Development Of Colorectal Cancer Research Articles

Non-coding RNAs and exosomal ncRNAs in colorectal cancer

Abstract Colorectal cancer (CRC) is a complex disease with many genetic and epigenetic changes leading to dysregulation of cell signaling pathways. In recent years, increasing attention has been paid to the role of non-coding RNA (ncRNA) and exogenous ncRNA in the development and progression of CRC. ncRNAs play an essential role in the regulation of gene expression and cell function, and dysregulation of ncRNA expression is associated with the onset and progression of CRC. In this review, we discuss the molecular pathways involved in CRC and the emerging roles of ncRNAs and exogenous ncRNAs in the regulation of these pathways. We focus on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and exogenous ncRNAs and their roles in regulating key signaling pathways such as the Wnt/β signaling pathway. β-catenin, PI3K/Akt, and TGF-β. We also discuss the potential of ncRNAs and exogenous ncRNAs as diagnostic and prognostic biomarkers for CRC, as well as their potential as therapeutic targets for CRC. Advances in ncRNA-based therapies present promising opportunities for the development of new therapies for CRC. A better understanding of the roles of ncRNAs and exogenous ncRNAs may lead to the development of new therapeutic strategies for this disease.

Lysyl oxidase inhibitors in colorectal cancer progression.

The lysine oxidase (LOX) family, consisting of LOX and LOX-like-1-4 (LOXL1-LOXL4), catalyses the cross-linking reaction of collagen and elastin in the extracellular matrix (ECM). Numerous studies have demonstrated that LOX family members are dysregulated in a variety of cancers, including colorectal cancer (CRC), and play a key role in cancer cell migration, proliferation, invasion and metastasis. Targeting LOX family proteins with specific inhibitors has therefore been developed as a new therapeutic strategy for cancer. In this paper, we review the role of LOX enzymes in the development and progression of CRC. In addition, we address recent advances in the development of LOX/LOXL inhibitors, highlighting the potential use of this inhibitor as an effective and complementary treatment for CRC.

STAT3-related lncRNAs in colorectal cancer progression; Special focus on immune cell's evasion.

Colorectal cancer (CRC) is globally ranked as the third leading cause of cancer-related deaths in both men and women. There is an urgent need for novel biomarkers to facilitate early diagnosis and enhance patient care, thereby improving treatment response and reducing mortality rates. Signal transducer and activator of transcription 3 (STAT3) is essential for controlling the anti-tumor immune response since it is a hub for several oncogenic signaling pathways. In the tumor environment, STAT3 is widely overactivated in both malignant and non-cancerous cells. It is involved in suppressing the expression of critical immune activation regulators and encouraging the synthesis of immunosuppressive substances. Long noncoding RNAs (lncRNAs), a kind of non-coding RNA, are critical for CRC development, apoptosis, and metastasis because they influence important signaling pathways such as STAT3 signaling and contribute to gene regulation at the epigenetic, transcriptional, and post-transcriptional levels. Moreover, lncRNAs have a significant role in modifying the TME and control the expression of important immunological checkpoints, such as PD-L1. Therefore, a comprehensive understanding of the regulatory roles of lncRNAs is crucial for identifying diagnostic, prognostic, and predictive biomarkers for CRC. Thus, the objective of the present review study is to provide a comprehensive overview of the interaction between the STAT3 signaling pathway and various lncRNAs, as well as their implications for apoptosis, metastasis, and immune evasion in CRC.

Risk factors for relapse based on the molecular profiling of Japanese patients with stage II colorectal cancer.

215 Background: The association between the molecular profiles and prognosis of Stage II colorectal cancer (CRC) remains unclear. This study aimed to evaluate the long-term outcomes of Stage II CRC based on the molecular profiling and to examine the risk factors for relapse. Methods: We retrospectively enrolled Japanese patients with pStage II CRC without pre- and/or postoperative adjuvant therapy and whose surgically resected specimens were evaluated using gene expression and whole exome analyses from January 2014 to December 2018. We evaluated the 5-year overall survival (OS) and relapse-free survival (RFS), and examined the risk factors for RFS. Results: We evaluated 322 patients with pStage II CRC, including 126 (39.1%) with right colon cancer, 133 (41.3%) with left colon cancer and 63 (19.6%) with rectal cancer. There were 87 patients (27.0%) with pT4, 175 (54.3%) with venous invasion, 120 (37.3%) with lymphatic invasion, and 68 (21.1%) with perineural invasion. Whole exome analyses revealed that there were 48 patients (14.9%) with MSI-High, and the presence of mutations in key genes for colorectal cancer development was as follows: APC , 245 (76.1%); TP53 , 208 (64.6%); KRAS , 134 (6.5%); PIK3CA , 64 (19.9%); FBXW7 , 27 (8.4%); and BRAF , 21 (6.5%). The 5-year OS and RFS rates were 98.0% and 90.7%, respectively. According to the consensus molecular subtype (CMS) classification based on gene expression, 76 patients (23.6%) had CMS4 and a significantly lower RFS than the other patients (5-year RFS: 83.8% vs. 92.9%, p=0.017). The independent risk factors for RFS were perineural invasion (Hazard ratio [HR] 5.316, p<0.001) and CMS4 (HR 2.399, p=0.020). Conclusions: Molecular profiling of Stage II CRC to assess the risk factors for relapse may contribute to the indication and drug selection for postoperative adjuvant chemotherapy and lead to personalized treatment to improve prognosis.

Polyp and tumor microenvironment reprogramming in colorectal cancer: insights from mucosal bacteriome and metabolite crosstalk

BackgroundHighly frequent colorectal cancer (CRC) is predicted to have 3.2 million novel cases by 2040. Tumor microenvironment (TME) bacteriome and metabolites are proposed to be involved in CRC development. In this regard, we aimed to investigate the bacteriome and metabolites of healthy, adenomatous polyp, and CRC tissues.MethodsSixty samples including healthy (H), adenomatous polyps (AP), adenomatous polyps-adjacent (APA), cancer tumor (CT), and cancer tumor-adjacent (CA) tissues were collected and analyzed by 16 S rRNA sequencing and 1H NMR spectroscopy.ResultsOur results revealed that the bacteriome and metabolites of the H, AP, and CT groups were significantly different. We observed that the Lachnospiraceae family depleted concomitant with acetoacetate and beta-hydroxybutyric acid (BHB) accumulations in the AP tissues. In addition, some bacterial species including Gemella morbillorum, and Morganella morganii were enriched in the AP compared to the H group. Furthermore, fumarate was accumulated concomitant to Aeromonas enteropelogenes, Aeromonas veronii, and Fusobacterium nucleatum subsp. animalis increased abundance in the CT compared to the H group.ConclusionThese results proposed that beneficial bacteria including the Lachnospiraceae family depletion cross-talk with acetoacetate and BHB accumulations followed by an increased abundance of driver bacteria including G. morbillorum, and M. morganii may reprogram polyp microenvironment leading to tumor initiation. Consequently, passenger bacteria accumulation like A. enteropelogenes, A.veronii, and F. nucleatum subsp. animalis cross-talking fumarate in the TME may aggravate cancer development. So, knowledge of TME bacteriome and metabolites might help in cancer prevention, early diagnosis, and a good prognosis.

The Role of APOA1-AS in Colorectal Cancer: Investigating Its Association with Malignant Biological Behaviors.

Colorectal cancer (CRC) is a common malignant tumor associated with high morbidity and mortality. Long non-coding RNAs (lncRNAs) play crucial roles in cancer development and progression. This study aimed to explore the role of lncRNA APOA1-AS in colorectal cancer and elucidate its underlying mechanisms. Clinical samples were collected, and high-throughput sequencing was performed to identify differentially expressed lncRNAs in colorectal cancer. Among these, the key lncRNA APOA1-AS was selected for further investigation. The expression of APOA1-AS in colorectal cancer tissues and cells was evaluated. The effects of APOA1-AS on cell proliferation, migration, invasion, and apoptosis were assessed through knockdown and overexpression of APOA1-AS in SW620 and RKO cells. Additionally, the relationship between APOA1-AS and the malignant biological behaviors of colorectal cancer cells was also investigated. Furthermore, the involvement of APOA1-AS in glucose metabolism reprogramming and the cGMP-PKG signaling pathway was analyzed. A total of 2,985 differentially expressed lncRNAs were identified in colorectal cancer, including APOA1-AS, which showed the most significant upregulation. APOA1-AS expression was significantly higher in colorectal cancer tissues compared to normal tissues. Overexpression of APOA1-AS promoted cell proliferation, migration, and invasion while inhibiting apoptosis in SW620 and RKO cells. Furthermore, APOA1-AS was found to regulate glucose metabolism reprogramming, enhance tumor malignant biological behaviors and facilitate tumor cell drug resistance through the cGMP-PKG signaling pathway. Our study demonstrates that APOA1-AS is a potential key regulator in colorectal cancer development and progression. It functions via glucose metabolism reprogramming and the cGMP-PKG signaling pathway, offering a novel therapeutic target for colorectal cancer.

Clustering-Based Hybrid Model for Predicting Symptoms for Colorectal Cancer: A Fuzzy Machine Learning Approach

Colorectal cancer (CRC) is a form of cancer that originates in the colon (large intestine) or rectum, which are components of the digestive system. It generally begins as small, benign growths known as polyps that can form on the inner lining of the colon or rectum. In Malaysia, colorectal cancer ranks among the most prevalent cancers, especially within the Chinese and Malay communities. A study released by the Malaysian National Cancer Registry indicates that colorectal cancer is the second most common cancer type following breast cancer, impacting both genders. The occurrence of colorectal cancer in Malaysia has been consistently increasing, with approximately 15–20% of cancer cases in the nation being colorectal cancer. This type of cancer arises when cells in the body start to multiply excessively, leading to various symptoms. In this research, a novel hybrid fuzzy linear regression with symmetric parameter clustering combined with a support vector machine (FLRWSPCSVM) model is employed to predict the high-risk symptoms associated with the onset of colorectal cancer in Malaysia. The study analyzed secondary data from 180 patients diagnosed with colorectal cancer and treated in a general hospital in Kuala Lumpur, considering twenty-five independent variables with various combinations of variable types. Furthermore, the model included parameters, errors, and explanations, along with two statistical measurement errors. The findings revealed that FLRWSPCSVM identified ovarian symptoms and a history of cancer symptoms as high-risk indicators for the development of colorectal cancer, with the lowest mean square error (MSE) recorded at 100.605 and a root mean square error (RMSE) of 10.030.

Vaccines for cancer interception in familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an inherited autosomal dominant disorder caused by germline mutations in the adenomatous polyposis coli (APC) gene. FAP is associated with the development of hundreds of adenomas in the small and large intestines of individuals starting in the teenage years with a near 100% risk of developing colorectal cancer by adulthood. Eventually polyps develop throughout the gastrointestinal tract. Chemoprevention approaches have been somewhat successful in reducing polyp burden, but have not reduced the risk of the development of colorectal cancer or other cancers. The lack of efficacy of more standard drug approaches may be due to limited exposure to the agent only to specific periods while the drug is being metabolized, limited drug penetrance in the colon, and patient adherence to daily dosing and drug side effects. The success of immune therapy for the treatment of invasive cancer has led to research focused on the use of immune based approaches for polyp control in FAP, specifically polyp directed vaccines. Vaccines targeting antigens expressed in FAP lesions may be a superior method to control polyp burden and prevent disease progression as compared to classic chemoprevention drugs. A limited number of vaccines can be administered over a short period of time to generate a lasting immune response. Appropriately primed antigen specific T-cells can traffic to any site in the body where antigen is expressed, recognize, and eliminate the antigen expressing cell. Immunologic memory will allow the immune response to persist and the specificity of the immune response will limit toxicity to the targeted polyp. This review will examine the current state of vaccines directed against FAP lesions and highlight the challenges and opportunities of translating vaccines for cancer interception in FAP to the clinic.

The Relationship of the Pathogenic Variant rs721048 in the Intron of the EHBP1 Gene with the Development of Prostate Cancer and Colorectal Cancer in the Kazakh Population

Background: Prostate cancer (PC) is one of the most common oncological diseases among men. Up to 20% of PC cases are associated with hereditary risks or syndromes. The impact of common variants, particularly EHBP1 c.1185+30064G>A rs721048, on developing PC and other malignancies remains unclear. There are also no data on the frequency of this variant in the Kazakh population or its association with PC, nor its potential connection with other malignancies, particularly colorectal cancer (CRC). Methods: We utilized the TruSight Cancer Sequencing Panel to assess pathological genomic variants in 72 male patients with histologically verified aggressive PC and 119 patients of Kazakh nationality with histologically confirmed CRC compared to the control group. Results: A variant in the intron of the EHBP1 gene c.1185+30064G>A rs721048 was identified in 18 patients (25%) out of 72 with PC, while in the control group of 41 healthy males, the rs721048 variant was found in only 4 (9.8%) individuals. In the CRC group, rs721048 was detected in 17 cases (14.2%) and eight control individuals (10%). Conclusions: The frequency of the EHBP1 c.1185+30064G>A rs721048 variant in the PC group was significantly higher (p < 0.05) than in healthy males of Kazakh nationality. Identifying EHBP1 c.1185+30064G>A among the male population of Kazakhstan will help form the high-risk groups for PC to prevent the development of malignant neoplasms. The presence of rs721048 was not significantly associated with the risk of developing CRC in our study.

Role of Crosstalk Between Gut Microbiota and Immune Cells in Colorectal Cancer: A Narrative Review

Abstract Colorectal cancer (CRC) ranks among the most prevalent and deadly cancers globally, with its incidence increasing due to lifestyle factors such as increased consumption of red meat and decreased vegetable intake. A distinctive aspect of CRC is its strong connection to the gut microbiota, which is crucial in both tumorigenesis and immune regulation. This narrative review provides a comprehensive analysis of the interactions between gut microbiota and the immune system, focusing on their importance in CRC progression and responses to immunotherapy. Imbalances in the composition of gut microbes are strongly associated with CRC development. Notably, species such as Fusobacterium nucleatum and Bacteroides fragilis have been identified as key regulators of immune responses within the tumor microenvironment. These microbes affect the functions of immune cells, such as T cells, macrophages and myeloid-derived suppressor cells, thereby influencing cancer progression and prognosis. Additionally, this review underscores the potential of gut microbiota as biomarkers for CRC detection and outcome prediction. There is also growing interest in the use of probiotics, fecal microbiota transplantation and dietary modifications as supplementary treatments. A deeper understanding of how microbial communities interact with the immune system may pave the way for novel personalized therapies, particularly by enhancing the effectiveness of immune checkpoint inhibitors.

Synergistic inhibition of colorectal cancer progression by silencing Aurora A and the targeting protein for Xklp2.

Unraveling the pathogenesis of colorectal cancer (CRC) can aid in developing prevention and treatment strategies. Aurora kinase A (AURKA) is a key participant in mitotic control and interacts with its co-activator, the targeting protein for Xklp2 (TPX2) microtubule nucleation factor. AURKA is associated with poor clinical outcomes and high risks of CRC recurrence. AURKA/TPX2 co-overexpression in cancer may contribute to tumorigenesis. Despite its pivotal role in CRC development and progression, the action mechanism of AURKA remains unclear. Further research is needed to explore the complex interplay between AURKA and TPX2 and to develop effective targeted treatments for patients with CRC. To compare effects of AURKA and TPX2 and their combined knockdown on CRC cells. We evaluated three CRC gene datasets about CRC (GSE32323, GSE25071, and GSE21510). Potential hub genes associated with CRC onset were identified using the Venn, search tool for the retrieval of interacting genes, and KOBAS platforms, with AURKA and TPX2 emerging as significant factors. Subsequently, cell models with knockdown of AURKA, TPX2, or both were constructed using SW480 and LOVO cells. Quantitative real-time polymerase chain reaction, western blotting, cell counting kit-8, cell cloning assays, flow cytometry, and Transwell assays were used. Forty-three highly expressed genes and 39 poorly expressed genes overlapped in cancer tissues compared to controls from three datasets. In the protein-protein interaction network of highly expressed genes, AURKA was one of key genes. Its combined score with TPX2 was 0.999, and their co-expression score was 0.846. In CRC cells, knockdown of AURKA, TPX2, or both reduced cell viability and colony number, while blocking G0/G1 phase and enhancing cell apoptosis. Additionally, they were weakened cell proliferation and migration abilities. Furthermore, the expression levels of B-cell lymphoma-2-Associated X, caspase 3, and tumor protein P53, and E-cadherin increased with a decrease in B-cell lymphoma-2, N-cadherin, and vimentin proteins. These effects were amplified when both AURKA and TPX2 were concurrently downregulated. Combined knockdown of AURKA and TPX2 was effective in suppressing the malignant phenotype in CRC. Co-inhibition of gene expression is a potential developmental direction for CRC treatment.

Crosstalk between GLTSCR1-deficient endothelial cells and tumour cells promotes colorectal cancer development by activating the Notch pathway.

Cancer stem cells (CSCs) typically reside in perivascular niches, but whether endothelial cells of blood vessels influence the stemness of cancer cells remains poorly understood. This study revealed that endothelial cell-specific GLTSCR1 deletion promotes colorectal cancer (CRC) tumorigenesis and metastasis by increasing cancer cell stemness. Mechanistically, knocking down GLTSCR1 induces the transformation of endothelial cells into tip cells by regulating the expression of Neuropilin-1 (NRP1), thereby increasing the direct contact and interaction between endothelial cells and tumour cells. In addition, GLTSCR1 inhibits JAG1 transcription by competing with acetylated p65(Lys-310) to bind to the BRD4 interaction site. Therefore, GLTSCR1 deficiency increases JAG1 expression in endothelial cells. Subsequently, increased JAG1 levels on tip cell membranes bind to Notch on CRC cell membranes, activating the Notch signalling pathway in tumour cells and increasing CRC cell stemness. Taken together, our findings highlight the roles of endothelial cells in CRC development.

Colorectal cAncer and CrohN's DIsease study (CANDID): An international multicentre retrospective audit

AbstractBackgroundInflammatory bowel disease (IBD) affects more than 10 million people worldwide. Men and women are equally affected by Crohn's disease (CD). It has been shown that patients with CD are at an increased risk of a colorectal cancer (CRC) diagnosis and CRC‐related mortality. During the last two decades, biological therapies have revolutionized the treatment of CD. There are no current studies investigating the prevalence of CRC in patients with CD in the era of biological therapy and the possible features of patients with CD who are at high risk of developing CRC.AimWe aim to assess the prevalence of CRC, risk factors and profile of CRC in patients with CD receiving biological treatment compared with those who are not under biological therapy and the impact of CD‐associated colorectal strictures on CRC development. The study hypothesis is that the use of biological therapy in the control of CD activity may decrease the risk of developing CRC.Study design and settingAn international, retrospective, snapshot of the prevalence of CRC in patients with CD, reported according to the SPIRIT guidelines. The study will involve centres that hold regular IBD multidisciplinary team meetings and have both IBD colorectal surgeons and gastroenterologists. Each participating centre will provide a local consultant lead and a local trainee lead. Data will be collected within a 2‐year recruitment period (January 2017–January 2019).Study populationAdult patients who presented with CD during the study period. Patients with an incidental diagnosis of CD during evaluation for CRC will be excluded.Statistical planBaseline patient characteristics will be summarized using the appropriate descriptive statistics. Univariable, multivariable and Cox regression models will be used to identify factors significantly associated with CRC. For noncontinuous variables a comparison between the subgroups will be carried out using the chi‐square test corrected by Fisher's exact test if appropriate. A p‐value of <0.05 will be considered statistically significant.Data storageData will be stored on a secured server, pin‐code protected according to the local data management agreement.

HDAC2 promotes colorectal tumorigenesis by triggering dysregulation of lipid metabolism through YAP1.

Dysfunction of lipid metabolism is important for the development and progression of colorectal cancer, but the underlying mechanisms remain unclear. Here, HDAC2 was identified as highly expressed in both adenoma and colorectal cancer. We aimed to explore the roles and mechanisms of HDAC2 in lipid metabolism in colorectal cancer. HDAC2 expression in adenoma and colorectal cancer tissues was measured using tissue arrays. The function of HDAC2/YAP1 was identified using in vitro and in vivo experiments. Coimmunoprecipitation experiments, DNA pull-down assays, luciferase analyses, and ChIP-qPCR (Chromatin Immunoprecipitation-quantitative real-time polymerase chain reaction) assays were used to identify the potential mechanisms of HDAC2. We found that HDAC2 can disrupt lipid metabolism in colorectal cancer by mediating the deacetylation of YAP1. Mechanistically, HDAC2 can bind to YAP1 and mediate deacetylation of the K280 site of YAP1. Furthermore, the deacetylation of YAP1 reduces the efficiency of its binding to the ZMYND11 promoter region, exacerbating lipid metabolism disorders, which in turn reduce lipid accumulation and increase lipid catabolism in colorectal cancer cells. Our study identified a novel regulatory mechanism of lipid metabolism in colorectal cancer in which HDAC2 increases lipid catabolism by regulating the deacetylation of the K280 site of YAP1, revealing that HDAC2 promotes tumor progression through the regulation of lipid metabolism.

Deciphering the impact of dietary habits and behavioral patterns on colorectal cancer.

Colorectal cancer (CRC) is a malignant tumor that originates from the epithelial cells of the colon and rectum. Global epidemiological data shows that in 2020, the incidence and mortality rate of CRC ranked third and second, respectively, posing a serious threat to people's health and lives. The factors influencing CRC are numerous and can be broadly categorized as modifiable and non-modifiable based on whether they can be managed or intervened upon. Non-modifiable factors include age, gender, family history, among others. Among the modifiable factors, dietary habits and behavioral practices are the main intervention measures that people can take to prevent CRC. Numerous studies indicate that a high intake of red and processed meats, fats, as well as habits such as smoking, alcohol consumption, and prolonged sitting, increase the risk of developing CRC. Conversely, consuming ample vegetables, fruits, high dietary fiber, and engaging in moderate regular exercise may reduce the risk of CRC. This article primarily discusses the impact of dietary habits and behavioral practices on the occurrence and development of CRC, along with possible mechanisms, laying the foundation and providing direction for the prevention and control of CRC occurrence and development.

Inhibition of BRD4 attenuated IFNγ-induced apoptosis in colorectal cancer organoids

BackgroundThis study aimed to analyze the functional role of Brd4 in colorectal cancer (CRC) organoids. Brd4 was identified as a CRC-related gene by our previous Sleeping Beauty mutagenesis transposon screening in mice. Brd4 is a transcriptional regulator that recognizes acetylated histones and is known to be involved in inflammatory responses. The role of Brd4 in CRC development remains largely unknown.MethodsWe knocked out Brd4 in tumor organoids carrying mutations in Apc and Kras to generate Brd4KO organoids, and performed RNA-seq. The response of Brd4KO organoids to IFNγ was analyzed via a cell viability assay, an apoptosis assay, and RNAseq. The results were validated by pharmacological inhibition experiments with JQ1 in human CRC organoids.ResultsIn Brd4KO organoids, the IFNγ signaling genes Il33 and Myc target genes were downregulated. The addition of IFNγ to the colon organoids induced apoptosis, but IFNγ-induced apoptosis was attenuated in the Brd4KO organoids compared with the control organoids (two-sided t-test, P < 0.05). Similar results were obtained from pharmacological inhibition with JQ1 in human CRC organoids; IL33 expression was decreased, and IFNγ-induced apoptosis was attenuated in the presence of JQ1.ConclusionsOur results showed that the inhibition of Brd4 suppressed IFNγ-induced cytotoxicity by modulating the Jak-Stat pathway. These data suggested that the inhibition of Brd4 could increase cell viability in the cancer microenvironment where IFNγ is abundant, revealing a new aspect of the molecular mechanism of CRC development. Our results may help in evaluating the application of Bet inhibitors in treating CRC. Additionally, our RNA-seq data sets will be helpful for clarifying the relationship between Brd4 and immunomodulators, such as Il33, or for studying the responses of colonic epithelial cells to IFNγ.

P0031 The role of LAT1 in colitis and colitis-associated tumourigenesis

Abstract Background Inflammatory bowel disease (IBD) remains a public health challenge, with its incidence and prevalence increasing globally [1]. IBD is known to have an increasing risk of developing colitis-associated cancer (CAC) [2], and it is important to elucidate the pathophysiology of CAC to invent a counteraction to prevent it. L-type amino acid transporter 1 (LAT1) has been reported to be upregulated during the active phase of ulcerative colitis [3] and colorectal cancer (CRC) [4]. However, its role and mechanisms in the progression of colitis and CRC development from a chronic inflammatory background remain unclear. Methods To investigate the role of LAT1 in tumour development with a colitis background, mice with intestinal epithelium-specific deletions of LAT1 (LAT1fl/fl; vil-cre) were subjected to azoxymethane/ dextran sulfate sodium (AOM/DSS) CAC model. Organoids derived from these mice were also analysed. Results LAT1 was detected at the base of colonic crypts and upregulated in DSS-induced colitis. Deletion of LAT1 in intestinal epithelium led to more severe inflammatory injury and delayed tissue repair following DSS treatment. Crypts derived from LAT1fl/fl; vil-cre mice formed fewer colonic organoids than LAT1fl/fl crypts. Furthermore, LAT1 was also upregulated in AOM/DSS-induced tumour tissues. The expression of inflammatory cytokine genes was significantly increased in LAT1-deleted tumours; however, no overall difference in colon tumour number or size was observed between the two groups. Accordingly, cell proliferation and apoptotic cell number were similar between LAT1-deleted tumours and those with sufficient LAT1. Conclusion The results of this study showed that LAT1 deficiency exacerbated intestinal inflammatory injury and delayed tissue repair by impairing the maturity of colonic crypt cells. Contrary to the expectation, however, LAT1 deficiency did not phenotypically affect overall colonic tumour development in the AOM/DSS-induced model. It may be partly because of the severe chronic colitis and increased inflammatory status within the tumours due to LAT1 deficiency in LAT1fl/fl; vil-cre mice, which might have compensated for tumour growth advantage of sufficient amino acid supplementation in LAT1 expressing control mice. Our results offer insights into how nutrient intake, such as daily diet, may influence the progression of colitis, and provide insights into the potential of LAT1-targeted therapies for clinical CRC treatment.

P1197 Progression to colorectal cancer or high-grade dysplasia in individuals with inflammatory bowel disease and low-grade dysplasia: A cohort study of risk factors and incidence

Abstract Background Individuals with inflammatory bowel disease (IBD) face an increased risk for colorectal cancer (CRC) and high grade dysplasia (HGD) compared with individuals without IBD.1,2 Low-grade dysplasia (LGD) is recognized as a key risk factor for HGD and CRC development in IBD.3 However, the risk for progression from LGD to HGD or CRC is still debated. Studies report diverging results and are often limited by small sample sizes and selection bias.4 The influence of diagnosis-year and medications is particularly underexplored. Therefore, we sought to utilize the Danish healthcare registers to examine the impact of candidate risk factors for progression from LGD to either HGD or CRC among Danish individuals with IBD. Methods We conducted a cohort study, including all Danish individuals diagnosed with IBD and LGD between 1977 and 2022. IBD with LGD was defined as individuals with a LGD diagnosis up to 180 days before or any time after their first IBD diagnosis, using the latest date as index date. Individuals with a colectomy, HGD, or CRC before the index date were excluded. We investigated the cumulative incidence of progression to HGD or CRC, treating death as a competing risk. A univariate Cox regression model was used to assess hazard ratios (HRs) for potential risk factors. Variables with a P-value of ≤ 0.1 were included in the final multivariable cox regression model. Results We included 7,082 individuals with IBD and LGD for further analysis. As illustrated in figure 1 the cumulative incidence of progression from LGD to HGD or CRC at 15 years post-index was 6.70% (95% CI: 5.93–7.54). Several risk factors were identified (table 1). Of particular interest was the influence of index-year and treatment with prednisone and anti-TNF-α. In the final model, we observed a reduction in progression risk over time, with a decreased risk for progression in the period 2018-2021 (HR: 0.32 [95% CI: 0.21-0.50]) and 2015-2018 (HR: 0.53 [95% CI: 0.34-0.69]) relative to 1977-2010. High-dose prednisone treatment was associated with progression to HDG or CRC (HR: 1.77 [95% CI: 1.23-2.57]), whereas anti-TNF-α treatment was not (HR: 0.81 [95% CI:0.38–1.74]). Conclusion Among Danish individuals with IBD the risk of progression from LGD to HGD or CRC declined over time. Treatment with High-dose prednisone was associated with an increased risk of progression, whereas anti-TNF-α treatment was not. We speculate that recent advancements in biological treatments of IBD, the implementation of 'treat-to-target' strategies, and improved detection and resection of LGD lesions, may partly explain declining progression risk.

DOP128 Spatial transcriptomic analysis reveals evolutionary dynamics in colitis-associated colorectal cancer

Abstract Background Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease, particularly ulcerative colitis. Despite its clinical significance, the spatiotemporal dynamics of neoplastic progression in CAC remain poorly understood. This study aimed to elucidate the evolutionary trajectory of CAC using spatial transcriptomics. Methods We employed spatial transcriptomics to analyze four tissue samples from three patients with ulcerative colitis at various stages of neoplastic progression. Whole-slide spatial transcriptomics RNA sequencing was performed, enabling simultaneous analysis of gene expression and tissue architecture. Integrated spatial transcriptomic data revealed recurring epithelial programs along the progression of copy number alteration. Results Our analysis using copy number variation (CNV) score and Hematoxylin and Eosin (H&amp;E) staining image revealed progressive changes in gene expression patterns as tissue transitioned from non-tumor to pre-tumor and finally to tumor states. This progression was quantified using beta coefficient values, allowing us to track gradual alterations in gene expression across the disease continuum. We identified a core set of 48 genes that exhibited consistent changes across all four analyzed samples. Among these, 40 genes showed a progressive decrease in expression, while eight genes, including CLDN1, E2F1, and RECQL4, demonstrated a gradual increase in expression as the tissue advanced towards a tumorous state. These upregulated genes pointed to potential oncogenic drivers or compensatory mechanisms activated during tumor development. Pathway analysis of the 48 genes revealed enrichment in key cellular processes, including p53 signaling, transcriptional regulation by E2F factors, and role of PKR in interferon induction and antiviral response. Upstream Regulator analysis revealed YAP1 and TGFB1 as the most significant regulators, highlighting the importance of transcriptional control and growth factor signaling in CAC development. Conclusion This study provides unprecedented insights into the spatiotemporal dynamics of CAC progression. By leveraging spatial transcriptomics, we have mapped the evolutionary trajectory of CAC at high resolution, revealing key molecular events and spatial features associated with disease progression. These findings not only enhance our understanding of CAC pathogenesis but also highlight potential targets for early intervention and personalized treatment strategies.

Hypoxia Promotes Malignant Progression of Colorectal Cancer by Inducing POSTN+ Cancer-Associated Fibroblast Formation.

Colorectal cancer (CRC) is one of the most common malignancies. Hypoxia can promote the occurrence and development of CRC. However, how hypoxia regulates the CRC immune microenvironment needs to be further explored. The bulk RNA sequencing data and clinicopathological information of CRC patients were enrolled from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. The single-cell RNA sequencing (scRNA-seq) datasets of CRC were collected from and analyzed from the GEO database and the ArrayExpress database. The score of the hypoxia gene set was estimated using the "ssGSEA" algorithm in the "GSVA" R package. The functional characteristics of CAF subtypes were studied by bioinformatics analysis and in vitro experiments, and a prognostic model was constructed based on machine learning correlation. Hypoxia is associated with poor prognosis in CRC patients. Periostin (POSTN) + Fib is a cancer-associated fibroblast (CAF) closely associated with hypoxia, and high infiltration of POSTN + Fib is associated with adverse outcomes in overall survival (OS) and relapse-free survival (RFS) in CRC patients. Hypoxia can induce POSTN expression and secretion in CAFs. Hypoxia-induced increase of POSTN expression in CAFs can significantly promote the migration and proliferation of CRC cells. Hypoxia-induced increase of POSTN expression in CAFs can significantly promote the proliferation and migration of CRC cells. The POSTN+Fib Hypoxia-Related Risk Model (PFHRM) can predict the survival and immunotherapy response of CRC patients. Our study identified a POSTN+Fib cell subpopulation closely associated with hypoxia, which promotes the malignant progression of CRC. The development of PFHRM provides a theoretical basis for improving patient survival and prognosis.