Early detection is paramount when reducing incidence and mortality of colorectal cancer (CRC). Current population-based screening programs primarily use fecal immunochemical test (FIT) to allocate individuals for colonoscopy although low specificity challenges colonoscopy capacities. We aimed to assess the potential of circulating tumor (ct)DNA markers for early CRC detection in a dual-test CRC screening approach among FIT positive individuals.

Plasma samples from 774 FIT positive (≥100 ng Hemoglobin/mL) individuals from the Danish CRC screening program were analyzed for hypermethylated DNA in the genes Branched Chain Amino-acid Transaminase 1 (BCAT1), Ikaros-Family Zinc Finger transcription 1 (IKZF1), and Interferon Regulator Factor 4 (IRF4). Multivariate logistic regression models were generated adding the ctDNA markers and age to the FIT value. The dual-test approach was benchmarked to FIT at specific thresholds.

The dual-test approach improved CRC detection compared to the FIT alone (AUC of 87.2 [95% CI, 82.9-91.4] vs AUC of 72.5 [95% CI, 67.0-77.9]). This was also seen when adding advanced adenomas to the outcome resulting in AUCs of 71.8 [95% CI, 67.8-75.8] for the dual-test approach compared to 65.5 [95% CI, 61.3-69.7] for the FIT model alone. Benchmarking the dual-test approach at FIT cut-offs between 100 and 600 ng Hb/mL showed a potential for either reducing the colonoscopy requirement by up to 56% or increasing CRC detection by up to 28%.

As increasing FIT cutoff will decrease CRC detection rate, application of the ctDNA panel can increase the sensitivity and specificity in a dual-test approach among asymptomatic individuals.

Metabolic syndrome (MetS) is defined by the presence of at least three of five clinical parameters including abdominal obesity, insulin resistance, elevated triglycerides, reduced high-density lipoprotein (HDL) and hypertension. Major features describing MetS have been recognized risk factors for cancer onset, with an alarming impact on gastrointestinal (GI) tumors. Intriguingly, therapeutic administration of drugs to improve glycemic control and dyslipidemia (including metformin, statins) has been shown to have a preventive role in the development and in prognosis improvement of several cancer types. Overall, these observations highlight the key role of altered metabolism prevalently in cancer risk development and unveil anti-MetS agent repurposing potential beyond their conventional pharmacological action. The objective of this review is to summarize the current knowledge about the antitumor activity of anti-diabetic and anti-lipemic agents in GI cancer onset and progression. Here, pre-clinical evidence of their therapeutic potential and of their integration in novel compelling therapeutic strategies will be discussed. Possible clinical outcomes of these novel therapeutic combined protocols specifically dedicated to GI cancer patients will be put under the spotlight. In the future, these novel therapeutic options should be considered to improve conventional chemotherapy response and prognosis of this group of patients.

Microsatellite stability influences the prognosis of patients with colorectal cancer (CRC). However, there are few studies on the relationship between microsatellite stability and lymph node metastasis (LNM) in CRC.

This study aims to elucidate the relationship between microsatellite stability and LNM in CRC and to investigate potential underlying mechanisms.

A retrospective analysis was performed on a cohort of 309 CRC patients, who were categorized into microsatellite instability (MSI) and microsatellite stability (MSS) groups based on their microsatellite status. Clinical and pathological indicators were collected, and differences between the two groups were assessed. The tertiary lymphoid structures (TLS) in both groups were examined using immunohistochemistry and immunofluorescence to compare differences in density, maturity, and the ratio of CD8+T cells. Establishing the relationship between microsatellite stability, TLS characteristics, and lymph node metastasis.

The TNM staging for patients in the MSI group was significantly earlier compared to those in the MSS group. Subsequent analysis of pathological indicators demonstrated that the MSI group exhibited a significantly lower incidence of lymph node metastases (31.4% vs. 47%, P=0.005), while no statistically significant differences were observed in other pathological indicators (P>0.05). Examination of CRC tissue sections revealed that the MSI group possessed a greater number and maturity of tertiary lymphoid structures, as well as a higher proportion of CD8+T cells.

MSI may decrease the incidence of LNM in CRC, potentially as a result of the activation of local anti-tumor immune responses facilitated by MSI.

Most colorectal cancers (CRCs) are characterized by a low mutational burden and an immune-cold microenvironment, limiting the efficacy of immune checkpoint blockade (ICB) therapies. While advanced tumors exhibit diverse immune evasion mechanisms, emerging evidence suggests that aspects of immune escape arise much earlier, within precancerous lesions. In this review, we discuss how early driver mutations and epigenetic alterations contribute to the establishment of an immunosuppressive microenvironment in CRC. We also highlight the dynamic crosstalk between cancer cells, stromal niche cells, and immune cells driving immune evasion and liver metastasis. A deeper understanding of these early events may guide the development of more effective preventive and therapeutic strategies for CRC.

ObjectiveThis study aimed to explore the risk factors for colorectal sessile serrated lesions and construct a risk nomogram model.MethodsPatients were enrolled retrospectively from the Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University from January 2019 to September 2023 and randomized to the training and validation sets at a ratio of 7:3. The predictors for constructing the nomogram model were screened via univariate analysis and multivariate logistic regression analysis. Subsequently, the performance of the model was evaluated.ResultsMultivariate logistic regression analysis revealed that age, history of smoking, history of alcohol consumption, and triglyceride-glucose index were independent risk factors for colorectal sessile serrated lesions (p < 0.05). The area under the curve values of the nomogram model in the training and validation sets were 0.715 (95% confidence interval: 0.676-0.753) and 0.742 (95% confidence interval: 0.669-0.815), respectively. The calibration curves showed good homogeneity between the predicted and actual values. Decision curve analysis showed that this nomogram model can achieve positive clinical benefits.ConclusionsAge, history of smoking, history of alcohol consumption, and triglyceride-glucose index are independent predictors of colorectal sessile serrated lesions. This nomogram model may predict the risk of colorectal sessile serrated lesions.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. This disease is complex and heterogeneous, influenced by a variety of genetic, epigenetic, and environmental factors that drive CRC initiation and progression. Despite advances in therapeutic strategies, the five-year survival rate for metastatic CRC is alarmingly low. Traditional two-dimensional (2D) cell culture systems have been the foundation of cancer research, but their inability to replicate the complex tumor microenvironment (TME) limits their effectiveness.

This paper explores the evolution of CRC models, starting with the limitations of traditional 2D cell culture systems and the significant advancements offered by 3D models. Additionally, it highlights 3D bioprinting and on-chip CRC models, which have enhanced the ability to mimic in vivo conditions.

The transition to advanced 3D models represents a pivotal shift in CRC research, offering considerable improvements over the established 2D models. These models hold promise for the development of patient-specific models that better mimic in vivo conditions. However, the inherent complexity of CRC continues to pose challenges in developing models that can fully capture the disease's multifaceted nature. This complexity and high costs associated with these technologies, along with the need for standardized protocols, pose significant challenges to their widespread adoption.

This research aimed to investigate the effect of 6-Paradol on sorafenib cytotoxicity in colorectal cancer (CRC) cell lines (HT-29, HCT-116, LS-174T, CaCo-2) through its effects on cellular processes.

CRC, which ranks as the third most prevalent cancer, arises in the colon or rectum due to a multifaceted interplay of dietary, lifestyle, genetic, and age-related factors. Sorafenib (multikinase inhibitor), a drug targeting multiple cancer signals, shows promise against liver, thyroid, and kidney tumors but faces resistance in CRC. 6-Paradol (Zingiberaceae), a natural compound, offers the potential for overcoming this resistance.

The current study investigates whether 6-paradol potentiates sorafenib's anti-cancer activity in CRC cells by promoting increased drug entrapment, uptake, and metabolism.

Sulpharodamine B assay, caspase-3 activity, PARP cleavage, cell cycle distribution analysis, and P-gp efflux activity were assessed for Cytotoxicity using CRC cell lines (HT-29, HCT-116, LS-174T, CaCo-2).

Sorafenib showed potent cytotoxicity across CRC cell lines (IC50: 2.0-11.1 µM). Notably, 6-Paradol synergistically enhanced its effect in HT-29 and HCT-116 cells, reducing IC50 from 338 ± 55.7 to 107 ± 5.3 µM, respectively. 6-Paradol synergized with sorafenib, reducing HCT-116 cell proliferation from from 14.25 ± 0.62 to 20.7 ± 0 fg/cell and Paradol didn't show any significant change in c-PARP concentration which equaled 289.82 ± 27.32 pg/cell, suggesting enhanced cytotoxicity. 6-Paradol exposure resulted in a concentration-dependent (1-100 µM) increase in intracellular p-gp accumulation in CaCo-2, HCT-116, and HT-29. Co-incubation with 6-paradol significantly enhanced sorafenib cellular internalization within CaCo-2 cells, resulting in a concomitant decrease in its extracellular concentration from 1491 ± 132 ng/ml to 216 ± 39 ng/ml. 6-Paradol increased sorafenib intracellular accumulation ranges from 239 ± 16 to 327 ± 34 pg/cell, respectively in HCT-116 cells. 6-Paradol significantly increased the intracellular conversion of sorafenib to its active N-oxide metabolite and facilitated its retention within the CaCo-2 cell compartment.

In conclusion, 6-Paradol marked elevation in sorafenib's cytotoxic profile by influencing its cellular uptake and metabolism. Future research should expand in vitro studies to diverse cell lines, conducting in vivo elucidating underlying mechanisms and rigorously evaluating safety and toxicity.

Polyps are macroscopically visible protrusions of the mucosa in hollow organs. In the colon, epithelial neoplasms deriving from the mucosa dominate. These can be classified based on their morphology into classic and serrated adenomas and show different degrees of epithelial dysplasia. The histological subtypes show various molecular alterations and can be assigned to different pathways of carcinogenesis. These must be separated from hamartomatous polyps of the colon mucosa, which can occur sporadically or as part of hereditary syndromes.

Fixed focal fluorine 18 fluorodeoxyglucose (18F-FDG) uptake in colorectal areas is commonly seen in PET/CT scan and may indicates malignant tumor. This study aims to investigate the diagnostic efficacy of dual-time-point 18F-FDG PET/CT in detecting colorectal carcinoma or advanced adenoma in patients with fixed focal colorectal 18F-FDG uptake.

A retrospective analysis was conducted on patients who underwent dual-time-point 18F-FDG PET/CT scans between January 2019 and December 2023. Patients showing fixed focal colorectal 18F-FDG uptake in both early and delayed scans, and subsequently undergoing colonoscopy within one month, were included in the study. Advanced adenoma was defined as an adenoma larger than 10 mm in diameter and/or with villous histology and/or presenting with high-grade dysplasia. The maximum standardized uptake value (SUV) in the early and delayed scans, as well as the retention index (RI), were compared between colorectal carcinoma/advanced adenomas and non-advanced lesions. Predictive factors for colorectal carcinoma/advanced adenoma were identified by uni- and multivariable analysis.

A total of 122 patients were enrolled in this study. A total of 141 lesions was studied, 80 (56.7%) of which were diagnosed as colorectal carcinoma or advanced adenoma. When compared with non-advanced lesions, colorectal carcinoma/advanced adenoma had higher SUVmax in delayed scan (25.1 ± 14.2 vs. 14.5 ± 7.5, P<0.001), and higher RI (32.9%±25.4% vs. 7.8%±28.4%, P<0.001) in dual-time-point PET/CT. SUVmax in delayed scan (odds ratio [OR],1.084; 95% confidence interval [CI]: 1.037, 1.134; P<0.001) and RI (OR, 20.120; 95% CI: 4.068, 99.516; P<0.001) were identified as independent predictors for colorectal carcinoma/advanced adenoma by multivariable logistic regression analysis. When combining the SUVmax in the delayed scan with the retention index, the area under the receiver operating characteristic (ROC) curve achieved 0.801, and the sensitivity and specificity for predicting colorectal carcinoma/advanced adenoma were found to be 65.0% and 80.3%, respectively. Based on the threshold values of SUVmax in the delayed scan and RI, we observed prediction rates of 13.9% (5 out of 36), 58.6% (34 out of 58), and 87.2% (41 out of 47) for colorectal carcinoma/advanced adenoma in the low-, moderate-, and high-risk subgroups, respectively.

Dual-time-point PET/CT aids in distinguishing between colorectal cancer/advanced adenoma and non-advanced lesions in fixed focal FDG uptake. Higher SUVmax in delayed scan and higher RI are predictive factors for colorectal carcinoma/advanced adenoma.

Colorectal cancer (CRC) is ranked as the third most prevalent malignancy and is a leading cause of cancer-related mortality globally, significantly affecting the health and longevity of middle-aged individuals and the elderly. The primary risk factors for CRC are mainly due to unhealthy dietary habits and lifestyle choices, and they have been shown to profoundly influence the composition of the gut microbiota. Given that dietary patterns are critical determinants of gut microbial diversity, a compelling association exists between gut microbiota and the pathogenesis of CRC. Recent research has increasingly focused on the intricate interplay between gut microbiota and CRC, exploring its role in disease initiation, progression, and the modulation of host immune responses. Investigations have demonstrated that certain specific microbial communities can promote inflammation, disrupt metabolic pathways, and produce carcinogenic compounds, thereby contributing to the development of CRC. Conversely, a diverse and balanced gut microbiome may confer protective effects against cancer through mechanisms such as the production of short-chain fatty acids and the enhancement of intestinal barrier integrity. This article provides a comprehensive overview of the characteristics of the gut microbial community and its complex relationship with CRC. It highlights potential mechanisms through which gut microbiota may influence CRC pathogenesis, including chronic inflammation, toxins, metabolites, epigenetic dysregulation, and immune regulatory dysfunction. Additionally, this review summarizes innovative strategies for CRC prevention and treatment, emphasizing the therapeutic potential of probiotics and natural plant extracts. By elucidating these connections, this work aims to enhance the understanding of the gut microbiome's role in CRC.

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.

Metabolic dysregulation has been implicated as a key factor in colorectal cancer (CRC) initiation, however, the underlying driving forces and mechanisms remain poorly understood. Herein, transcriptome profiling of paired early-stage CRCs and adenomas identifies Nudix hydrolase 13 (NUDT13) as a critical suppressor. Elevated NUDT13 expression impedes the proliferation of CRC cells under hypoxic conditions and markedly inhibits CRC initiation by upregulating PKM1. Mechanistically, NUDT13 directly binds and stabilizes PKM1 protein by reducing its poly ADP-ribosylation (PARylation), which is catalyzed by PARP1 at E275/D281/E282/E285/D296, thereby inducing an oxidative phosphorylation (OXPHOS) phenotype in CRC cells. Moreover, spatiotemporal knockout of Nudt13 enhances intestinal tumorigenesis in mice, which can be significantly suppressed by PARP1 inhibitor Olaparib. Notably, residues E245/E248/E249 within the Nudix box motif of NUDT13 are essential for PKM1 PARylation, and a mimic peptide derived from this motif is sufficient to stabilize PKM1 protein and robustly inhibit CRC tumorigenesis. Collectively, this study reveals a previously unknown PARylation-dependent mechanism that regulates PKM1 protein stability and switches the metabolic pathway of CRC cells, providing a promising target for CRC treatment.

This American Gastroenterological Association (AGA) guideline is intended to provide an overview of the evidence and support endoscopists and patients on the use of computer-aided detection (CADe) systems for the detection of colorectal polyps during colonoscopy.

A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation framework and relied on the following sources of evidence: (1) a systematic review examining the desirable and undesirable effects (ie, benefits and harms) of CADe-assisted colonoscopy, (2) a microsimulation study estimating the effects of CADe on longer-term patient-important outcomes, (3) a systematic search of evidence evaluating the values and preferences of patients undergoing colonoscopy, and (4) a systematic review of studies evaluating health care providers' trust in artificial intelligence technology in gastroenterology.

The panel reached the conclusion that no recommendation could be made for or against the use of CADe-assisted colonoscopy in light of very low certainty of evidence for the critical outcomes, desirable and undesirable (11 fewer colorectal cancers per 10,000 individuals and 2 fewer colorectal cancer deaths per 10,000 individuals), increased burden of more intensive surveillance colonoscopies (635 more per 10,000 individuals), and cost and resource implications. The panel acknowledged the 8% (95% CI, 6%-10%) increase in adenoma detection rate and 2% (95% CI, 0%-4%) increase in advanced adenoma and/or sessile serrated lesion detection rate.

This guideline highlights the close tradeoff between desirable and undesirable effects and the limitations in the current evidence to support a recommendation. The panel acknowledged the potential for CADe to continually improve as an iterative artificial intelligence application. Ongoing publications providing evidence for critical outcomes will help inform a future recommendation.

Colorectal cancer (CRC) is one of the most prevalent cancers, posing a significant threat to human life. Although therapeutic approaches for advanced-stage patients have improved in recent years, there is still room for enhancing treatment response. Recent evidence suggests that dysregulation of nucleotide sugar transporters (NSTs) is associated with the development and progression of tumors. Therefore, this study aims to explore the potential therapeutic and prognostic implications of the solute carrier family 35 A (SLC35A) members in CRC. To achieve this, we performed integrative bioinformatics analysis using various publicly available databases, including GENT2, TCGA, UALCAN, cBioPortal, Kaplan-Meier plotter, The ROC plotter, GDSC, TISIDB, and TIMER. We compared gene expression profiles between CRC tumors and adjacent normal tissues, revealing that only SLC35A2 exhibited significant upregulation in tumors, while the other family members were downregulated. Additionally, higher SLC35A2 expression was found in microsatellite stable (MSS) colorectal tumors. Further analysis of TCGA and GEO datasets showed that patients with high SLC35A2 expression experienced poorer relapse-free survival. Next, we conducted gene set enrichment analysis (GSEA), and the results indicated that the upregulation of SLC35A2 is linked to cellular metabolism pathways, such as MYC Targets V2, Steroid Biosynthesis, Pentose Phosphate Pathway, and TCA Cycle. Furthermore, our CRC cell models revealed the tumor-promoting role of SLC35A2 and discovered that the upregulation of SLC35A2 is associated with chemoresistance against irinotecan. Additionally, we observed a negative correlation between SLC35A2 expression and the infiltration of immune cells, particularly cytotoxic CD8+ T cells and B cells. This suggests the immunomodulatory role of SLC35A2. In summary, SLC35A2 is abnormally upregulated in CRC, and patients with high SLC35A2 expression tend to have poor relapse-free survival. This may be due to its involvement in regulating cancer cell metabolic reprogramming, promoting tumor progression, modulating the immune landscape, and influencing treatment response. Consequently, SLC35A2 could serve as a significant prognostic factor and a potential therapeutic target in CRC.

Colorectal cancer (CRC) incidence is associated with lower circulating selenium and zinc and elevated copper concentrations. Moreover, copper and selenium accumulate within tumor tissue, indicating a disturbed homeostasis of these essential trace elements in CRC.

This study aimed to identify associations between CRC characteristics (based on genomic, transcriptomic and proteomic data) and trace element concentrations.

The concentrations of copper, selenium, and zinc were measured in 83 human CRC cell lines and correlated with transcript and protein expression levels to identify trace element-related gene signatures. By using publicly available gene expression data from The Cancer Genome Atlas we investigated the association between those signatures with the survival probability of CRC patients.

The CRC cell lines differed in their copper (fold change 7.3), selenium (fold change 6), and zinc (fold change 2.6) concentrations. The concentrations were not associated with genetic or cellular characteristics, except for lower copper concentrations in KRAS mutant cells. Expression levels of known copper- and zinc-related proteins correlated significantly with the respective trace element concentrations, serving as a proxy for trace element concentrations in tumors, and with patient survival. This was not the case for selenium and selenoproteins. In addition, an unbiased approach identified novel high and low copper- and zinc-related gene expression signatures significantly associated with patient's outcome.

Herein we identify gene signatures associated with intracellular copper and zinc concentrations in CRC cell lines. Extrapolating these signatures to primary colorectal tumors revealed that they can inform outcome of CRC patients.

Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality, influenced by both genetic and epigenetic factors. Long non-coding RNAs (lncRNAs) such as GAS5 and CASC8 have been implicated in cancer susceptibility. This study aimed to assess the association of GAS5 rs145204276 ins/del and CASC8 rs10505477 A>G polymorphisms with CRC risk in a Romanian population. A case-control study was conducted, including 156 CRC patients and 195 healthy controls. Genotyping for GAS5 and CASC8 polymorphisms was performed using real-time PCR, and the association with CRC risk was evaluated using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). The carriers of GAS5 rs145204276 del allele was significantly associated with increased CRC risk (OR: 2.13, 95% CI: 1.24-3.63, p = 0.005) in a dominant model. In the subgroup analysis, the association of GAS5 rs145204276 ins/del polymorphism was restricted to distal colon cancer cases (OR: 2.98, 95% CI: 1.57-5.66, p = 0.001), advanced tumor stages (III + IV) (OR: 2.54, 95% CI: 1.31-4.91, p = 0.007), and poorly differentiated tumors (G3) (OR: 3.98, 95% CI: 1.49-10.59, p = 0.009). No significant correlation was found for the CASC8 rs10505477 A>G polymorphism. GAS5 rs145204276 polymorphism may influence CRC susceptibility, particularly in distal tumors and advanced stages. However, CASC8 rs10505477 polymorphism showed no association with CRC risk in this Romanian cohort.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Conventional treatments such as chemotherapy and radiotherapy are often associated with severe side effects and limited effectiveness. Curcumin, a polyphenol derived from Curcuma longa, has demonstrated anti-inflammatory and anticancer properties. A systematic review of the recent scientific literature followed PRISMA guidelines to evaluate the benefits of a curcumin-enriched diet for adults with colorectal cancer. Articles published between 2018 and 2024 were retrieved from PubMed, SciELO, Google Scholar, and Scopus. Studies meeting the inclusion criteria focused on curcumin, adults, and colorectal cancer outcomes. The administration of curcumin-containing products was associated with improved survival rates, enhanced quality of life, tumor reduction, and anti-inflammatory effects. A curcumin-enriched diet shows potential as an effective adjunct therapy for CRC patients, though its limited bioavailability and potential side effects, such as gastrointestinal discomfort, pose challenges. Addressing these limitations through larger cohorts, extended study durations, and improved formulations to enhance bioavailability is essential. Such efforts could enable the development of personalized dietary recommendations for CRC management.

Background/Objectives: Research on colorectal adenoma is significantly less comprehensive compared to studies on colorectal carcinoma. Although colorectal adenoma is a precursor of the majority of sporadic colorectal cancers, not all adenomas develop into carcinomas. The complex interaction of immune responses in the premalignant tumor microenvironment might be a factor for that. Methods: In this systematic review, we aim to provide a thorough analysis of the current research examining the immune infiltration patterns in sporadic colorectal adenoma tissues in the context of immune cell-based, cytokine-based, and other immunological factor-related changes along the conventional adenoma-carcinoma sequence. The articles included in the review extend up to December 2024 in PubMed and Web of Science databases. Results: Most included studies have shown significant differences in immune cell counts, densities, and cytokine expression levels associated with premalignant colorectal lesions (and/or colorectal cancer). No consensus on the immune-related tendencies concerning CD4+T cells and CD8+T cells was reached. Decreasing expression of mDCs and plasma and naïve B cells were detected along the ACS. The increased density of tissue eosinophils in the adenoma tissue dramatically diminishes after the transition to carcinoma. As the adenoma progresses, the increasing expression of IL-1α, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-21, IL-23, IL-33, and TGF-β and decreasing levels of IL-12A, IL-18, IFN-γ, and TNFα cytokines in the invasive carcinoma stage is being detected. The over-expression of COX-2, PD-1/PD-L1, CTLA-4, and ICOS/ICOSLG in the colorectal adenomatous and cancerous tissues was also observed. Conclusions: Further studies are needed for a better understanding of the whole picture of colorectal adenoma-associated immunity and its impact on precancerous lesion's potential to progress.

Colorectal carcinogenesis induces changes in the colon, such as the appearance of aberrant crypt foci (ACF). This process is influenced by genetic and environmental factors, such as diet. Hibiscus sabdariffa L. is a considerable source of phenolic compounds, such as anthocyanins, and dietary fibers that may exert anti-inflammatory, antioxidant and prebiotic properties, attenuating the appearance of ACFs.

To investigate whether supplementation with 5% or 10% of dehydrated calyces of Hibiscus sabadariffa (DHSC) influences the composition of the intestinal microbiota and the expression of genes related to colorectal carcinogenesis in BALB/c mice.

The in vivo experiment lasted 12 weeks and the animals were divided into 3 experimental groups: the control group and the supplemented groups (5% or 10% DCHS) and induced pre-neoplastic lesions with the drug Dimethylhydrazine. Serum aspartate aminotransferase and alanine aminotransferase markers, liver cytokine profile, gut microbiota composition and tumor protein 53, cellular myelocytomatosis oncogene, caspase-3 and Proliferating Cell Nuclear Antigen gene expression were determined.

Supplementation with 5% or 10% of DCHS altered the composition of the intestinal microbiota, increasing the abundance of the families Lachnospiraceae, Ruminococcaceae, Clostridiaceae and of the genus Clostridum, important producers of butyrate. Furthermore, 5% and 10% DCHS supplementation increased caspase-3 and c-Myc expression, respectively, which may suggest apoptotic events.

Therefore, the effects of DHSC, rich in anthocyanins and dietary fiber, on the composition of the intestinal microbiota and on the expression of genes associated with cell apoptosis may contribute to reducing the risk of developing preneoplastic lesions.

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.

This study reports the design, synthesis, and characterization of a novel series of benzene sulfonamide-triazole hybrid derivatives, to evaluate their anticancer potential against colorectal cancer. The synthesized compounds were characterized using NMR and HRMS spectroscopic techniques. In vitro cytotoxicity assessments revealed that compounds 5g and 5j exhibited significant anticancer effects. 5g showed the highest potency in the DLD-1 cell line (IC50 = 11.84 µM), while 5j demonstrated robust activity in the HT-29 cell line (IC50 = 9.35 µM). Apoptotic analysis indicated that compound 5g effectively induced early and total apoptosis, surpassing the chemotherapeutic agent 5-fluorouracil (5-FU), highlighting its therapeutic potential. Molecular docking studies showed strong binding interactions with key proteins involved in colorectal cancer progression, such as TGFβ2 and VEGFR1. 5j displayed a high binding affinity for TGFβ2 (MM-GBSA ΔG = -92.52 kcal/mol) and 5g showed promising interactions with VEGFR1 (ΔG = -70.63 kcal/mol). Molecular dynamics simulations confirmed the stability of the ligand-protein complexes, indicating potential as targeted therapeutic agents. Compounds 5g and 5j demonstrate significant promise for further development in colorectal cancer treatment.

Microsatellite instability (MSI) stratification can guide the clinical management of patients with colorectal cancer (CRC). This study aimed to establish a radiomics model for predicting the MSI status of patients with CRC before treatment.

This retrospective study was performed on 366 patients diagnosed with CRC who underwent preoperative magnetic resonance imaging (MRI) and immunohistochemical staining between February 2016 and September 2023. The participants were divided randomly into training and testing cohorts in a 7:3 ratio. The tumor volume of interest (VOI) was manually delineated on T2-weighted imaging (T2WI) and apparent diffusion coefficient (ADC) sequences using 3D Slicer software, and radiomics features were extracted. Feature selection was performed using the least absolute shrinkage and selection operator method. A radiomics nomogram was developed using multiple logistic regression, and the predictive performance of the models was evaluated and compared using receiver operating characteristic curves. The calibration curve, clinical decision curve analysis (DCA) and clinical impact curve (CIC) were used to evaluate the clinical application value of the model.

The radiomics normogram combined with history of chronic enteritis, tumor location, MR-reported inflammatory response, D2-40, carcinoembryonic antigen, tumor protein 53, and monocyte was an excellent predictive tool. The area under the curve for the training and testing cohorts were 0.927 and 0.984, respectively. The DCA and CIC demonstrated favorable clinical application and net benefit.

A radiomics nomogram based on T2WI and ADC sequences and clinicopathologic features can effectively and noninvasively predict the MSI status in CRC. This approach helps clinicians in stratifying CRC patients and making clinical decisions for personalized treatment.

Chronic gut inflammation and dysbiosis contribute significantly to colorectal cancer (CRC) development. Shaoyao decoction (SYD) is a well-established Chinese medicine prescription. Besides ameliorating CRC via anti-inflammatory effects, SYD modulates gut microbiota (GM) to improve inflammatory responses in ulcerative colitis (UC). However, whether and how SYD suppresses CRC by regulating GM remains largely unknown.

SD rats were orally administered SYD for 7 days to obtain medicated serum. We utilized liquid chromatography-mass spectrometry (LC-MS) analysis, GeneCards, DisGeNET, and SwissTargetPrediction databases to analyze blank and SYD-medicated rat serum, comparing the findings with those of SYD aqueous extract in previous studies to identify SYD circulating compounds/components with predictable target genes. Using network pharmacology, the potential active compounds and corresponding hub genes associated with modulating GM to suppress CRC were selected for molecular docking. In vivo experiments, a CRC transplantation tumor model was established in BALB/c mice using CT26 cells, with SYD gavage for 14 days. To investigate the mechanism of SYD-regulated GM against CRC, HE and IHC staining, Western blotting, and 16S rRNA sequencing were employed.

LC-MS identified 26 SYD compounds with computationally predicted target genes. Network pharmacology prioritized 13 compounds targeting 8 inflammation/immunity-related genes (IL-17/TNF pathways), validated by molecular docking. In vivo experiments, SYD dose-dependently suppressed tumor growth (p < 0.05, medium/high doses), as confirmed by HE staining and IHC analysis of Ki-67. Notably, SYD potentially delayed CRC liver metastasis and alleviated hepatic injury in tumor-bearing mice. Western blotting demonstrated SYD's inhibition of the IL-17/TNF/NF-κB axis, aligning with computational predictions. 16S rRNA sequencing revealed SYD-enriched Akkermansia and GM structural shifts, mechanistically linking microbiota remodeling to anti-tumor efficacy.

SYD combats CRC via dual modulation of IL-17/TNF/NF-κB signaling and GM ecosystems (e.g., Akkermansia enrichment). This microbiota-immune crosstalk positions SYD as a potential adjunct to conventional therapies, particularly for CRC patients with dysbiosis.

The vast majority of colon cancers occur in pre-existing adenomas. Little is known about the impact of adenoma type on behavior and outcome of subsequent carcinomas. The present study aimed to assess characteristics, behavior, and outcome of colon adenocarcinoma based on histologic type of pre-existing adenoma.

US-National Cancer Database was searched between 2005 and 2019 for patients with colonic adenocarcinoma with known adenoma type who underwent colectomy. Patients were divided into 3 groups according to type of adenoma in which carcinoma developed: tubular adenoma (TA), villous adenoma (VA), and tubulovillous adenoma (TVA)-associated carcinomas. The main outcome of the study was 5-year overall survival (OS).

66,854 patients were included. 79.3% of carcinomas originated from TVA, 10.2% from VA, and 0.5% from TA. Patients with adenocarcinoma in VA were more often female whereas carcinomas in TA affected patients of Asian race more often. Approximately one-third of carcinomas in villous and tubulovillous adenomas were in the cecum whereas one-third of carcinomas in tubular adenomas were in the sigmoid colon. More TA-associated carcinomas were of clinical T1-2 stage (30.2% vs. 20.8%; P < .001), clinical N0 stage (69% vs. 62.2%, P < .001), and high grade (15.9% vs. 11.5%, P < .001) compared to VA-associated carcinomas. Patients with TA-associated carcinomas had longer mean OS than patients with VA and TVA-associated carcinomas (130.1 vs. 116.9 vs. 123.5 months, P < .0001).

Adenocarcinomas that arose in TA had more T1-2 stage and N0 stage, higher grade, and longer OS than did adenocarcinomas that arose in VA and TVA.

Novel thiazepine-based hybrids (9 a-d) were designed and synthesized to create lead molecules with exceptional anti-colon cancer efficacy. Analytical methods, including IR, NMR, and HR-MS, characterized the synthesized compounds. The in vitro colorectal study was carried out to compare the biological activity of newly developed compounds with the computational data. The tested compounds induced cytotoxicity in HT-29 cells for both 24 h and 48 h in a dose-dependent manner. However, compound 9 a induced cytotoxicity at much higher concentrations compared to the rest of the compounds. 9 b and 9 c caused 50 % cell death (compared to the untreated cells) at a dose of ~50 μM and 40 μM in case of 24-hour exposure, respectively. On the contrary, for 48 h exposure, both 9 b and 9 c induced 50 % cell death concerning untreated cells at a dose of around ~20 μM, whereas 9 d exhibited 50 % cell death at 5 μM in the case of 48 h exposure. In silico ADMET was also carried out to understand the pharmacokinetics and safety profiles of the drug candidates. We found some of the critical targets of these compounds, which eventually will be integral to exploring the mechanistic actions of these compounds in colon cancer.

Colorectal cancers (CRCs) are traditionally divided into those with either chromosomal instability (CIN) or microsatellite instability (MSI). By utilizing TCGA data, the Laird team found a subset of CRCs, namely, genome-stable CRCs (GS CRCs), which lack both CIN and MSI. Although the molecular features of GS CRCs have been described in detail, the clinicopathological features are not well defined. A total of 437 CRCs were analyzed for copy number variation (CNV) statuses in eight genes (ARID1A, EGFR, FGFR1, KDM5B, MYBL2, MYC, SALL4, and SETDB1) using droplet-digital PCR. CRCs that showed CNV in ≤ one gene and no MSI were defined as GS-like CRCs. Clinicopathological and molecular features of GS-like CRCs were compared with those of CIN-like CRCs. GS-like CRCs comprised 4.6% of CRCs and showed a predilection toward the proximal colon, lower nuclear optical density, KRAS mutation, PIK3CA mutation, and aberrant expression of KRT7. Survival analysis showed no significant difference between the three subgroups. Through our study, the GS-like subtype was found to comprise a minor proportion of CRCs and have proclivity toward a proximal bowel location, hypochromatic tumor nuclei, aberrant KRT7 expression, and a high frequency of KRAS and PIK3CA mutations.

Mutations in KRAS and BRAF genes are prevalent in colorectal cancer (CRC), which strikingly promote tumorigenesis and lead to poor response to a variety of treatments including immunotherapy by activating the MAPK/ERK pathway. Thus, there is an urgent need to discover effective therapeutic targets and strategies.

CRISPR-Cas9 lentiviral knockout library was used to screen the suppressors of anti-PD1 immunotherapy. Bioinformatic analysis was used to analyze the correlation between PHF8 expression and immune indicators in CRC. In vitro and in vivo experiments were utilized to determine the effects of PHF8 on the immune indexes and malignant phenotypes of CRC cells. qRT-PCR, western blotting, immunohistochemical (IHC) staining, and chromatin immunoprecipitation (ChIP)-qPCR assays were used to determine the regulatory effects of PHF8 on PD-L1, KRAS, BRAF, and c-Myc and the regulatory effect c-Myc/miR-22-3p signaling axis on PHF8 expression in CRC cells.

This study identified histone lysine demethylase PHF8 as a negative regulator for the efficacy of anti-PD1 therapy and found that it was highly expressed in CRCs and strongly associated with poor patient survival. Functional studies showed that PHF8 played an oncogenic role in KRAS- or BRAF-mutant CRC cells, but not in wild-type ones. Mechanistically, PHF8 up-regulated the expression of PD-L1, KRAS, BRAF, and c-Myc by increasing the levels of transcriptional activation marks H3K4me3 and H3K27ac and decreasing the levels of transcriptional repression mark H3K9me2 within their promoter regions, promoting immune escape and tumor progression. Besides, our data also demonstrated that PHF8 was up-regulated by the c-Myc/miR-22-3p signaling axis to form a positive feedback loop. Targeting PHF8 substantially improved the efficacy of anti-PD1 therapy and inhibited the malignant phenotypes of KRAS- or BRAF-mutant CRC cells.

Our data demonstrate that PHF8 may be an effective therapeutic target for KRAS- or BRAF-mutant CRCs.

Low relative muscle mass was identified to be related to ascending risk of pre-cancerous polyps (adenoma) in recent cohort study. Our study aimed to dig out the correlation between muscle mass and different pathological types of colorectal polyps in Chinese asymptomatic population.

In all, 5923 adults were included. The effects of low skeletal muscle mass index (SMI) on colorectal polyp occurrence, including different pathological types, and the effects modification of age and BMI were analyzed using univariate and multivariate logistic regression.

Lower SMI was connected with the lower occurrence of colorectal polyp (OR: 0.810, 95% CI: 0.683~0.960, p=0.015). Considering different pathological types of colorectal polyps, lower SMI was associated with lower occurrence of inflammatory polyp (OR: 0.633, 95% CI: 0.434~0.898, p=0.013), rather than conventional adenoma and serrated polyp (all p>0.05). Besides, SMI was positively related to the occurrence of 2 pathological types of colorectal polyp in males: inflammatory polyp (OR: 1.237, 95% CI: 1.058~1.444, p=0.007) and serrated polyp (OR: 1.288, 95% CI: 1.143~1.456, p<0.001). The interaction effect of BMI and SMI on occurrence of inflammatory polyp after adjusting age and smoking status was significant (p=0.015). For individuals with low SMI (compared with the normal SMI group), the incidence of inflammatory polyp was reduced from 8.95% to 3.50% in the low BMI quartile (Q1) in the adjusted model (OR of 0.332, 95% CI: 0.005-0.061, p<0.001). It was noticeable for males rather than females that individuals with colorectal polyps had higher levels of SMI (p=0.003). In addition, individuals with inflammatory polyps as well as serrated polyps possessed higher levels of SMI in males (all p<0.05).

Generally, especially in Chinese asymptomatic males, low SMI kept independent effect on the presence of inflammatory polyp and serrated polyp, rather than conventional adenoma.

Early detection of colorectal cancer (CRC) significantly improves its management and patients' survival. Circular RNAs (circRNAs) are peculiar covalently closed transcripts involved in gene expression modulation whose dysregulation has been extensively reported in CRC cells. However, little is known about their alterations in the early phases of colorectal carcinogenesis.

In this study, we performed an integrative analysis of circRNA profiles in RNA-sequencing (RNA-Seq) data of 96 colorectal cancers, 27 adenomas, and matched adjacent mucosa tissues. We also investigated the levels of cognate linear transcripts and those of regulating RNA-binding proteins (RBPs). Levels of circRNA-interacting microRNAs (miRNAs) were explored by integrating data of small RNA-Seq performed on the same samples.

Our results revealed a significant dysregulation of 34 circRNAs (paired adj. p < 0.05), almost exclusively downregulated in tumor tissues and, prevalently, in early disease stages. This downregulation was associated with decreased expression of circRNA host genes and those encoding for RBPs involved in circRNA biogenesis, including NOVA1, RBMS3, and MBNL1. Guilt-by-association analysis showed that dysregulated circRNAs correlated with increased predicted activity of cell proliferation, DNA repair, and c-Myc signaling pathways. Functional analysis showed interactions among dysregulated circRNAs, RBPs, and miRNAs, which were supported by significant correlations among their expression levels. Findings were validated in independent cohorts and public datasets, and the downregulation of circLPAR1(2,3) and circLINC00632(5) was validated by ddPCR.

These results support that multiple altered regulatory mechanisms may contribute to the reduction of circRNA levels that characterize early colorectal carcinogenesis.

Comprehensive protein profiling in intestinal tissues provides detailed information about the pathogenesis of colorectal cancer (CRC). This study quantified the expression levels of 92 oncology-related proteins in tumors, paired para-carcinoma tissues, and remote normal tissues from a cohort of 52 CRC patients utilizing the Olink technology. The proteomic profile of normal tissues closely resembled that of para-carcinoma tissues while distinctly differing from that of tumors. Among the 68 differentially expressed proteins (DEPs) identified between the tumor and normal tissues, WISP-1, ESM-1, and TFPI-2 showed the most pronounced alterations and exhibited relatively strong correlations. These markers also presented the highest AUC values for distinguishing between tissue types. Bioinformatic analysis of the DEPs revealed that the plasma membrane and the PI3K-AKT signaling pathway were among the most enriched GO terms and KEGG pathways. Furthermore, although TFPI-2 is typically recognized as a tumor suppressor, both Olink and enzyme linked immunosorbent assay (ELISA) analyses have demonstrated that its expression is significantly elevated in tumors compared with paired normal tissues. To the best of our knowledge, this is the first study to profile the proteome of intestinal tissue using the Olink technology. This work offers valuable insights into potential biomarkers and therapeutic targets for CRC, complementing the Olink profiling of circulating proteins.

Colorectal cancer (CRC) is an exceedingly common and profoundly impactful malignancy of the digestive system, posing a grave threat to human health. Endoplasmic reticulum stress (ERS) is an intracellular biological reaction that mobilizes the unfolded protein response (UPR) to tackling dysregulation in protein homeostasis. This process subtly modulates the cell to either restore normal cellular function or steer it towards apoptosis. The high metabolic demands of CRC cells sculpt a rigorous tumor microenvironment (TME), compelling CRC cells to experience ERS. Adaptive responses induced by mild ERS furnish the necessary conditions for the survival of CRC cells, whereas the cell death mechanisms triggered by sustained ERS could be considered a prospective strategy for cancer therapy. Considering the complex regulation of ERS in cancer development, this article offers a comprehensive review of the molecular mechanisms through which ERS influences CRC fate. It provides crucial insights for exploring the role of ERS in the occurrence and progression of CRC, laying a new theoretical foundation for devising precise therapeutic strategies targeting ERS. Furthermore, by synthesizing extensive clinical and preclinical studies, we delve into therapeutic strategies targeting ERS, including the potential of targeting ERS in immunotherapy, the utilization of native compounds, advancements in proteasome inhibitors, and the potential synergies of these strategies with traditional chemotherapy agents and emerging therapeutic approaches.

Colorectal cancer (CRC) arises from the epithelial lining of the colon or rectum, often following a progression from benign adenomatous polyps to malignant carcinoma. Screening modalities such as colonoscopy, faecal immunochemical tests (FIT), and FIT-DNA are critical for early detection and prevention, but non-invasive methods lack sensitivity to polyps and early CRC. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression. We have previously developed an epigenetic assay, EpiSwitch®®, that employs an algorithmic-based CCs analysis. Using EpiSwitch®® technology, we have shown the presence of cancer-specific CCs in peripheral blood mononuclear cells (PBMCs) and primary tumours of patients with melanoma and prostate cancer. EpiSwitch®®-based commercial tests are now available to diagnose prostate cancer with 94% accuracy (PSE test) and response to immune checkpoint inhibitors across 14 cancers with 85% accuracy (CiRT test). Methods/Results/Conclusions: Using blood samples collected from n = 171 patients with CRC, n = 44 patients with colorectal polyps and n = 110 patients with a 'clear' colonoscopy we performed whole Genome DNA screening for CCs correlating to CRC diagnosis. Our findings suggest the presence of two eight-marker CC signatures (EpiSwitch®® NST) in whole blood that allow diagnosis of CRC and precancerous polyps, respectively. Independent validation cohort testing demonstrated high accuracy in identifying colorectal polyps and early versus late stages of CRC with an exceptionally high sensitivity of 79-90% and a high positive prediction value of 60-84%. Linking the top diagnostic CCs to nearby genes, we have built pathways maps that likely underline processes contributing to the pathology of polyp and CRC progression, including TGFβ, cMYC, Rho GTPase, ROS, TNFa/NFκB, and APC.

Colorectal cancer (CRC) ranks as the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Studies have shown that CRC patients with KRAS mutations, especially KRASG12D, have an increased risk of metastasis. Emerging evidence indicates that long non-coding RNAs (lncRNAs) are crucial in the carcinogenesis and progression of various cancers, regulating multiple biological processes but the link between KRASG12D mutations and lncRNAs in CRC remains unclear. Therefore, this study was designed to identify a novel lncRNA involved in KRASG12D-mutated CRC and to elucidate its molecular mechanisms. The analysis of differentially expressed lncRNAs in the GSE201412 dataset revealed that LINC02159 was significantly upregulated following treatment with the KRASG12D inhibitor MTRX1133 Data from the GTEx database indicated that LINC02159 is highly expressed in CRC tumour tissues and is associated with better patient outcomes. In vitro and in vivo experiments suggest that LINC02159 acts as a tumour suppressor in CRC progression. Specifically, LINC02159 knockdown negated the inhibitory effects of MRTX1133 on tumourigenesis and its promotive effect on ferroptosis in KRASG12D-mutated CRC cells. LINC02159 expression is regulated by METTL14, with METTL14 knockdown decreasing m6A methylation of LINC02159, leading to its increased expression in CRC cells. Additionally, LINC02159 stabilised FOXC2 expression through de-ubiquitination. Rescue experiments further clarified that the METTL14/LINC02159/FOXC2 signalling axis is crucial for the inhibitory effects of MRTX1133 in KRASG12D-mutated CRC. Our study provides novel insights into the therapeutic potential of MRTX1133 in treating KRASG12D-mutated CRC by identifying a METTL14/LINC02159/FOXC2 signalling axis that mediates drug response. Our findings highlight the importance of understanding the molecular mechanisms of lncRNAs in cancer to develop effective targeted therapies.

The identification of biomarkers correlated with colorectal cancer (CRC) prognosis holds substantial importance from both clinical and scientific perspectives. Zinc finger protein 26 (ZNF26) has not been previously investigated or documented in solid tumors; thus, further research is necessary to ascertain its prognostic value in CRC. Gene expression profiles and clinicopathological data were acquired from The Cancer Genome Atlas (TCGA) database. Subsequently, expression correlation was assessed utilizing the TCGA CRC cohort. The prognostic value of ZNF26 was evaluated through Kaplan-Meier (KM) and ROC curve analyses. Following this, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to perform enrichment analysis between high- and low-ZNF26 expression groups. The association between immune cells, immune checkpoint genes, and ZNF26 expression levels was examined. Lastly, the research findings were further validated using CRC tissue samples. The results revealed that, in comparison to healthy controls, CRC significantly reduced ZNF26 expression. Elevated ZNF26 expression was associated with poorer overall survival in CRC patients. Additionally, high ZNF26 expression exhibited an inverse relationship with the immunological score and immune checkpoint gene expression in CRC patients. The findings from the TCGA data analysis were corroborated by the PCR results obtained from CRC tissue samples. ZNF26 is markedly upregulated in colorectal cancer tissues, potentially serving as a biomarker for CRC.