells and activating various oncogenic pathways, including MAPK/JNK-AP1 pathway [39]. A previous study has demonstrated that JNK in macrophages play a critical role in inflammatory response and development of hepatocellular carcinoma using myeloid cell-specific JNK-deficient mice [40]. In the present study, we found increased staining score of p-Jnk in stromal tissues of mice with CAC or colitis, and DEX administration could alleviate the inflammation and inhibit the growth of tumors in colonic tissue in AOM/DSS-induced CAC mouse model by blocking the MAPK/JNK pathway. This was supported by a previous study that DEX administration decreased the content of JNK protein and phosphorylated JNK [41].
The fact that DEX administration from both the second cycle and the third cycle of DSS drinking significantly reduced tumor size in colon, while had no effect on total tumor number, suggesting that the first cycle of DSS administration may be critical for AOM/DSS-induced tumorigenesis. Besides, although DEX intervention at early stage showed greater suppression of colonic inflammation, the inhibitory effect on tumor progression was just as prominent as that in DEX intervention at late stage. This was at least partly ascribed to the destruction of tumor immunology due to the long-term immunosuppression by DEX administration. As supported, previous studies demonstrated that DEX could suppress the activation of T cell by inhibiting inflammatory cytokines and upregulating PD-1 expression [42, 43]. There is evidence showing that DEX administration can impair intratumoral immunity, thereby causing the failure of cancer immunotherapy in vivo [44]. These observations indicate that immunosuppression and modulation of tumor microenvironment by GCs exposure may contribute to tumor progression [45].
Recently, there was study demonstrating that DEX accelerated the onset and severity of colitis and colitis-associated cancer mediated by mTOR signaling pathway, in which mice were treated with DEX (2.5 mg/kg) at the beginning of DSS drinking [46]. Besides, another study concluded that corticosterone, which was given in feeding solution (50 mg/L) one week after DSS administration, could inhibit the inflammation but promoted the development of AOM/DSS-induced colon cancer by activating NF-κB and COX-2 [16]. This may be explained by that different options and periods of drug feeding will cause diverse effects on experimental animals. These studies suggest that GCs have different effects on tumor progression and inflammatory response, depending on the form and dosage of GCs, time and duration of drug treatment [9], predisposition of animal, the concentration and duration of DSS administration [36]. High dose and high frequency of GCs may be necessary to obtain their anti-tumor activity [47], but the prior exposure of DEX may be unfavorable, even stimulate inflammatory response [48]. Thus, to define proper dosage and time window of GCs application, robust pre-clinical studies and clinical trials are desired to carry out in the near future.
In this study, we systematically determined the different effects of GCs given at different points of time on colitis-associated tumorigenesis and tumor progression. Our results implied that DEX intervention suppressed DSS-induced colitis and the progression of AOM/DSS-induced CAC in mice. However, DEX treatment aggravated the body weight loss and rectal bleeding in mice with DSS exposure. These findings indicate that the strict selection of time and dosage in GCs treatment become crucially important whether in experimental studies or clinical practices, to gain their inhibitory activities and reduce the side effects. Thus, we need to enlarge the number of animals and subdivide groups to further clarify the different effects of GCs under different conditions. Besides, prospective clinical trials are needed to assess the effect of GCs in the progression of colitis-associated cancer.