Pathogenesis Of Colitis-associated Cancer Research Articles

Non‐coding RNAs and colitis‐associated cancer: Mechanisms and clinical applications

Colitis-associated cancer (CAC) is one of the most severe complications of inflammatory bowel disease (IBD), which has caused a worse survival rate in IBD patients. Although the exact aetiology and pathogenesis of CAC are not completely elucidated, evidence indicates that non-coding RNAs are closely involved and play a key role. This review aims to summarise the major findings of non-coding RNAs in the development of CAC and present the potential mechanistic links between non-coding RNAs and CAC pathogenesis. The results show that non-coding RNAs can hinder DNA mismatch repair proteins and obstruct chromosome passenger complexes to increase microsatellite instability and accumulate chromosomal instability, respectively. The data also suggest that DNA promoter methylation or RNA methylation modifications of non-coding RNA are the main mechanisms to regulate oncogene or tumour suppressor expression during the CAC progression. Other factors, including gut microbiota perturbations, immune dysregulation and barrier dysfunction, are also regulated and influenced by non-coding RNAs. Besides, non-coding RNAs as molecular managers are associated with multiple critical signalling pathways governing the initiation, progression and metastasis of CAC, including the janus kinase/signal transducer and activator of transcription (JAK/STAT), nuclear factor-kappa B (NF-κB), extracellular signal-regulated kinase (ERK), Toll-like receptor 4 (TLR4), Wnt/β-catenin and phosphatidylinositol 3-Kinase/Protein Kinase B (PI3K/AKT) pathways. In addition, non-coding RNAs can be detected in colon tissues or blood, and their aberrant expressions and diagnostic and prognostic roles are also discussed and confirmed in CAC patients. It is believed that a deepening understanding of non-coding RNAs in CAC pathogenesis may prevent the progression to carcinogenesis, and will offer new effective therapies for CAC patients.

The HIF-prolyl hydroxylases have distinct and non-redundant biological roles in the pathogenesis of colitis-associated cancer

Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD). HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) control cellular adaption to hypoxia and are considered promising therapeutic targets in IBD. However, their relevance in the pathogenesis of CAC remains elusive. We induced CAC in Phd1-/-, Phd2+/-, Phd3-/-, and WT mice with azoxymethane (AOM) and dextran sodium sulfate (DSS). Phd1-/- mice were protected against chronic colitis and displayed diminished CAC growth compared to WT mice. In Phd3 -/- mice, colitis activity and CAC growth remained unaltered. In Phd2+/- mice, colitis activity was unaffected, but CAC growth was aggravated. Mechanistically, Phd2 deficiency (i) increased the number of tumor-associated macrophages (TAMs) in AOM/DSS-induced tumors, (ii) promoted the expression of EGFR ligand epiregulin ( Ereg) in macrophages, and (iii) augmented signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling which at least in part contributed to aggravated tumor cell proliferation in colitis-associated tumors. Consistently, Phd2 deficiency in hematopoietic ( Vav:Cre-Phd2f/f) but not in intestinal epithelial cells ( Villin:Cre-Phd2f/f) increased CAC growth. In conclusion, the three different PHD isoenzymes have distinct and non-redundant, either promoting (PHD1), diminishing (PHD2), or neutral effects (PHD3) on CAC growth. KBK received funding from the German Cancer Aid. MJS. received funding from the German Research Foundation (DFG; STR 1570/1-1) and the Braun Foundation (Braun®; BBST-D-18-00018). MSch received funding from the German Federal Ministry of Education and Research (BMBF; 031L0084). JMH received funding from the Heidelberg Stiftung Chirurgie. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis-associated cancer.

BackgroundMitochondria are key regulators in cell proliferation and apoptosis. Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis. This study aimed to investigate whether mitochondrial transcription factor A (TFAM), a key regulator of mitochondrial DNA transcription and replication, is involved in the initiation and progression of colitis‐associated cancer (CAC).MethodsTFAM expression was examined in tissue samples of inflammatory bowel diseases (IBD) and CAC by immunohistochemistry. Intestinal epithelial cell (IEC)‐specific TFAM‐knockout mice (TFAM △IEC) and colorectal cancer (CRC) cells with TFAM knockdown or overexpression were used to evaluate the role of TFAM in colitis and the initiation and progression of CAC. The underlying mechanisms of TFAM were also explored by analyzing mitochondrial respiration function and biogenesis.ResultsThe expression of TFAM was downregulated in active IBD and negatively associated with the disease activity. The downregulation of TFAM in IECs was induced by interleukin‐6 in a signal transducer and activator of transcription 3 (STAT3)/miR‐23b‐dependent manner. In addition, TFAM knockout impaired IEC turnover to promote dextran sulfate sodium (DSS)‐induced colitis in mice. Of note, TFAM knockout increased the susceptibility of mice to azoxymethane/DSS‐induced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis‐associated tumorigenesis. By contrast, TFAM expression was upregulated in CAC tissues and contributed to cell growth. Furthermore, it was demonstrated that β‐catenin induced the upregulation of TFAM through c‐Myc in CRC cells. Mechanistically, TFAM promoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity.ConclusionsTFAM plays a dual role in the initiation and progression of CAC, providing a novel understanding of CAC pathogenesis.

TRIM21 Is Decreased in Colitis-associated Cancer and Negatively Regulates Epithelial Carcinogenesis.

Tripartite motif-containing (TRIM)21 is reported to be associated with the regulation of immune response in gut mucosa. Here we studied the underlying mechanisms of TRIM21 in the pathogenesis of colitis-associated cancer (CAC). We analyzed TRIM21 expression in tumor tissues from patients with colorectal cancer (CRC) and ulcerative colitis (UC)-associated cancer by immunohistochemistry and real-time polymerase chain reaction and established a CAC model in TRIM21-∕- and wild type mice by azoxymethane (AOM) and dextran sodium sulfate (DSS). Associated gene expression of tumor cell proliferation, adhesion, tissue remodeling and angiogenesis, and inflammatory cytokines were examined in normal colon and CAC by immunohistochemistry and real-time polymerase chain reaction. Expression of TRIM21 was found to be decreased in tumor tissues from patients with CRC and UC-associated cancer than that in controls, and TRIM21-∕- deficiency promoted AOM/DSS-induced CAC, characterized by more weight loss and multiple, large colon tumors in TRIM21-∕- mice. Moreover, associated gene expression of tumor cell proliferation (eg, Ki67), tissue remodeling and angiogenesis (eg, MMP10, HIF1-α, COX2, Ang4), and pro-inflammatory cytokines (eg, IL-6, TNF-α, IL-1β) markedly upregulated, whereas associated gene expression of tumor cell adhesion (E-cadherin) and inflammatory cytokines (eg, IL-10, TGF-β, Foxp3, IFN-γ) downregulated in tumor tissues from TRIM21-/- mice compared with controls. TRIM21 is decreased in colitis-associated cancer and negatively regulates intestinal epithelial carcinogenesis by modulating epithelial cell proliferation, adhesion, tissue remodeling and angiogenesis, and pro-inflammatory responses. Therefore, TRIM21 may serve as a novel therapeutic target for CAC therapy.

Analysis of colon-infiltrating γδ Tcells in chronic inflammatory bowel disease and in colitis-associated cancer.

Inflammatory bowel disease (IBD) remains a global health problem with a significant percentage of patients progressing to chronic inflammation and colitis-associated cancer (CAC). Whether or not γδ Tcells contribute to initiation and maintenance of inflammation in IBD and in the development of CAC is not known. We have evaluated the frequency, phenotype, and functions of γδ Tcells among tissue-infiltrating lymphocytes in healthy donors and IBD and CAC patients. Results show that Vδ1 Tcells are the dominant γδ T-cell population in healthy tissue, whereas Vδ2 T significantly abound in chronic IBD. Vδ2 Tcells produce more IFN-γ, TNF-α, and IL-17 than Vδ1 Tcells in chronic inflamed IBD. In CAC patients no significant cytokine production was detected in tissue-resident Vδ1 Tcells, but Vδ2 Tcells produced remarkable amounts of IFN-γ and TNF-α; these data were confirmed by the analysis of an independent cohort of IBD transcriptomes. Moreover, transcriptomes of IBD patients revealed a clear-cut clusterization of genes related with the maintenance of the inflammatory status. In conclusion, our results demonstrating that Vδ2 Tcells have a proinflammatory profile in chronic IBD are suggestive of their participation in IBD and CAC pathogenesis.

Role of transient receptor potential vanilloid subtype 4 in the regulation of azoymethane/dextran sulphate sodium-induced colitis-associated cancer in mice

Ca2+-permeable ion channels, such as transient receptor channels, are one of the potential therapeutic targets in cancer. Transient receptor potential vanilloid subtype 4 (TRPV4) is a nonselective cation channel associated with cancer progression. This study investigates the roles of TRPV4 in the pathogenesis of colitis-associated cancer (CAC) in mice. The role of TRPV4 was examined in azoxymethane (AOM)/dextran sulphate sodium (DSS)-induced murine CAC model. The formation of colon tumours induced by AOM/DSS treatment was significantly attenuated in TRPV4-deficient mice (TRPV4KO). TRPV4 was co-localised with markers of angiogenesis and macrophages. AOM/DSS treatment upregulated the expression of CD105, vascular endothelial growth factor receptor 2, and TRPV4 in wildtype, but the upregulation of CD105 was significantly attenuated in TRPV4KO. Bone marrow chimera experiments indicated that TRPV4, expressed in both vascular endothelial cells and bone marrow-derived macrophages, played a significant role in colitis-associated tumorigenesis. There was no significant difference in the population of hematopoietic cells, neutrophils, and monocytes between untreated and AOM/DSS-treated WT and TRPV4KO on flow cytometric analysis. TRPV4 activation by a selective agonist induced TNF-α and CXCL2 release in macrophages. Furthermore, TRPV4 activation enhanced the proliferation of human umbilical vein endothelial cells. These results suggest that TRPV4 expressed in neovascular endothelial cells and bone marrow-derived macrophages contributes to the progression of CAC in mice.

Protective Role of Fecal Microbiota Transplantation on Colitis and Colitis-Associated Colon Cancer in Mice Is Associated With Treg Cells.

Colitis-associated cancer (CAC) is the most serious outcome of inflammatory bowel disease, which has an alteration of commensal intestinal microbiota. However, the role of intestinal microbiota on CAC progression is not well-understood. Fecal microbiota transplantation (FMT) was used for treating murine azoxymethane–dextran sodium sulfate (AOM-DSS) model of CAC. Composition of gut microbiota during FMT treatment was analyzed. RT-PCR and ELISA were used to detect the inflammatory factors, and immunofluorescence was applied to examine the phospho-nuclear factor (NF)-κB p65/p100 and Ki67-positive cells in the colons. In addition, flow cytometry was performed to analyze the immune cell after FMT treatment. Rehabilitation of the intestinal microbiota by FMT restored both the ratio and diversity of microbiota during CAC progression. Remarkably, a favorable morphometric outcome characterized by decreased tumor load and size was observed in CAC mice with FMT treatment. In addition, an anti-inflammatory function of FMT was demonstrated by decreasing pro-inflammatory factors but increasing anti-inflammatory factors through inhibiting canonical NF-κB activity and cellular proliferation in colons of CAC mice. The expression of CD4+CD25+Foxp3+ regulatory T cells (Tregs) was significantly increased after FMT treatment in CAC mice, but not T helper (Th)1/2/17 cells. Our study aids in the understanding of CAC pathogenesis and reveals a previously unrecognized role for FMT in the treatment of CAC through restoring the intestinal microbiota and inducing regulatory T cells.

Spliceosome protein Eftud2 promotes colitis-associated tumorigenesis by modulating inflammatory response of macrophage

Alternative splicing (AS) of mRNA is known to be involved in regulation of immune cell differentiation and activation. Elongation factor Tu GTP binding domain containing 2 (Eftud2) is an AS factor to potentially modulate innate immune response in macrophages. In this study, we investigate its involvement in the pathogenesis of colitis-associated cancer (CAC). Using an established mouse model of CAC, we show that Eftud2 is constantly overexpressed in the colonic tissues as well as infiltrating macrophages. Myeloid-specific knockout of Eftud2 remarkably suppresses chronic intestinal inflammation and tumorigenesis, which is associated with decreased production of inflammatory cytokines and tumorigenic factors. Repression of colonic inflammation and colorectal tumor development in Eftud2-deficient mice is due to the impaired activation of NF-κB signaling in LPS-challenged macrophages. Furthermore, the alteration of Eftud2-mediated AS involving the components of TLR4-NF-κB cascades underlies the impairment of NF-κB activation. Overall, these findings provide new insights into the tight link between inflammation and cancer and modulation of AS in innate immune signals may be a potentially therapeutic avenue for CAC treatment.

Post-transcriptional Gene Regulation in Colitis Associated Cancer.

Colitis-associated cancer (CAC) has been linked to microRNA (miRNA) aberrant expression elicited by inflammation. In this study, we used the AOM/DSS-induced CAC mice model to explore the ectopic expression of miRNAs in the precancerous stage of CAC. As a result, we found that miR-31-5p, miR-223-3p, and let-7f-5p were dysregulated during the development of intestinal dysplasia. Subsequently, we first identified the role of these three miRNAs in CAC. Adenomatous polyposis coli (APC) was revealed as a new target of miR-223-3p, and solute carrier family 9- subfamily A-member 9 (SLC9A9) and APC membrane recruitment protein 3 (AMER3) were suggested as two new targets for let-7f-5p. For miR-31-5p, we proved that it can target LATS2 mRNA so as to modulate Hippo pathway in Caco2 cells. Second, to examine if targeting these three miRNAs would lead to CAC prevention, pedunculoside, a natural triterpene glycoside capable of rescuing the down-regulation of LATS2 and APC caused by either miR-31-5p or miR-223-3p overexpression, respectively, was used in the in vivo AOM/DSS-induced CAC model. The results showed that pedunculoside (25 mg/kg) substantially mitigated the damage to mice intestine caused by DSS/AOM. These results suggested that miRNAs-elicited post-transcriptional regulation is involved in the pathogenesis of CAC, and CAC can be prevented through targeting key miRNAs that are ectopically expressed in CAC.

MicroRNAs, intestinal inflammatory and tumor.

Colorectal cancer (CRC) is the third most malignant tumor. Inflammatory bowel disease (IBD) can increase the risk of colorectal cancer. And colitis-associated cancer (CAC) is a CRC subtype, representing the inflammation-related colorectal cancer. For the past decades, we have known that ectopic microRNA (miRNA) expression was involved in the pathogenesis of IBD and CRC, playing a pivotal role in the progression of inflammation to colorectal cancer. Thus, this review provides the recent advances in altered human tissue-specific miRNAs that contribute to IBD, CRC and CAC pathogenesis, diagnosis and treatment. Meanwhile, the potential utilization of miRNAs as novel therapeutic targets for the prevention of CRC was also discussed.

Natural CAC chemopreventive agents from Ilex rotunda Thunb.

Colitis-associated cancer (CAC) is one of the most serious complications of inflammatory bowel disease. The pathogenesis of CAC is complicated and so far elusive, and the anti-inflammatory effect does not assure CAC preventive activity, making it difficult to discover CAC preventive drugs. In this study, we report the CAC preventive effect of the ethyl acetate (EIR) of Ilex rotunda Thunb., a traditional Chinese herbal medicine being clinically used to treat intestinal disease. We also report the results of screening for CAC preventive agents from EIR via a nuclear factor-kappa B (NF-κB) translocation model in Caco2 cells, since activated NF-κB can be used by tumor cells at the early stage of tumorigenesis. Twenty-four components were isolated from EIR and identified by multiple chromatography and spectral analysis. MTT experiments in IEC-6 and RAW264.7 cells showed that all 24 compounds were toxic-free to normal cell lines. Furthermore, compound rotundic acid (RA) (19) exhibited an inhibitory effect on LPS-induced NF-κB translocation in Caco2 cells. Moreover, RA did not induce apoptosis in Caco2 tumor cells while possessing an anti-inflammatory effect both in immune and intestinal epithelium cells (RAW264.7 and IEC-6 cells, respectively). Removing RA (19) and its 28-O-glucopyranoside (17) from EIR definitely undermined the in vivo CAC preventive activity of EIR. Therefore, the current study suggested that RA (19) could be a potential therapeutic agent against CAC.

Tauroursodeoxycholic acid attenuates colitis-associated colon cancer by inhibiting nuclear factor kappaB signaling.

Inflammatory bowel diseases is associated with an increased risk for the development of colorectal cancer. However, the mechanism of immune signaling pathways linked to colitis-associated cancer (CAC) has not been fully elucidated. Tauroursodeoxycholic acid (TUDCA) exhibits anti-inflammatory and anti-cancer activities. The aim of this study is to investigate the role of TUDCA in the pathogenesis of CAC. Colitis-associated cancer was induced in mice using azoxymethane and dextran sodium sulfate administration, and TUDCA's effect on tumor development was evaluated. HCT 116 and COLO 205 were treated with TUDCA or vehicle and then stimulated with tumor necrosis factor-α (TNF-α). Expression of interleukin (IL)-8 was determined by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, and IκBα phosphorylation and degradation was evaluated by immunoblot assay. The DNA-binding activity of NF-κB was assessed by electrophoretic mobility shift assay. Cell viability assay and real-time reverse transcription-polymerase chain reaction of bcl-xL, MCL1, c-FLIP-L, and VEGF were performed. Tauroursodeoxycholic acid significantly attenuated the development of CAC in mice. Exposure to TUDCA resulted in extensive epithelial apoptosis and reduced levels of phospho-IκB kinase in the colon. In HCT 116 cells stimulated with TNF-α, TUDCA significantly inhibited IL-8 and IL-1α expression and suppressed TNF-α-induced IκBα phosphorylation/degradation and DNA-binding activity of NF-κB. Furthermore, in both HCT 116 and COLO 205 cells, TUDCA reduced cell viability and downregulated the expression of bcl-xL, MCL1, c-FLIP-L, and VEGF. These results demonstrated that TUDCA suppresses NF-κB signaling and ameliorates colitis-associated tumorigenesis, suggesting that TUDCA could be a potential treatment for CAC.

Lentiviral vector-mediated IL-9 overexpression stimulates cell proliferation by targeting c-myc and cyclin D1 in colitis-associated cancer.

Colorectal cancer caused by inflammatory bowel disease is referred as colitis-associated cancer (CAC). The mechanism underling CAC is not fully understood. In the present study, the role of interleukin-9 (IL-9) in CAC was examined. The current study included 12 colorectal tissue specimens and matched adjacent tissues from CAC. The expression of IL-9 protein was examined using immunohistochemical staining. The expression of IL-9 in cancer tissues was markedly higher compared with that in adjacent tissues. Furthermore, IL-9 gene overexpression lentiviral vectors were constructed to overexpress IL-9 in RKO and Caco-2 cell lines. The role of IL-9 in cell proliferation was investigated using a Cell Counting Kit-8 assay, and MYC proto-oncogene bHLH transcription factor (c-Myc) and cyclinD1 expression levels were detected by reverse transcription-quantitative polymerase chain reaction. Notably, IL-9 overexpression promoted the proliferation of colonic epithelial cells by upregulating of the expression of c-Myc and cyclinD1. In conclusion, the present results suggested that IL-9 may exhibit an essential role in the pathogenesis of CAC, and IL-9 promotes the proliferation of colonic epithelial RKO and Caco2 cells, partially via the upregulation of c-Myc and cyclinD1 expression.

The oncoprotein gankyrin promotes the development of colitis-associated cancer through activation of STAT3.

Although long-standing colonic inflammation due to refractory inflammatory bowel disease (IBD) promotes the development of colitis-associated cancer (CAC), the molecular mechanisms accounting for the development of CAC remains largely unknown. In this study, we investigated the role of gankyrin in the development of CAC since gankyrin is overexpressed in sporadic colorectal cancers. We analyzed gene expression of colon tissues obtained from 344 patients with IBD and CAC and found that expression of gankyrin was much higher in colonic mucosa of patients with refractory IBD than in those with IBD in remission. Expression of gankyrin was upregulated in inflammatory cells as well as tumor cells in colonic mucosa of patients with CAC. Over-expressing studies utilizing tagged ganlyrin-cDNA identified physical interaction between ganlyrin and Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1). Importantly, the interaction between ganlyrin and SHP-1 leads to inhibition of STAT3 activation and to enhancement of TNF-α and IL-17 in inflammatory cells. To further address the role of gankyrin in the development of CAC, we created mice with intestinal epithelial cell-specific gankyrin ablation (Vil-Cre;Gankyrinf/f) and deletion of gankyrin in myeloid and epithelial cells (Mx1-Cre;Gankyrinf/f). Gankyrin deficiency in myeloid cells, but not in epithelial cells, reduced the activity of mitogen activated protein kinase and the expression of stem cell markers, leading to attenuated tumorigenic potential. These findings provide important insights into the pathogenesis of CAC and suggest that gankyrin is a promising target for developing therapeutic and preventive strategies against CAC.

Use of Cancer Stem Cells to Investigate the Pathogenesis of Colitis-associated Cancer.

Colitis-associated cancer (CAC) can develop in patients with inflammatory bowel disease with long-term uncontrolled inflammation. The mutational history and tumor microenvironment observed in CAC patients is distinct from that observed in sporadic colon cancer and suggests a different etiology. Recently, much attention has been focused on understanding the cellular origin of cancer and the cancer stem cells, which is key to growth and progression. Cancer stem cells are often chemo-resistant making them attractive targets for improving patient outcomes. New techniques have rapidly been evolving allowing for a better understanding of the normal intestinal stem cell function and behavior in the niche. Use of these new technologies will be crucial to understanding cancer stem cells in both sporadic and CAC. In this review, we will explore emerging methods related to the study of normal and cancer stem cells in the intestine, and examine potential avenues of investigation and application to understanding the pathogenesis of CAC.

Inflammatory bowel disease and cancer: The role of inflammation, immunosuppression, and cancer treatment

In patients with inflammatory bowel disease (IBD), chronic inflammation is a major risk factor for the development of gastrointestinal malignancies. The pathogenesis of colitis-associated cancer is distinct from sporadic colorectal carcinoma and the critical molecular mechanisms underlying this process have yet to be elucidated. Patients with IBD have also been shown to be at increased risk of developing extra-intestinal malignancies. Medical therapies that diminish the mucosal inflammatory response represent the foundation of treatment in IBD, and recent evidence supports their introduction earlier in the disease course. However, therapies that alter the immune system, often used for long durations, may also promote carcinogenesis. As the population of patients with IBD grows older, with longer duration of chronic inflammation and longer exposure to immunosuppression, there is an increasing risk of cancer development. Many of these patients will require cancer treatment, including chemotherapy, radiation, hormonal therapy, and surgery. Many patients will require further treatment for their IBD. This review seeks to explore the characteristics and risks of cancer in patients with IBD, and to evaluate the limited data on patients with IBD and cancer, including management of IBD after a diagnosis of cancer, the effects of cancer treatment on IBD, and the effect of IBD and medications for IBD on cancer outcomes.

Urinary Level of D‐2‐Hydroxyglutarate During Inflammation Predicts Severity of Colitis‐Associated Tumorigenesis in Mice

Although the association between inflammatory bowel diseases (IBD) and an increased risk of developing colorectal cancer is well‐established, the pathogenesis of colitis‐associated cancer is poorly understood. Quantitative metabolic profiling is a promising method to detect molecular pathways involved in disease progression from colitis to cancer. Wild‐type C57BL/6 male mice were i.p. injected with 7.6 mg/kg azoxymethane followed by 2 cycles of 3% dextran sodium sulfate (DSS; 1 week DSS and 3 weeks recovery). Urine was serially collected at baseline, the end of the first cycle of DSS (colitis stage), and the day before sacrifice (polyp stage). Urinary metabolites were analyzed using gas chromatography‐mass spectrometry. Excised colons were observed for polyp number and embedded for dysplasia scoring or scraped for mucosal extracts. Findings in the mouse model were corroborated using human mucosal biopsies of IBD and matched IBD‐associated cancer. Six urinary metabolites were significantly altered during colitis and returned to baseline at the polyp stage. Of these, urinary D‐2‐hydroxyglutarate (D‐2‐HG) during colitis, an emerging oncometabolite, directly correlated with polyp number and dysplasia score. Colonic expression of D‐2‐hydroxyglutatric dehydrogenase, an enzyme that eliminates D‐2‐HG, was decreased during DSS colitis and human IBD but restored at the polyp stage and in IBD cancer. These results suggest that elevated D‐2‐HG during colitis may play a role in progression to cancer.

Immunopathogenesis of Colitis-Associated Cancer in an Animal Model

Chronic inflammation, such as that seen in patients with inflammatory bowel disease (IBD), greatly increases the risk of developing colon cancer. Growing evidence supports a role for T cell-mediated immune response and release of various cytokines in the pathogenesis of colitis-associated cancer (CAC). In fact, CD4+ effector T cells promote chronic inflammation associated with IBD through release of proinflammatory cytokines, which leads to initiation and progression of colon cancer. Furthermore, CD8+ T cells reduce tumor growth through cancer immunosurveillance, which can also contribute to intestinal inflammation and thereby might promote tumor growth. In contrast, regulatory T cells (Tregs) release the immunosuppressive cytokines IL-10, TGF-β and thus have protective effects in CAC. In addition, dendritic cells (DCs) are important components of antitumor immunity. Recently, a novel mouse model that was associated with repeated inflammation was established for investigating the immunopathogenesis of CAC. This review discusses the role of T cell-mediated immune response, and DCs and involved cytokines in the immunopathogenesis of CAC in an animal model, which may also provide future therapeutic targets in CAC.

Mechanisms of Immune Signaling in Colitis-Associated Cancer

The inflammatory bowel diseases ulcerative colitis and Crohn’s disease are associated with an increased risk for the development of colorectal cancer. During recent years, several immune signaling pathways have been linked to colitis-associated cancer (CAC), largely owing to the availability of suitable preclinical models. Among these, chronic intestinal inflammation has been shown to support tumor initiation through oxidative stress–induced mutations. A proinflammatory microenvironment that develops, possibly as a result of defective intestinal barrier function and host–microbial interactions, enables tumor promotion. Several molecular pathways such as tumor necrosis factor/nuclear factor-κB or interleukin 6/signal transducer and activator of transcription 3 signaling have been identified as important contributors to CAC development and could be promising therapeutic targets for the prevention and treatment of CAC.

Tumor-Derived GM-CSF Promotes Inflammatory Colon Carcinogenesis via Stimulating Epithelial Release of VEGF

Chronic inflammation is a major driving force for the development of colitis-associated cancer (CAC). Elevated production of granulocyte macrophage colony-stimulating factor (GM-CSF) has been observed in mucosa of patients with inflammatory bowel disease. Its actions in the progression from colitis to cancer, however, remain poorly understood. Herein, we demonstrated that colonic epithelial cells (CEC) were a major cellular source of GM-CSF and its production was significantly augmented when CAC model was established by administration of azoxymethane and dextran sulfate sodium. Furthermore, we showed that GM-CSF was a driver for VEGF release by CEC in autocrine and/or paracrine manners through the extracellular signal-regulated kinase (ERK)-dependent pathway. Blocking GM-CSF activity in vivo significantly decreased epithelial release of VEGF, thereby abrogating CAC formation. In vitro treatment of transformed CEC with recombinant GM-CSF dramatically augmented its invasive potentials, largely in VEGF-dependent fashion. Furthermore, commensal microbiota-derived lipopolysaccharides were identified as a trigger for GM-CSF expression in CEC, as antibiotics treatment or Toll-like receptor 4 ablation considerably impaired its epithelial expression. Overall, these findings may have important implications for the understanding of mechanisms underlying CAC pathogenesis and the therapeutic potentials of regimens targeting GM-CSF or VEGF in clinic.