Inflammatory bowel disease (IBD) is a chronic nonspecific inflammatory disease of the intestine that includes ulcerative colitis (UC) and Crohn’s disease (CD). UC lesions involve only the colon (large intestine), whereas CD lesions can involve all parts of the gastrointestinal tract, with the terminal ileum and adjacent colon predominating (see figure below). Nowadays, the incidence of IBD is increasing. An article on the key points of clinical knowledge of IBD was published in JAMA on May 21, which briefly described the knowledge about the main clinical manifestations, diagnosis and treatment of IBD, bringing medical inculcation and popularization to more IBD patients, and a systematic sorting out for clinicians. Enhancing research on the role of inflammation in tumor development Many chronic inflammatory conditions, both infectious and non-infectious (or idiopathic) inflammation can lead to tumors. It is now recognized that cervicitis and cervical cancer, inflammation caused by EBV infection and nasopharyngeal cancer, etc. Many inflammatory conditions of the digestive system are also associated with tumorigenesis (Table 1). Inflammation as a predisposing factor for tumor development has attracted increasing attention. Although the role of inflammation in all stages of tumor development is still not fully elucidated, many research efforts in this field have made important progress. How inflammation induces tumors and how to intervene through these pathways are important scientific questions in the current field of oncology research. Table 1, Major digestive tumor-associated inflammation and corresponding tumors. Tumor-associated inflammation Corresponding tumor Barrett’s esophagus Esophageal adenoma Gastric ulcer Gastric cancer Hp-associated gastritis Gastric MALT lymphoma, gastric cancer Chronic hepatitis caused by HBV, HCV Liver cancer Inflammatory bowel disease Colon cancer Chronic pancreatitis Pancreatic cancer Schistosoma mansoni Bile duct cancer Chronic cholecystitis Gallbladder inflammation (Note: Hp: Helicobacter pylori; MALT. Mucosa-associated lymphoid tissue) I. Inflammation causing tumor The mechanism of. 1. Inflammation and tumor initiation: Acute inflammation is often self-limiting, whereas persistent chronic inflammation is the initiating and persistent promoter of tumor stem cell transformation into tumor. Inflammation is “non-controllable” when the target tissues are in long-term or over-reaction and repeated repair due to continuous or low-intensity inflammatory stimulation. During tumorigenesis, tumor stem cells, stromal cells and inflammatory cells form a complex regulatory network involving numerous “nodes” of genes, non-coding RNAs, proteins and metabolic small molecules, and forming an “internet” of interactions. In tumor initiation, the nuclear transcription factor NF-KB and transcriptional activator 3 (STAT3) pathways are the most important. Through these pathways, pro-inflammatory factors and important mediators are released that are equally important for tumor proliferation and maintenance of inflammation. Among them, activation of NF-KB has apoptosis-inhibiting, accelerating cell cycle progression, pro-angiogenic and metastatic effects; STArI3 pathway is a signal transduction pathway that regulates and participates in a variety of tumors, including regulation of anti-apoptotic genes and cell cycle control genes. 2. Inflammation and tumor evasion of immune surveillance and proliferation: Tumor survival is associated with suppression of effector T cells and humoral immune responses. The failure of the immune system to produce sufficient antitumor effects is due to the undifferentiated nature of tumor cells and their direct suppressive effect on the immune system and evasion of immune surveillance. Regulatory T cells (Tregs) have an immunosuppressive function and accumulate in tumor tissues, and these cells are also recruited and activated by dendritic cells in the inflammatory response. Bone marrow-derived suppressor cells (MDSCs) are also pro-inflammatory cells, which are activated by the inflammatory response and accumulate to specific sites to promote angiogenesis, and they also have immunosuppressive effects. Therefore, tumor-associated inflammation leads to tumor growth and evades immune surveillance by generating pro- and anti-inflammatory signals. Inflammation and tumor progression and metastasis: The “seed and soil” theory suggests that tumor seeds can survive and metastasize in the tumor microenvironment (TME), which depends on the interaction between various factors and tumor cells. Stromal cells include fibroblasts, immune cells, endothelial cells, MDSCs, etc.; cytokines include TNF, VEGF, IL-1, etc.; chemokines include CXCL12, CCL27, CCl21, etc. These cells and factors are produced and present in tumor-associated inflammation and can promote tumor growth, angiogenesis, invasion, and metastasis. Tumors themselves can promote their own expression of chemokine (including the cxc chemokine family) receptors through paracrine pro-inflammatory factors (IL I1B, IL-6, TNFa) and autocrine cytokines. Tumor progression is dependent on tumor-associated macrophages (TAMs), which have been actively studied and can promote tumor growth and metastasis by disrupting the basement membrane through the secretion of various growth factors (e.g., VEGF). The distribution of TAMs in tumor tissues determines the stage and invasive ability of tumors. Second, the relationship between various components in TME and tumor. 1.Cytokines: Cytokines play a key role in the process of inflammation to tumor. Both inflammation and tumor cells can activate cytokines, which play a key role in maintaining chronic inflammation, promoting tumor progression, maintaining TME and suppressing immune surveillance against tumors. Inflammatory factors are divided into pro-inflammatory and anti-inflammatory factors, of which TNFα and L-1β are the most important in initiating the inflammation to tumor process and they activate NF-KB. Transforming growth factor β (TGFβ) is a multipotent cytokine that plays a role in both tumor suppression and tumor progression. TCFβ recruits MDSCs to the TME, reduces natural killer (NK) cells and IL-IB plays a key role in the recruitment of MDSCs, which produce IL-6, which in turn activates STAT3 in epithelial cells, leading to tumorigenesis, and blocking this pathway has the potential to serve as a target for tumor treatment. IL-6 mediates colon carcinogenesis and proliferation through activation of STATI and STAT3. It not only acts on intestinal epithelial cells, but also activates dendritic cells and T helper cells, which can produce a large number of cytokines and promote the formation of chronic inflammation and precancerous microenvironment. 2. Reactive oxygen clusters (ROS) and reactive nitrogen clusters (RNS): Long-term exposure of cells in chronic inflammation to ROS and RNS leads to oxidative stress, followed by genetic alterations (including DNA strand breaks and base mutations, oncogene mutations), lipid and protein peroxidation and activation of signal transduction pathways. In addition oxidative stress disrupts the function of DNA methylation transferase l and metal binding proteins, leading to epigenetic alterations. RNS can cause oncogene point mutations through induction of lipid peroxidation, increasing the risk of chronic inflammation leading to carcinogenesis. rns is also involved in MARK signaling pathway, inducing the expression of proto-oncogenes c-Fos and c-Jun, and inducing the expression of AP-I genes involved in cell proliferation, differentiation, transformation and death. 3. Matrix metalloproteinases (MMPs): In TME, MMPs play an important role in intercellular dialogue and mutual regulation. Overall, high expression of MMPs is associated with poor prognosis, and most MMPs are expressed in tumor-associated stromal cells and immune cells. MMP-9 is closely related to epithelial cell proliferation and vascular growth factor synthesis. mmp-7 is associated with tumor metastasis. 4. cyclooxygenase (cox): cOx is the rate-limiting enzyme for prostaglandin synthesis from arachidonic acid. one isoform, COX-2, is highly expressed in inflammation, activates the Wnt pathway and promotes tumor formation. In gastrointestinal tumors, its expression plays an important role. 5. MDSCs: MDSCs are a heterogeneous population of bone marrow precursor cells containing early myeloid progenitor cells, naïve granulocytes, macrophages and dendritic cells at different stages of differentiation. They are capable of suppressing both the cytotoxicity of NK and NKT cells and the adaptive immune response mediated by CD4+ and CD8+ cells. They are induced by pro-inflammatory factors and accumulate in the inflammatory environment. III. Prospects for clinical applications Tumorigenesis and development are dependent on inflammatory stimuli. However, once a tumor forms, it will progress according to its own pattern and the dependence on environmental stimuli is greatly reduced or disappeared. Eliminating and controlling inflammation in the early stage has positive significance to reduce the occurrence of tumor. After tumor formation, even if inflammation is controlled or eliminated, the effect on controlling tumor progression is not significant. Many studies have also confirmed that curing inflammation at the right stage can prevent tumor development to a great extent. More successful examples are the eradication of H. pylori that reduces the incidence of gastric cancer and anti-HBV and HCV treatment that reduces the incidence of primary liver cancer. Current research in this area is focused on the following questions: What are the mechanisms that refer the chronic healing process of inflammation to the pre-tumor stage? How to interfere with such mechanisms? Inhibition of nuclear transcription factor production, modification of TME (e.g. alteration of local immunosuppressive environment, reduction of ROS/RNS formation, etc., treatment targeting specific cytokines and MMPs) are all quite promising applications. Since the mechanism of tumor formation is quite complex, there is a long way to go for future research.