The nervous system can profoundly influence cancer prognosis, and this frontier of cancer neuroscience has increasingly garnered research attention. However, the involvement of neural signals in colorectal cancer remains incompletely understood. In this study, we exploit advanced three-dimensional imaging and conventional immunohistochemistry to observe a transitional loss of local sympathetic inputs from colorectal adenomas to adenocarcinomas in human patients. This negative correlation similarly occurs in the mouse models of colorectal cancer. Of importance, the pharmacologic ablation of sympathetic innervations significantly exaggerates the progression of colorectal tumors in the chemical-induced mouse model. We then demonstrate that the sympathetic neurotransmitter norepinephrine acts via α2-adrenergic receptors to elevate the cancer cell expression of chemokines to recruit CD8+ T cells, and the destruction of sympathetic signals leads to their reduction within the tumor microenvironment. Together, these results have elucidated a novel aspect of the neurodegeneration of local sympathetic inputs in promoting colorectal cancer progression.

Ulcerative colitis (UC) brings inconvenience to many patients with inflammatory bowel disease (IBD). Although colonic pathology is widely investigated, little attention has been paid to the disorders in small intestine of UC. In this study, we investigated the impairments of UC to small intestine and further explored how iron metabolism regulated epithelial integrity and the activity of intestinal stem cells (ISCs).

Mice were treated by 2.5% dextran sulfate sodium (DSS) for 7 days to established acute experimental colitis. Small intestinal tissues were collected at different time points in the process of DSS-induced colitis. Histological analysis was used to evaluate the changes of small intestine, including H&E, Alcian blue and PAS staining, immunostaining, and qRT-PCR. Iron content was modulated by the supplementation of ferric citrate or depletion by deferoxamine (DFO). The influence of iron on the barrier integrity and stem cell function was further determined by histology, IEC-6 cell, and enteroid culture. ROS content was demonstrated by DHE staining. The proliferation of intestinal stem cells (ISCs) was shown by BrdU and Olfm4 staining, and Lgr5-tdTomato mice were used for lineage tracing study.

It was shown that during DSS-induced colitis, small intestine underwent a serious injury process, including dysregulated integrity and decreased proliferation of ISCs. Iron overload significantly exacerbated intestinal injury in tissues, epithelial cell line, and intestinal organoids. However, iron chelation by deferoxamine (DFO) would greatly suppress small intestinal injury. Mechanistically, iron overload exacerbated the generation of ROS and enhanced the infiltration of immune cells. In addition, STAT3 and ERK pathways in intestinal epithelium were impaired during experimental colitis, and iron content significantly interrupted the expression of p-STAT3 and p-ERK1/2 within small intestine.

In summary, this study proved that small intestine was also impaired in experimental colitis, and iron content could affect DSS-induced small intestinal damage and regeneration, indicating the strategy of iron supplementation in clinical practice needs to be more cautious and consider more factors.

The complement system is associated with inflammatory bowel disease (IBD) pathology. Complement activation induces C5a production, which signals through the C5a1 receptor (C5aR1) to drive inflammatory responses that may underlie IBD.

We examined mucosal biopsies from ulcerative colitis patients and identified C5a1 receptor up-regulated in active lesions, supporting the C5a1 receptor as a target for therapeutic intervention. Cyclic peptide C5a1 receptor antagonists such as PMX205 are orally efficacious in preclinical colitis models; however, their clinical application may be limited by rapid metabolism. We therefore encapsulated PMX205 within pH-sensitive polymers to target drug for colon delivery following oral administration.

PMX205 nanoparticles were non-toxic and released bioactive PMX205 in simulated colon fluid. In vivo imaging of Cy5-labelled nanoparticles demonstrated rapid entry and persistence in the mouse colon for up to 48 h. Next, we utilised the dextran sodium sulphate-induced colitis model to examine efficacy of the C5a1 receptor-antagonist formulation. We show that oral administration of PMX205 nanoparticles every 2 days from symptom onset significantly mitigated weight loss, clinical illness, colon length reduction and epithelial damage to a similar degree as C5a1 receptor-/- mice. Notably, unformulated PMX205 was markedly less effective in this dosing regimen.

This novel colon-targeted formulation therefore offers a potent therapeutic strategy for translating C5a1 receptor antagonists for IBD conditions such as ulcerative colitis.

Colorectal cancer is one of the most lethal tumors, posing a financial and healthcare burden. This study investigates how helminths and pre-existing diseases such as colitis, obesity, diabetes, and gut microbiota issues influence colon cancer development and prognosis. The immune system's protective immunosuppressive response to helminth invasion minimizes inflammation-induced cell damage and DNA mutations, lowering the risk of colorectal cancer precursor lesions. Helminth infection-mediated immunosuppression can hasten colorectal cancer growth and metastasis, which is detrimental to patient outcomes. Some helminth derivatives can activate immune cells to attack cancer cells, making them potentially useful as colorectal cancer vaccines or therapies. This review also covers gene editing approaches. We discovered that using CRISPR/Cas9 to inhibit live helminths modulates miRNA, which limits tumor growth. We propose more multicenter studies into helminth therapy's long-term effects and immune regulation pathways. We hope to treat colorectal cancer patients with helminth therapy and conventional cancer treatments in an integrative setting.

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of the biliary tree, leading to significant liver function impairment over time. There is a strong association with inflammatory bowel diseases (IBD), together representing a distinct and complex medical condition. Patients with PSC-IBD face a heightened risk of various cancers, particularly colorectal carcinoma (CRC) and cholangiocarcinoma (CCA) as the most common types. In this review, we aim to characterize the distinctive features of PSC-IBD-associated carcinomas. Cancer pathogenesis in PSC-IBD is shaped by various factors including dysregulated bile acid metabolism, gut dysbiosis, and unique immune responses. PSC-IBD-associated CRC is often right-sided and warrants vigilant monitoring due to its higher incidence and unique morphological features compared to CRC arising in the terrain of IBD alone. CCA shares substantial genetic similarities with extrahepatic CCA and poses diagnostic challenges since it is frequently detected at advanced stages due to symptom overlap with PSC. Besides, reliable predictive biomarkers for targeted therapy remain largely unexplored. The distinct molecular, genetic, and histopathological profiles of CRC and CCA in PSC-IBD underscore the complexity of these malignancies and highlight the need for continued research to develop precise therapeutic strategies.

Inflammatory bowel disease (IBD) is a relapsing disorder characterized by uncontrolled chronic inflammation of the gastrointestinal tract, posing a significant therapeutic challenge owing to the limited efficacy and undesirable side effects of current therapeutic options. A key pathological hallmark of IBD is the excessive production of reactive oxygen species (ROS). Hence, therapeutic strategies aimed at reducing ROS levels are promising for relieving these inflammatory conditions. Vitamin C-a natural nutrient for the human body-is well known for its potent antioxidant effects. However, the clinical development of vitamin C as a therapeutic drug has been hindered by its poor stability, rapid metabolism, and inadequate tissue accumulation. Herein, we report that the bioavailability of vitamin C can be enhanced by chemically reprogramming it with a small panel of long-chain fatty acids that aid in the aqueous self-assembly of the resulting drug conjugates to create self-deliverable nanoassemblies, enhancing their inflammation disease-oriented delivery and cellular uptake. In mice with dextran sulfate sodium-induced colitis, the optimal vitamin C-lipid nanoassemblies preferentially accumulated in inflamed colonic tissues following systemic administration and substantially ameliorated disease severity. We extended this strategy to incorporate the clinically approved glucocorticoid budesonide into the vitamin C nanosystem, facilitating a synergistic combination. In the chronic colitis model, the combination treatment reduced inflammation without compromising global immunity. Mechanistically, the treatment modulated the intestinal inflammatory microenvironment and altered the immune cell landscape, partly through regulation of the gut microbiome. Given its anticipated negligible side effects, this novel nanoassembly platform leveraging small-molecule lipidation may become a promising therapeutic for treating various inflammatory diseases.

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths worldwide, with its progression intricately linked to gut microbiota dysbiosis. Disruptions in microbial homeostasis contribute to tumor initiation, immune suppression, and inflammation, establishing the microbiota as a key therapeutic target. Fecal microbiota transplantation (FMT) has emerged as a transformative approach to restore microbial balance, enhance immune responses, and reshape the tumor microenvironment. This review explores the mechanisms underlying FMT's therapeutic potential, evaluates its advantages over other microbiota-based interventions, and addresses challenges such as donor selection, safety concerns, and treatment standardization. Looking forward, the integration of FMT into personalized CRC therapies requires robust clinical trials and the identification of predictive biomarkers to optimize its efficacy and safety.

Inflammatory bowel disease (IBD) is associated with a higher risk of developing colorectal cancer, according to the inflammation-dysplasia-cancer (IDC) sequence from inflammation to colitis-associated colorectal cancer (CAC). The objective of this study was to identify and generate a transcriptomic signature and score, related to the IDC sequence, that could ultimately classify dysplasia and cancer in IBD.

Demographics, clinical parameters, histological characteristics, and RNA-sequencing data were evaluated on 134 formalin-fixed paraffin-embedded lesions from 2 independent cohorts of IBD patients with low- or high-grade dysplasia (LGD, HGD) and/or CAC. An ordinal logistic regression screened for significant IDC sequence-associated genes that were computed in a transcriptomic signature score.

Principal component analysis and unsupervised clustering on 1% of the most variable genes showed a good clustering between the 4 lesion groups (Normal Mucosa, Inflamed Mucosa, LGD/HGD, and CAC). A gene signature was identified on 27 genes that correlated with the lesion groups in the exploratory cohort. The most weighted gene in this transcriptomic signature was the long non-coding regulatory RNA KCNQ1OT1, a gatekeeper against genomic instability and transposon activation. Based on the expression of these 27 genes, we built and validated a transcriptomic signature score to classify dysplasia and CAC. The overall accuracy of the transcriptomic signature score was 85.71% in the exploratory cohort and 90.91% in the validation cohort.

We identified a tissue-based transcriptomic score to classify IDC lesions in IBD patients and uncovered some of the pivotal genes in carcinogenesis related to inflammation in IBD.

Colorectal cancer (CRC) ranks among the most prevalent malignant neoplasms globally. A growing body of evidence underscores the pivotal roles of genetic alterations and dysregulated epigenetic modifications in the pathogenesis of CRC. In recent years, the reprogramming of tumor cell metabolism has been increasingly acknowledged as a hallmark of cancer. Substantial evidence suggests a crosstalk between tumor cell metabolic reprogramming and epigenetic modifications, highlighting a complex interplay between metabolism and the epigenetic genome that warrants further investigation. Biomarkers associated with the pathogenesis and metabolic characteristics of CRC hold significant clinical implications. Nevertheless, elucidating the genetic, epigenetic, and metabolic landscapes of CRC continues to pose considerable challenges. Here, we attempt to summarize the key genes driving the onset and progression of CRC and the related epigenetic regulators, clarify the roles of gene expression and signaling pathways in tumor metabolism regulation, and explore the potential crosstalk between epigenetic events and tumor metabolic reprogramming, providing a comprehensive mechanistic explanation for the malignant progression of CRC. Finally, by integrating reliable targets from genetics, epigenetics, and metabolic processes that hold promise for translation into clinical practice, we aim to offer more strategies to overcome the bottlenecks in CRC treatment.

Activation of inflammasomes is the activation of inflammation‑related caspase mediated by the assembly signal of multi‑protein complex and the maturity of inflammatory factors, such as IL‑1β and IL‑18. Among them, the Nod‑like receptor family pyrin domain containing 3 (NLRP3) inflammasome is the most thoroughly studied type of inflammatory corpuscle at present, which is involved in the occurrence and development of numerous human diseases. Therefore, targeting the NLRP3 inflammasome has become the focus of drug development for related diseases. In this paper, the research progress of the NLRP3 inflammasome in recent years is summarized, including the activation and regulation of NLRP3 and its association with diseases. A deep understanding of the regulatory mechanism of NLRP3 will be helpful to the discovery of new drug targets and the development of therapeutic drugs.

Ulcerative colitis (UC) is a known contributor to the development of colitis-associated cancer (CAC), although the exact mechanism remains to be elucidated. CAC typically presents as a flat type macroscopically and manifests histologically as mucinous carcinoma and signet ring cell carcinoma. While the relationship between disease duration and chronic inflammation has been studied, the impact of disease duration on CAC outcomes has yet to be thoroughly investigated. The aim of this study is to examine the effect of UC duration on the clinicopathological features of CAC.

This study analysed data from the Japan Society for Colorectal Cancer Research involving UC patients diagnosed with colorectal cancer. The sample consisted of 1200 patients, and their histological and clinicopathological features were analysed. Cutoff values were established at 5 and 15 years for comparisons. Trends and prognostic outcomes corresponding to disease duration were evaluated.

Comparison between two groups (disease duration 0-5 and >5 years) revealed a significant correlation in terms of diagnostic opportunity, vascular invasion, N factor, pathological stage and tumour location. However, between the two groups of 0-15 and >15 years, a significant correlation was identified only in diagnostic opportunity, the presence of primary sclerosing cholangitis. Trend analysis of disease duration showed significant correlations between diagnostic opportunity, histological type, vascular invasion and tumour location, with no significant differences observed in prognostic outcomes.

Our analysis highlighted distinct histological and clinical features in the short-term and long-term disease groups, and these features appear to intensify with increased disease duration. Since no significant difference in prognosis was found, there may not be a need to distinguish between them in cancer treatment.

Patients with long-standing inflammatory bowel disease (IBD) involving the colon are at higher risk of developing colorectal dysplastic or neoplastic lesions. While from sporadic colorectal cancer follows an "adenoma-carcinoma" sequence, IBD colitis-associated carcinogenesis is mainly related to an "inflammation-dysplasia-carcinoma" sequence. Currently, specific endoscopic surveillance strategies involving dye spray and virtual chromoendoscopy have been standardized, aiming for early CRC diagnosis. When detected, colitis-associated dysplasia should be classified according to standard classification, thus allowing for better treatment. Indeed, most IBD-associated dysplastic lesions can be treated with endoscopic resection, even though available procedures are usually more challenging than those in the general population. The higher frequency of severe submucosal fibrosis and the difficulty in the definition of lesions' margins account for this issue. Current endoscopic resection techniques include polypectomy, endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). Recent evidence suggests the relevance of en bloc resection, as this may be associated with lower rates of recurrence. Therefore, particularly for larger (>20 mm) lesions, ESD should be preferred, even though it is considered the most difficult technique due to frequent severe submucosal fibrosis. Considering the growing number of new endoscopic resective techniques, including underwater EMR or ESD, which in the general population have been suggested to lower procedure-related risks and may also allow a larger spread of advanced endoscopic resection in IBD. However, additional data are needed to assess the medium- and long-term efficacy of endoscopic resection of visible dysplasia in IBD patients, which are burdened by a high risk of local and, more importantly, metachronous recurrence.

Ulcerative colitis (UC), a chronic inflammatory bowel disease, significantly increases the risk of colon adenocarcinoma (COAD). Disulfidptosis, a novel form of programmed cell death, has been implicated in various diseases, including UC. This study investigates the expression of disulfidptosis-related genes, particularly CD2AP and MYH10, in UC and COAD. Through analysis of public datasets, we found MYH10 significantly upregulated and CD2AP downregulated in UC compared to healthy controls, with consistent patterns in COAD. Immune infiltration analysis revealed correlations between these genes and specific immune cell types, suggesting their roles in immune modulation. Molecular docking showed strong binding affinities of UC drugs such as budesonide and sulfasalazine with CD2AP and MYH10. Connectivity Map analysis identified additional drug candidates, including simvastatin and mephenytoin, which may be repurposed for UC and COAD therapy. These findings suggest disulfidptosis-related genes as potential biomarkers and therapeutic targets, linking chronic inflammation to cancer progression.

We explored the clinical characteristics, treatment, and outcomes of colitis-associated colorectal cancer (CAC) and compared with sporadic colorectal cancer in Taiwan.

In this retrospective study spanning 1987-2022, CACs diagnosed according to endoscopic and pathological reports from 14 tertiary centers were reported to our cohort. Clinical demographics, endoscopic findings, histological results, treatment modalities, and outcomes were analyzed. Sporadic colorectal cancer data were retrieved from the Cancer Registry Annual Report, Ministry of Health and Welfare, Taiwan.

We enrolled 65 patients with CAC (median age: 56 years; male: 66.2%). Distal colon was the most common tumor location (41.5%). Of patients with ulcerative colitis, 77.2% had extensive colitis, and 76.5% had Mayo endoscopic subscores of ≥2. Moreover, 50% of lesions were nonpolypoid with indistinct borders in 66.7%. Signet-ring cell subtype consisted of 12.3%. Surveillance colonoscopy adherence was 78.4%, yet 51.3% interval cancers occurred. Disease stage 0-4 distribution was 15%, 20%, 13.3%, 20%, and 31.7%, respectively. Endoscopic resection was feasible for 14%, whereas 67.7% required surgery. During follow-up (median: 21.5 months), we recorded 23.2% recurrence and 34.5% mortality. Lesions with indistinct borders were associated with adverse outcomes (adjusted odds ratio = 11.5 [1.35-98.16]). Colitis-associated rectal cancers, diagnosed later ( P < 0.001), had worse outcomes than sporadic rectal cancers.

This is the largest Asian CAC cohort study, emphasizing the need for stringent disease control, improving detection, and reducing interval cancers. Signet-ring cell subtype was prevalent. Rectal colitis-associated cancers were diagnosed later with poorer outcomes than sporadic rectal cancers.

The Traditional Chinese Medicine Formulas (TCMFs) represent a distinctive medical approach to disease treatment and have been utilized in clinical practice for treating intestinal diseases for thousands of years. Recently, TCMFs have received increasing attention due to their advantages of high efficiency, safety, as well as low toxicity, providing promising strategies for preventing colorectal carcinoma (CRC). Nonetheless, the potential mechanism of TCMFs in preventing CRC has not been fully elucidated.

The literature from the past three years was reviewed to highlight the therapeutic effects and underlying mechanisms of TCMFs in preventing CRC.

The keywords have been searched, including "traditional Chinese medicine formulas," "herb pairs," "Herbal plant-derived nanoparticles," et al. in "PubMed" and "China National Knowledge Infrastructure (CNKI)," and screened published articles related to the treatment of intestinal precancerous lesions. This review primarily examined the effectiveness and mechanisms of TCMFs in treating intestinal precancerous lesions, highlighting their significant potential in preventing CRC.

Gegen Qinlian decoction, Shaoyao decoction, Wu Wei Wan, etc., exert substantial therapeutic effects on intestinal precancerous lesions. These therapeutic effects are demonstrated by a reduction in disease activity index scores, suppression of intestinal inflammation, and preservation of body weight and intestinal function, all of which contribute to the effective prevention of CRC. Besides, the classic Chinese herbal pairs and the extracellular vesicle-like nanoparticles of herbaceous plants have demonstrated superior efficacy in the treatment of intestinal precancerous lesions. Mechanistically, protecting the epithelial barrier, regulating gut microbiota as well as related metabolism, modulating macrophage polarization, and maintaining immune balance contribute to the role of TCMFs in CRC prevention.

This review demonstrates the great potential and mechanism of TCMFs in CRC prevention and provides a scientific basis for their utilization in CRC prevention.

Studies on the clinical outcomes after detecting low-grade dysplasia (LGD) in patients with inflammatory bowel disease (IBD) are insufficient. This study evaluated the clinical features, frequency, and risk factors for advanced neoplasia in patients with IBD after an LGD diagnosis.

The medical records of 166 patients with IBD from six university hospitals in Korea from 2010 to 2019 were reviewed retrospectively. LGD was diagnosed in all patients during surveillance. The frequency and risk factors for advanced neoplasia were evaluated, and the clinical features of patients with and without advanced neoplasia were compared.

Advanced neoplasia developed in 12 patients (six with large LGD, three with tubulovillous adenoma, and three with high-grade dysplasia), and all cases developed from UC. Patients with advanced neoplasia had significantly higher Mayo scores, and colitis-associated dysplasia was more common than sporadic lesions (83.3% vs. 29.9%; p<0.001). Multivariate analysis showed that colitis-associated LGD significantly increased the risk of developing advanced neoplasia (odds ratio [OR], 10.516; 95% confidence interval [CI], 2.064-53.577). Among patients with colitis-associated lesions, a significant risk factor for advanced neoplasia was a prior history of LGD (OR, 9.429; 95% CI, 1.330-66.863).

Advanced neoplasia developed in 7.2% of patients with IBD and LGD. Most advanced neoplasms developed from colitis-associated lesions, and the risk was higher in patients with a history of LGD before index colonoscopy.

Both intrinsic and extrinsic mechanisms underpin the profound intertumoral heterogeneity in breast cancer. Increasing evidence suggests that the intrinsic characteristics of breast epithelial precursor cells may influence tumour phenotype. These "cells-of-origin" of cancer preside in normal breast tissue and are uniquely susceptible to mutagenesis upon exposure to distinct oncogenic stimuli. Notably, molecular profiling studies have revealed strong concordance between the gene expression profiles of breast cancer subtypes and discrete cell types within the normal breast epithelium. Further characterisation of cells-of-origin of breast cancer requires comprehensive delineation of the normal mammary stem cell hierarchy. To this end, mouse models have provided valuable tools for exploring stem and progenitor cell function and identifying potential targets of neoplastic transformation via in vivo lineage-tracing studies. Nonetheless, the murine mammary differentiation hierarchy does not fully recapitulate human biology, and complementary studies using patient-direct breast tissue are critical. There is also accumulating evidence that extrinsic factors such as the microenvironment of premalignant cells can influence tumour initiation, highlighting opportunities for targeting cancer cells-of-origin via deconvolution of the premalignant epithelial niche. Pertinently, the identification of premalignant clones and targetable molecular perturbations responsible for driving their oncogenic transformation has critical implications for disease management and prevention.

Anal cancer incidence is rising globally, driven primarily by human papillomavirus (HPV) infection. HPV, especially high-risk types 16 and 18, is considered a necessary cause of anal squamous cell carcinoma. Certain populations like people living with HIV, men who have sex with men, inflammatory bowel disease patients, smokers, and those with compromised immunity face elevated risk. Chronic inflammation facilitates viral persistence, cell transformation, and immune evasion through pathways involving the PD-1/PD-L1 axis. HIV coinfection further increases risk by impairing immune surveillance and epithelial integrity while promoting HPV oncogene expression. Understanding these inflammatory processes, including roles of CD8 + T cells and PD-1/PD-L1, could guide development of immunotherapies against anal cancer. This review summarizes current knowledge on inflammation's role in anal cancer pathogenesis and the interplay between HPV, HIV, and host immune factors.

Bondarzewia dickinsii (BD) is a newly discovered edible mushroom with rich nutritional components. This study presents a thorough analysis of the components of BD, examining its inhibitory effects and the underlying mechanisms by which BD influences colitis-associated cancer (CAC).

AOM/DSS-induced CAC mice (male C57BL/6) were used, and a histopathological analysis, intestinal microbiota assessment, and metabolomics profiling were carried out, as well as an evaluation of relevant proteins and factors, to investigate the CAC-inhibitory effects of BD.

BD is rich in nutritional components, including a total sugar content of 37.29% and total protein content of 24.9%. BD significantly diminished colon inflammation, as well as the size and quantity of tumors. In addition, BD modified the diversity of intestinal microbiota and changed the levels of 19 serum metabolites, including arachidonic acid. BD significantly reduced prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) in colon tissue. Furthermore, it was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/COX-2 signaling pathway.

In general, BD inhibited the onset and progression of CAC by modulating the composition of intestinal microbiota and metabolite levels, suppressing the PI3K/AKT/COX-2 pathway, and decreasing PGE2 expression. This study provides a significant reference for the development of BD as a dietary supplement and pharmaceutical agent in the treatment of CAC.

Alterations in intestinal structure, mechanics and physiology underlie acute and chronic intestinal conditions, many of which are influenced by dysregulation of microbiome, peristalsis, stroma or immune responses. Studying human intestinal physiology or pathophysiology is difficult in preclinical animal models because their microbiomes and immune systems differ from those of humans. Although advances in organoid culture partially overcome this challenge, intestinal organoids still lack crucial features that are necessary to study functions central to intestinal health and disease, such as digestion or fluid flow, as well as contributions from long-term effects of living microbiome, peristalsis and immune cells. Here, we review developments in organ-on-a-chip (organ chip) microfluidic culture models of the human intestine that are lined by epithelial cells and interfaced with other tissues (such as stroma or endothelium), which can experience both fluid flow and peristalsis-like motions. Organ chips offer powerful ways to model intestinal physiology and disease states for various human populations and individual patients, and can be used to gain new insight into underlying molecular and biophysical mechanisms of disease. They can also be used as preclinical tools to discover new drugs and then validate their therapeutic efficacy and safety in the same human-relevant model.

Chronic inflammation is a significant driver in the development of various diseases, including cancer. Colitis-associated colorectal cancer (CA-CRC) refers to the increased risk of colorectal cancer in individuals with chronic inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease.

This narrative review examines the link between chronic inflammation and CA-CRC. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science, focusing on studies published between 2000 and 2024. Studies were selected based on relevance to the role of inflammation in CA-CRC, specifically targeting molecular pathways and clinical implications. Both clinical and mechanistic studies were reviewed.

Sustained inflammation in the colon fosters a pro-tumorigenic environment, leading to the initiation and progression of CA-CRC. Prevention strategies must focus on controlling chronic inflammation, optimizing IBD management, and implementing regular screenings. Emerging therapies targeting key inflammatory pathways and immune responses, along with microbiome modulation, hold promise for reducing CA-CRC risk. Understanding these molecular mechanisms provides a path toward personalized treatment and better outcomes for patients with IBD at risk of colorectal cancer.

Inflammatory bowel diseases (IBD) and their sequela (colitis-associate carcinoma and fibrostenotic complications) remain a significant clinical challenge and novel therapeutic targets are desperately needed. AXL, a receptor tyrosine kinase, has been implicated in myriad cellular functions central to the pathogenesis of IBD. These include facilitating epithelial-to-mesenchymal transition, dampening of Toll-like receptor and natural killer cell mediated immune responses, driving proliferation, and propagating fibrogenic signaling. The vast majority of preclinical research on AXL has focused on its role in cancer. As such, pharmacologic AXL inhibitors are currently in clinical trials, but the indications remain limited to malignancy. In this chapter, we summarize the current preclinical data of AXL in IBD, colitis associated carcinoma, and fibrostenotic disease, and highlight its potential as a novel therapeutic target.

Aberrant signaling through damage-associated molecular patterns (DAMPs) has been linked to several health disorders, attracting considerable research interest over the last decade. Adenosine triphosphate (ATP), a key extracellular DAMP, activates the purinergic receptor P2X7, which acts as a danger sensor in immune cells and is implicated in distinct biological functions, including cell death, production of pro-inflammatory cytokines, and defense against microorganisms. In addition to driving inflammation mediated by immune and non-immune cells, the persistent release of endogenous DAMPs, including ATP, has been shown to result in epigenetic modifications. In intestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), consequent amplification of the inflammatory response and the resulting epigenetic reprogramming may impact the development of pathological changes associated with specific disease phenotypes. P2X7 is overexpressed in the gut mucosa of patients with IBD, whereas the P2X7 blockade prevents the development of chemically induced experimental colitis. Recent data suggest a role for P2X7 in determining gut microbiota composition. Regulatory mechanisms downstream of the P2X7 receptor, combined with signals from dysbiotic microbiota, trigger intracellular signaling pathways and inflammasomes, intensify inflammation, and foster colitis-associated CRC development. Preliminary studies targeting the ATP-P2X7 pathway have shown favorable therapeutic effects in human IBD and experimental colitis.

Gastrointestinal (GI) cancers, including gastric, liver, esophageal, pancreatic, and colorectal cancers, represent significant global health burdens. Emerging evidence suggests that dietary patterns, particularly their inflammatory and oxidative properties, may influence cancer risk. The Dietary Inflammatory Index (DII) and Dietary Oxidative Balance Score (DOBS) assess the inflammatory and oxidative effects of diets, respectively. This study aims to explore the association between DII, DOBS, and the combined risk of GI cancers, and investigates the potential mediating roles of serum albumin and red cell distribution width (RDW).

Data from 26,320 participants in the NHANES 2005-2018 cycles were analyzed. DII was calculated based on 28 dietary components, and DOBS included 17 nutrients (3 pro-oxidants and 14 antioxidants). Logistic regression models assessed the associations between DII, DOBS, and GI cancers. Restricted cubic spline (RCS) models examined dose-response relationships. Mediation analysis evaluated the roles of serum albumin and RDW. Subgroup analyses explored interactions with demographic and health-related factors.

Higher DII was associated with increased GI cancer risk (OR: 1.26, 95% CI: 1.07-1.49 per unit increase), while higher DOBS was associated with reduced risk (OR: 0.90, 95% CI: 0.76-0.99 per unit increase). RCS analysis indicated a significant nonlinear relationship between DII and GI cancer risk. Serum albumin and RDW partially mediated the associations between DII, DOBS, and GI cancers. Subgroup analyses showed stronger associations for DII among certain demographics, and significant interactions were found between DII and BMI. For DOBS, significant interactions were observed with age and BMI.

This study reveals significant associations between dietary inflammatory and oxidative balance scores and GI cancer risk. Higher DII is linked to increased risk, while higher DOBS is protective. The mediating roles of serum albumin and RDW provide insights into underlying mechanisms. These findings underscore the potential of dietary modifications in GI cancer prevention and management, emphasizing the importance of anti-inflammatory and antioxidant-rich diets.

Colorectal cancer (CRC) screening is essential to reduce incidence and mortality rates. However, participation in screening remains suboptimal. ColonFlag, a machine learning algorithm using complete blood count (CBC), identifies individuals at high CRC risk using routinely performed tests. This study aims to review the existing literature assessing the efficacy of ColonFlag across diverse populations in multiple countries.

The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) were followed in reporting this systematic review. Searches were conducted on PubMed, Cochrane, ScienceDirect, and Google Scholar for English articles, using keywords related to CBC, machine learning, ColonFlag, and CRC, covering the first development study from 2016 to August 2023. The Cochrane Prediction Model Risk of Bias Assessment Tool (PROBAST) was used to assess the risk of bias.

A total of 949 articles were identified during the literature search. Ten studies were found to be eligible. ColonFlag yielded Area Under the Curve (AUC) values ranging from 0.736 to 0.82. The sensitivity and specificity ranged from 3.91% to 35.4% and 82.73% to 94%, respectively. The positive predictive values ranged between 2.6% and 9.1%, while the negative predictive values ranged from 97.6% to 99.9%. ColonFlag performed better in shorter time windows, tumors located more proximally, in advanced stages, and in cases of CRC compared to adenoma.

While ColonFlag exhibits low sensitivity compared to established screening methods such as the fecal immunochemical test (FIT) or colonoscopy, its potential to detect CRC before clinical diagnosis suggests an opportunity for identifying more cases than regular screening alone.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplements have exhibited inconsistent effects on cancer risk, and their potential efficacy as cancer preventive agents has been increasingly questioned, especially in recent large randomized clinical trials. The role of host factors that govern EPA and DHA metabolism in relation to their impact on carcinogenesis remains understudied. Resolvins, the products of EPA and DHA oxidative metabolism, demonstrate intriguing antitumorigenic effects through mechanisms such as promoting macrophage phagocytosis of cell debris and inhibiting the production of proinflammatory chemokines and cytokines by tumor-associated macrophages (TAMs), which are crucial for cancer progression. However, clinical studies have not yet shown a significant increase in target tissue levels of resolvins with EPA and DHA supplementation. 15-Lipoxygenase-1 (ALOX15), a key enzyme in EPA and DHA oxidative metabolism, is often lost in various major human cancers, including precancerous and advanced colorectal cancers. Further research is needed to elucidate whether the loss of ALOX15 expression in colorectal precancerous and cancerous cells affects EPA and DHA oxidative metabolism, the formation of resolvins, and subsequently carcinogenesis. The findings from these studies could aid in the development of novel and effective chemoprevention interventions to reduce cancer risk.

Colorectal cancer (CRC) is the third most common cancer worldwide, acting as a significant public health problem. 5-Fluorouracil (5-FU) is a key chemotherapy for various types of cancer, due to its broad anticancer activity. However, the emergence of drug resistance is a considerable limitation in the clinical application of 5-FU. Quercetin (QC) is proposed as an adjuvant therapy to minimize drug resistance to chemotherapeutics and enhance their pharmacological efficacy. The oral delivery of 5-FU and QC is challenged by poor aqueous solubility of QC and poor cellular permeability of 5-FU. To solve this issue, novel polylactide-co-glycolide (PLGA) combinatorial nanoparticles loading 5-FU and QC were prepared to deliver them directly to the colon. These sustained-release combinatorial nanoparticles recorded a significant decrease in cancer cell proliferation, C-reactive protein (CRP) level, and Interleukin-8 (IL-8) expression by 30.08%, 40.7%, and 46.6%, respectively. The results revealed that this combination therapy may offer a new strategy for the targeted delivery of chemotherapeutics to the colon.

Cancer neuroscience, a promising field dedicated to exploring interactions between cancer and the nervous system, has attracted growing attention. The gastrointestinal tracts exhibit extensive innervation, notably characterized by intrinsic innervation. The gut harbors a substantial population of glial cells, including Schwann cells wrapping axons of neurons in the peripheral nervous system and enteric glial cells intricately associated with intrinsic innervation. Glial cells play a crucial role in maintaining the physiological functions of the intestine, encompassing nutrient absorption, barrier integrity, and immune modulation. Nevertheless, it has only been in recent times that the significance of glial cells within colorectal cancer (CRC) has begun to receive considerable attention. Emerging data suggests that glial cells in the gut contribute to the progression and metastasis of CRC, by interacting with cancer cells, influencing inflammation, and modulating the tumor microenvironment. Here, we summarize the significant roles of glial cells in the development and progression of CRC and discuss the latest technologies that can be integrated into this field for in-depth exploration, as well as potential specific targeted strategies for future exploration to benefit patients.

Large nonpedunculated colorectal polyps ≥ 20 mm (LNPCPs) comprise 1% of all colorectal lesions. LNPCPs are more likely to contain advanced histology such as high-grade dysplasia and submucosal invasive cancer (SMIC). Endoscopic resection is the first-line approach for management of these lesions. Endoscopic resection options include endoscopic mucosal resection (EMR), cold-snare EMR (EMR), endoscopic submucosal dissection (ESD) and endoscopic full-thickness resection (EFTR). This review aimed to critically evaluate current endoscopic resection techniques.

Evidence-based selective resection algorithms should inform the most appropriate endoscopic resection technique. Most LNPCPs are removed by conventional EMR but there has been a trend toward C-EMR for endoscopic resection of LNPCPs. More high-quality trials are required to better define the limitations of C-EMR. Advances in our understanding of ESD technique, has clarified its role within the colorectum. More recently, the development of a full thickness resection device (FTRD) has allowed the curative endoscopic resection of select lesions.

Endoscopic resection should be regarded as the principle approach for all LNPCPs. Underpinned by high-quality research, endoscopic resection has become more nuanced, leading to improved patient outcomes.

Patients with inflammatory bowel diseases (IBDs), including both ulcerative colitis (UC) and Crohn's disease (CD), are at a higher risk of developing colorectal cancer (CRC). However, advancements in endoscopic imaging techniques, integrated surveillance programs, and improved medical therapies have led to a decrease in the incidence of CRC among IBD patients. Currently, the management of patients with IBD who have a history of or ongoing active malignancy is an unmet need. This involves balancing the risk of cancer recurrence/progression with the potential exacerbation of IBD if the medications are discontinued. The objective of this review is to provide an updated summary of the epidemiology, causes, risk factors, and surveillance approaches for CRC in individuals with IBD, and to offer practical guidance on managing IBD patients with history of previous or active cancer.

Estrogen is a significant hormone that is involved in a multitude of physiological and pathological processes. In addition to its pivotal role in the reproductive system, estrogen is also implicated in the pathogenesis of a multitude of diseases. Nevertheless, previous research on the role of estrogen in a multitude of diseases, including Alzheimer's disease, depression, cardiovascular disease, diabetes, osteoporosis, gastrointestinal diseases, and estrogen-dependent cancers, has concentrated on a single disease area, resulting in a lack of comprehensive understanding of cross-disease mechanisms. This has brought some challenges to the current treatment methods for these diseases, because estrogen as a potential therapeutic tool has not yet fully developed its potential. Therefore, this review aims to comprehensively explore the mechanism of estrogen in these seven types of diseases. The objective of this study is to describe the relationship between each disease and estrogen, including the ways in which estrogen participates in regulating disease mechanisms, and to outline the efficacy of estrogen in treating these diseases in clinical practice. By studying the role of estrogen in a variety of disease mechanisms, it is hoped that a more accurate theoretical basis and clinical guidance for future treatment strategies will be provided, thus promoting the effective management and treatment of these diseases.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, affecting millions each year. It emerges from the colon or rectum, parts of the digestive system, and is closely linked to both genetic and environmental factors. In CRC, genetic mutations such as APC, KRAS, and TP53, along with epigenetic changes like DNA methylation and histone modifications, play crucial roles in tumor development and treatment responses. This paper delves into the complex biological underpinnings of CRC, highlighting the pivotal roles of genetic alterations, cell death pathways, and the intricate network of signaling interactions that contribute to the disease's progression. It explores the dysregulation of apoptosis, autophagy, and other cell death mechanisms, underscoring the aberrant activation of these pathways in CRC. Additionally, the paper examines how mutations in key molecular pathways, including Wnt, EGFR/MAPK, and PI3K, fuel CRC development, and how these alterations can serve as both diagnostic and prognostic markers. The dual function of autophagy in CRC, acting as a tumor suppressor or promoter depending on the context, is also scrutinized. Through a comprehensive analysis of cellular and molecular events, this research aims to deepen our understanding of CRC and pave the way for more effective diagnostics, prognostics, and therapeutic strategies.

Neutrophils are recognized active participants in inflammatory responses and are intricately linked to cancer progression. In response to inflammatory stimuli, neutrophils become activated, releasing neutrophils extracellular traps (NETs) for the capture and eradication of pathogens, a phenomenon termed NETosis. With a deeper understanding of NETs, there is growing evidence supporting their role in cancer progression and their involvement in conferring resistance to various cancer therapies, especially concerning tumor reactions to chemotherapy, radiation therapy (RT), and immunotherapy. This review summarizes the roles of NETs in the tumor microenvironment (TME) and their mechanisms of neutrophil involvement in the host defense. Additionally, it elucidates the mechanisms through which NETs promote tumor progression and their role in cancer treatment resistance, highlighting their potential as promising therapeutic targets in cancer treatment and their clinical applicability.

The intricate consortium of microorganisms in the human gut plays a crucial role in different physiological functions. The complex known-unknown elements of the gut microbiome are perplexing and the absence of standardized procedures for collecting and preserving samples has hindered continuous research in comprehending it. The technological bias produced because of lack of standard protocols has affected the reproducibility of results. The complex nature of diseases like colorectal cancer, gastric cancer, hepatocellular carcinoma and breast cancer require a thorough understanding of its etiology for an efficient and timely diagnosis. The designated protocols for collection and preservation of stool specimens have great variance, hence generate inconsistencies in OMICS studies. Due to the complications associated to the nature of sample, it is important to preserve the sample to be studied later in a laboratory or to be used in the future research purpose. Stool preservation is gaining importance due to the increased use of treatment options like fecal microbiota transplantation to cure conditions like recurrent Clostridium difficile infections and for OMICS studies including metagenomics, metabolomics and culturomics. This review provides an insight into the importance of omics studies for the identification and development of novel biomarkers for quick and noninvasive diagnosis of various diseases.

Colorectal cancer has the highest mortality rate of all digestive system diseases. Considering the debate about cytokines and biases that exist in traditional observational study designs, we performed a two-sample Mendelian randomization (MR) analysis to explore the association of circulating cytokines with CRC risk. In this study, we used cytokine genetic variants from a recently published genome-wide association study (GWAS) including 14,824 European-ancestry participants. Summary-level data for colorectal cancer were obtained from genome-wide association analyses of the FinnGen consortium. In addition, we conducted independent supplementary analyses using genetic variation data of colorectal cancer and cytokines from a large public GWAS in 2021. Among 91 circulating factors, we only found IL-12B to be significantly associated with CRC risk (odds ratio [OR]: 1.19; 95% confidence interval [CI]: 1.00-1.42; p = .046). We used 2021 data for analysis and found that higher Interleukin-12p70 levels (IL-12p70) were revealed to have a significant positive association with CRC risk (OR: 1.27; 95% CI: 1.13-1.43; p < 1.22 × 10-3). Moreover, CRC was suggestively correlated with an elevated level of vascular endothelial growth factor (VEGF) (OR: 1.17; 95% CI: 1.02-1.35; p = .026), macrophage colony-stimulating factor (M-CSF) (OR: 0.85; 95% CI: 0.76-0.96; p = .005), IL-13 (OR: 1.15; 95% CI: 1.02-1.30; p = .028), IL-10 (OR: 1.23; 95% CI: 1.01-1.49; p = .037), and IL-7 (OR: 1.19; 95% CI: 1.02-1.39; p = .024). Our MR studies support that one cytokine IL-12 is significantly associated with CRC risk and that five cytokines VEGF, M-CSF, IL-13, IL-10, and IL-7 are associated with CRC risk.

Apart from cytotoxicity, inhibitors of the COX-2 enzyme have demonstrated additional effects important for cancer treatment (such as radiosensitization of tumor cells and cell antimigratory effects); however, the relationship between the inhibition of other inflammation-related enzyme 5-LOX inhibitors and anticancer activity is still not well understood. In our study, the cytotoxicity of thirteen COX-2 and 5-LOX inhibitors previously presented by our group (1-13) was tested on three cancer cell lines (HCT 116, HT-29 and BxPC-3) and one healthy cell line (MRC-5). Compounds 3, 5, 6 and 7 showed moderate cytotoxicity, but good selectivity towards cancer cell lines. IC50 values were in the range of 22.99-51.66 µM (HCT 116 cell line), 8.63-41.20 µM (BxPC-3 cell line) and 24.78-81.60 µM (HT-29 cell line; compound 7 > 100 µM). In comparison to tested, commercially available COX-2 and 5-LOX inhibitors, both cytotoxicity and selectivity were increased. The addition of compounds 6 and 7 to irradiation treatment showed the most significant decrease in cell proliferation of the HT-29 cell line (p < 0.001). The antimigratory potential of the best dual COX-2 and 5-LOX inhibitors (compounds 1, 2, 3 and 5) was tested by a wound-healing assay using the SW620 cell line. Compounds 1 and 3 were singled out as compounds with the most potent effect (relative wound closure was 3.20% (24 h), 5,08% (48 h) for compound 1 and 3.86% (24 h), 7.68% (48 h) for compound 3). Considering all these results, compound 3 stood out as the compound with the most optimal biological activity, with the best dual COX-2 and 5-LOX inhibitory activity, good selectivity towards tested cancer cell lines, significant cell antimigratory potential and a lack of toxic effects at therapeutic doses.

This study aimed to conduct a bibliometric analysis of research articles on the relationship between inflammatory bowel disease (IBD) and colorectal cancer (CRC) using CiteSpace to summarize the current research status, hotspots, and trends in this field and present the results visually.

Research articles on the relationship between IBD and CRC published from 2000 to 2023 and in English were selected from the Web of Science Core Collection (Woscc) database. The articles were downloaded as "full record and references". CiteSpace was used to conduct cooperative, cluster, co-citation, and burst analyses.

The literature search revealed 4244 articles; of which, 5 duplicates were removed, resulting in the inclusion of 4239 articles in this study. The United States of America had the highest number of publications, with Mayo Clinic and Harvard University being the most active institutions, and Bas Oldenburg being the most active author. Collaboration among core authors was inadequate. JA Eaden was the most cited author, and CRC was the most common keyword. Burst analysis indicated that Sun Yat-sen University might be one of the institutions with a large contribution to this research field in the future. Cluster analysis showed that earlier research focused more on microsatellite instability, whereas "gut microbiota" and "oxidative stress" are considered current research hotspots and trends.

At present, the primary focus areas of research are "gut microbiota" and "oxidative stress". With the improvement of healthcare policies and standards, regular endoscopic monitoring of patients with IBD has become an indispensable diagnostic and therapeutic practice. More drugs will be developed to reduce the risk of progression from IBD to CRC. The findings of this study provide valuable insights into the relationship between IBD and CRC for researchers in the same field.

Chronic inflammation drives the growth of colorectal cancer through the dysregulation of molecular pathways within the immune system. Infiltration of immune cells, such as macrophages, into tumoral regions results in the release of proinflammatory cytokines (IL-6; IL-17; TNF-α), fostering tumor proliferation, survival, and invasion. Tumors employ various mechanisms to evade immune surveillance, effectively 'cloaking' themselves from detection and subsequent attack. A comprehensive understanding of these intricate molecular interactions is paramount for advancing novel strategies aimed at modulating the immune response against cancer.