Search Results (190)

Colorectal cancer (CRC) remains a major cause of cancer-related mortality, with recurrence and treatment resistance as persistent challenges. Increasing evidence supports the cancer stem cell (CSC) model in CRC, in which a subpopulation of self-renewing colorectal cancer stem cells (CCSCs) sustains tumor growth, metastasis, and therapy resistance. CCSCs are increasingly recognized as key drivers of tumor progression, therapeutic resistance, and relapse, and are increasingly being investigated not only as therapeutic targets but also as biomarkers with diagnostic and prognostic relevance in CRC. Multiple signaling pathways regulate CCSC maintenance and aggressive behavior, including Wnt/β-catenin, Notch, Hedgehog, PI3K/AKT, MAPK/ERK, NF-κB, and TGF-β signaling. These pathways form the basis of therapeutic strategies aimed at modulating stemness-associated pathways, with several CSC-focused agents and pathway inhibitors currently under translational and clinical investigation. In parallel, CCSC surface markers and molecular signatures are being explored as putative tools for early detection, minimal residual disease monitoring, and outcome prediction. However, successful translation of CSC-directed approaches into effective and safe clinical applications remains difficult. Tumor heterogeneity, CSC plasticity, compensatory signaling mechanisms, and the shared regulatory networks between malignant and normal intestinal stem cells pose substantial barriers. In this review, we summarize the molecular mechanisms underlying CCSC biology, discuss their diagnostic and prognostic implications. We also focus on clinical trials that apply CCSC-directed therapeutic, biomarker, and prevention strategies in CRC., Finally, we emphasize the lessons learned and the translational challenges, including the need for rigorously validated, CCSC-specific biomarkers, that continue to shape the development of these therapeutic and biomarker strategies. Full article

Background/Objectives: Emergency presentation in colorectal cancer (CRC) is commonly regarded as a uniformly high-risk condition, although clinically distinct emergency phenotypes may carry substantially different prognostic implications. We aimed to characterise emergency diagnostic phenotypes, bowel obstruction, perforation, severe stenosis, and lower gastrointestinal bleeding, and to examine their associations with treatment allocation, perioperative mortality, and overall survival after adjustment for recorded covariates. Methods: We performed a retrospective, real-world cohort study of 1051 consecutive patients with CRC diagnosed between 2018 and 2021 at a tertiary referral centre. Patients were assigned to four mutually exclusive groups using a classification defined before outcome analysis (obstructive–perforative, stenotic, haemorrhagic, elective). Overall survival was assessed using Kaplan–Meier analysis and multivariable Cox regression, with formal testing of the proportional hazards assumption. Results: Emergency presentation occurred in 43.7% of patients but was markedly heterogeneous. Metastatic burden did not differ across phenotypes (p = 0.122). The obstructive–perforative phenotype showed the least favourable outcomes: perioperative mortality was 11.5%, and it remained associated with mortality after adjustment for recorded covariates (HR 1.58, 95% CI 1.25–2.00; p < 0.001), with hazard ratios ranging from 1.33 to 1.69 across six model specifications. Haemorrhagic presentation was rectal-predominant and behaved favourably, with survival comparable to elective diagnosis. Among 30-day survivors, the excess hazard was attenuated but persisted (HR 1.39, 95% CI 1.04–1.86). Conclusions: Emergency presentation in CRC is not a monolithic risk category. Recognising the presenting phenotype may offer a pragmatic framework for provisional risk characterisation at diagnosis, but external validation and adjustment for patient-level comorbidity and performance status are required before routine clinical use. Full article

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide despite substantial advances in screening, surgical techniques, systemic therapies, and multidisciplinary care. The increasing implementation of precision oncology has fundamentally transformed CRC management by enabling molecularly guided therapeutic strategies based on tumor-specific genetic alterations. In recent years, the molecular landscape of CRC has expanded considerably beyond traditional histopathological classification, incorporating a growing number of clinically actionable biomarkers with prognostic, predictive, and therapeutic significance. This review provides a comprehensive and up-to-date overview of the genetic landscape of CRC, focusing on established biomarkers currently integrated into clinical practice, including microsatellite instability/mismatch repair deficiency (MSI/dMMR), KRAS, NRAS, BRAF, HER2, and NTRK alterations. In addition, emerging biomarkers such as tumor mutational burden (TMB), POLE/POLD1 mutations, circulating tumor DNA (ctDNA), DNA damage repair (DDR) alterations, transcriptomic signatures, and artificial intelligence-based molecular prediction models are critically discussed. Particular emphasis is placed on their biological significance, diagnostic methodologies, prognostic and predictive value, and potential role in treatment selection. A structured, database-informed narrative review identified 140 relevant publications, primarily published between January 2020 and June 2026, supplemented by earlier seminal studies and major clinical guidelines. Based on the available evidence, we propose a Clinical Actionability Framework for CRC, categorizing biomarkers into three hierarchical tiers according to their level of clinical validation and therapeutic relevance: established standard-of-care biomarkers, emerging clinical biomarkers, and future precision oncology biomarkers. Collectively, current evidence supports a progressive transition from single-gene testing toward integrated multi-omics precision medicine. Advances in comprehensive genomic profiling, liquid biopsy technologies, transcriptomics, radiogenomics, and artificial intelligence are expected to further refine patient stratification, optimize therapeutic decision-making, and facilitate the development of adaptive precision oncology models. Understanding the evolving genetic landscape of CRC is therefore essential for maximizing treatment efficacy and improving patient outcomes in the era of personalized cancer care. Full article

Background/Objectives: Colorectal cancer (CRC) with bladder involvement represents a distinct subgroup of locally advanced disease frequently accompanied by urinary tract-related manifestations (UTRMs). However, the clinical relevance of prediagnostic UTRMs in this high-risk population remains unclear. This study investigated the association between UTRMs and oncologic outcomes in patients with bladder-involved CRC. Methods: We conducted a population-based retrospective cohort study using the National Health Insurance Research Database and Catastrophic Illnesses Database (2000–2020). A total of 2608 patients with CRC involving the bladder were included. Patients with prediagnostic UTRMs, including urinary frequency, urgency, dysuria, hematuria, and urinary tract infections, were identified using diagnostic codes recorded within 6 months before CRC diagnosis. Inverse probability of treatment weighting was applied to balance baseline characteristics. Patients were followed from CRC diagnosis until disease recurrence, death, or end of the study period. Weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Patients with UTRMs had a significantly higher risk of disease recurrence than those without UTRMs (adjusted HR 1.57). Patients with UTRMs requiring antibiotic treatment exhibited an even greater recurrence risk (adjusted HR 4.17), although this finding should be interpreted cautiously because of the limited sample size. Associations between UTRMs and recurrence were generally consistent across subgroup analyses. In contrast, UTRMs were not significantly associated with CRC-specific mortality. Conclusions: Prediagnostic UTRMs were associated with an increased risk of recurrence in patients with CRC involving the bladder. These readily obtainable preoperative clinical manifestations may provide supplementary information for postoperative surveillance in this high-risk population. Further studies are warranted to validate these findings. Full article

Background/Objectives: Colorectal liver metastases (CRLMs) are a major contributor to recurrence and mortality in colorectal cancer (CRC), with approximately a quarter of patients developing liver metastases over the course of the disease. Bone-marrow-derived myeloid lineages are sent into the circulatory system and colonize pre-metastatic niches, yet the transcriptional programs by which they establish a pro-metastatic microenvironment remain incompletely defined. Methods: Using an MC38 splenic-injection CRLM mouse model, we generated single-cell RNA sequencing (scRNA-seq) profiles of FACS-sorted CD11b⁺Gr1⁺ bone marrow myeloid cells, together with bulk RNA sequencing profiles of bone marrow and peripheral blood. Downstream analyses were performed in silico, including clustering and annotation, trajectory inference, cell–cell communication analysis, weighted gene co-expression network analysis (WGCNA), and pathway enrichment, with subset specificity examined against a public dataset of E. coli (Escherichia coli)-infected mice. Results: Within the CD11b⁺Gr1⁺ compartment, a CCR2⁺ neutrophil-like population (Ly6g⁺S100a8/9⁺) emerging during terminal differentiation was identified, which was enriched in CRLM mice but nearly absent in controls. Communication inference revealed an FN1-CD44 interaction involving mature neutrophils, which was associated with an epithelial–mesenchymal transition signature and upregulation of Tgfb1 and Il1b. This subpopulation was not recovered in the infection dataset, suggesting relative specificity to CRLMs. Conclusions: Within the constraints of a splenectomized hepatic colonization model, integrated transcriptomic analysis highlighted a CCR2⁺ bone marrow neutrophil-like population as a candidate contributor to CRLM, challenging the view that CCR2⁺ pro-metastatic myeloid cells are exclusively monocytic and suggesting candidate biomarkers and therapeutic targets for further study. Full article

Background/Objectives: Fecal immunochemical testing (FIT)-based screening for colorectal cancer (CRC) has been associated with reductions in CRC mortality and improvements in early-stage disease detection; however, most related evidence has been derived from large national registries. The present study investigated associations of FIT screening status with overall survival (OS) and several clinicopathological characteristics in a regional hospital setting. Methods: After propensity score matching, 912 patients with pathologically confirmed colorectal adenocarcinoma diagnosed between 2010 and 2025 at a regional hospital in Taiwan were included. Patients were categorized into screened (n = 304) and nonscreened (n = 608) groups by using propensity score matching based on age as a continuous variable, sex, and stage. OS and clinicopathological characteristics in each group were compared. Multivariable Cox regression was performed using a primary reduced model, an exploratory full model, and multiple imputation analysis. Results: Screened patients demonstrated better 15-year OS (58.38% vs. 45.80%; log-rank p = 0.005), especially those with early-stage disease (p = 0.001). FIT screening was independently associated with improved OS in the primary reduced model (hazard ratio [HR] = 0.63; 95% confidence interval [CI]: 0.45–0.88; p = 0.006) and multiple imputation analysis (HR = 0.68; 95% CI: 0.50–0.91; p = 0.010). Independent adverse prognostic factors were male sex, late-stage disease, perineural invasion, tumor obstruction, and abnormal pretreatment carcinoembryonic antigen level. Conclusions: FIT screening was associated with better long-term OS in a stage-balanced cohort, but interpretation is limited by the use of OS rather than CRC-specific survival and residual age imbalance. Improving FIT participation, timely colonoscopy follow-up, and complete pathological staging remains essential for CRC outcomes. Full article

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, largely due to late-stage diagnosis and the limited sensitivity of current screening approaches for early lesions. In recent years, the gut microbiota has emerged as a key factor in colorectal carcinogenesis, offering promising opportunities for the development of novel, non-invasive diagnostic and therapeutic strategies. Specific bacterial species and microbial metabolites have been implicated in colorectal carcinogenesis and are under investigation as potential biomarkers for CRC detection. However, despite growing evidence of association, most remain investigational and require further clinical validation before routine implementation. Among the proposed bacterial biomarkers, Fusobacterium nucleatum is one of the most promising candidates for clinical implementation, with encouraging evidence supporting its use in non-invasive stool-based CRC detection. Streptococcus gallolyticus subsp. gallolyticus and Clostridium septicum currently serve primarily as clinical warning markers due to their well-established association with occult colorectal malignancy rather than as screening biomarkers. In contrast, pks⁺Escherichia coli, enterotoxigenic Bacteroides fragilis, Enterococcus faecalis, and Peptostreptococcus anaerobius remain investigational. Helicobacter pylori has limited value for CRC detection because of its inconsistent association and low specificity. Overall, this review summarizes the most extensively studied bacterial species and microbial metabolites involved in colorectal cancer development, with particular emphasis on their underlying pathogenic mechanisms and highlighting their potential value as diagnostic biomarkers and therapeutic targets. It also highlights emerging bacterial taxa and microbial signatures that have been associated with early tumorigenesis in recent studies. Full article

Colorectal cancer (CRC) remains the third most common malignancy worldwide and a leading cause of cancer mortality, largely driven by metastatic dissemination. Among metastatic routes, lymphatic spread is crucial to determine the prognosis and establish an adequate therapeutic strategy. Lymph node metastasis (LNM) defines stage III disease in the TNM classification, guiding adjuvant chemotherapy and surgical planning. However, nodal staging based on lymphadenectomy and histopathology is invasive, time-consuming, and may lead to overtreatment. Conventional imaging modalities, including computed tomography, magnetic resonance imaging, and endorectal ultrasound, show limited sensitivity and specificity for small or micro-metastatic nodes. Despite multimodal progress, no non-invasive technique reliably identifies malignant nodes in real time. PET–MRI, contrast-enhanced ultrasound, photoacoustic and fluorescence approaches, ICG mapping, and sentinel node biopsy improve detection but remain limited by specificity, cost, or availability. Extranodal extension (ENE) and tumor deposits (TDs) carry major prognostic value, reflecting aggressive biology and association with distant spread. Meanwhile, phylogenetic studies challenge linear dissemination models, indicating that some metastases arise directly from the primary tumor or TDs rather than LNMs. These data support refinement of staging and surgical strategies according to tumor biology rather than purely anatomical criteria. High-frequency quantitative ultrasound (HF-QUS) enables real-time, operator-independent, three-dimensional nodal assessment with reported sensitivity and specificity exceeding 85%. Combined with artificial intelligence and molecular profiling, it may support biologically informed staging, reduce unnecessary surgery, and foster precision oncology. Lymphatic dissemination in CRC offers a platform to merge tumor biology with technological innovation, where advanced imaging, molecular insight, and artificial intelligence may redefine nodal staging toward precision, non-invasive care. Full article

Background: Colorectal cancer (CRC) remains a leading cause of mortality worldwide, with a significant proportion of patients presenting with metastatic disease (mCRC). While molecularly targeted therapies, including anti-EGFR and anti-VEGF agents, have improved survival outcomes, their efficacy is often limited by drug resistance, toxicity, and high costs. There is a growing need for sustainable strategies to enhance therapeutic efficacy. Methods: This review explores the emerging role of plant-derived compounds as synergistic adjuvants. Specifically, PubMed, Scopus, and Web of Science were searched for English-language articles published between January 2004 and June 2026, using combination of terms related to colorectal cancer, metastatic disease, anti-EGFR/anti-VEGF targeted therapy, phytochemicals/natural products, and gut microbiota; both primary studies and reviews were eligible. Results: Targeted therapies such as cetuximab and bevacizumab are the standard of care but face challenges related to RAS/BRAF mutations and primary tumour location. Clinical data demonstrate that while cetuximab improves overall survival in patients with RAS wild-type, left-sided tumours (median OS 31 vs. 26 months; HR 0.76, p = 0.012), progression-free survival remains comparable to that of bevacizumab. Concurrently, natural products like Vitis vinifera, Dendrobium candidum, and quercetin demonstrate significant preclinical potential in inhibiting angiogenesis, inducing apoptosis, and modulating the tumour microenvironment. The gut microbiome, particularly Fusobacterium nucleatum (whose reported prevalence varies widely across cohorts and reaches up to ~98% of CRC tissues only in selected series), has emerged as a key factor in chemoresistance. It should be emphasised that the great majority of the phytochemical-targeted therapy combinations discussed here are currently supported primarily by preclinical (in vitro and animal) studies rather than by clinical trials. Conclusions: Integrating evidence-based phytochemicals with conventional targeted therapies is a mechanistically compelling and potentially sustainable strategy that may enhance therapeutic efficacy, help overcome resistance, and mitigate adverse effects in mCRC management. However, because current support is largely preclinical, these combinations should be regarded as hypothesis-generating and require validation in prospective, biomarker-stratified clinical trials before clinical adoption. Full article

Background: Modifiable lifestyle factors may contribute additively to colorectal cancer (CRC) risk in individuals who already have non-modifiable risk factors, such as prior colorectal neoplasia or significant family history of CRC. However, the impact of multicomponent lifestyle interventions (such as dietary modification, physical activity, and counselling) on behavioural modification, risk of colorectal neoplasia, and quality of life (QoL) in this population has not yet been systematically reviewed. Aims: The primary aim was behavioural change (change in body weight, diet, physical activity, sedentary lifestyle, smoking, and alcohol consumption). The secondary aim was colorectal neoplasia outcomes, including the incidence of precancerous lesions and/or cancer and CRC mortality/survival, and QoL, including specific domains. Methods: This review was conducted following the Cochrane guidelines for Systematic Reviews of Interventions. Both randomised and non-randomised studies assessing the effect of multicomponent lifestyle interventions on behavioural modification, risk of colorectal neoplasia, mortality, and quality of life in people at above-average risk of CRC were included. Medline/Ovid, Cochrane Library, Web of Science, and Scopus were searched. Screening, data extraction, and risk of bias assessment were independently performed by two reviewers using the revised Cochrane Risk of Bias (RoB) tools. Results: Of the 4174 studies screened, 10 interventional studies were eligible for inclusion, which had outcomes for behavioural change or quality of life. No interventions assessed neoplasia risk or mortality outcomes. Multicomponent lifestyle interventions mainly targeting diet and physical activity, delivered via a telephone-based or health coaching approach, showed positive effects on healthy behaviours and quality of life compared with usual care, although some studies reported inconsistent results. Conclusions: There is emerging evidence that multicomponent lifestyle interventions may offer beneficial effects on practicing healthy behaviours and improving QoL for individuals at above-average risk for CRC and undergoing colonoscopy surveillance. Full article

Background: As survival after colorectal cancer (CRC) has improved, an increasing proportion of patients live beyond five years, making long-term outcomes increasingly relevant. In addition to cancer-related mortality, survivors remain at risk of death from other causes influenced by clinical and psychosocial vulnerabilities. Methods: We conducted a 10-year prospective cohort study including 838 patients with stage I–IV CRC treated in public hospitals in the Basque Country (Spain). Patients were recruited between November 2010 and December 2012 and followed for up to 10 years after surgery. Clinical, sociodemographic, lifestyle, and patient-reported outcomes were collected. Competing risk regression models (Fine-Gray) were used to estimate sub-distribution hazard ratios (sHRs) for CRC-specific and non-CRC mortality, stratified by tumor site and sex. Results: After 10 years, 40% of patients had died, with 66% of deaths attributable to CRC and 34% to other causes. CRC-specific mortality was mainly driven by tumor-related factors, including advanced stage (stage IV: sHR 7.18, p < 0.001) and residual disease after surgery (R1/R2: sHR 2.68; p < 0.001), with larger effect sizes observed in rectal cancer. In contrast, non-CRC mortality was associated with patient vulnerability, including age ≥75 years (sHR 3.57, p < 0.001), absence of adjuvant chemotherapy (sHR 5.59, p < 0.001), anemia, alcohol consumption, and poor functional status. Patients with rectal cancer and women reported poorer baseline quality of life. Sex-stratified analyses suggested differential patterns of vulnerability, with psychosocial and quality-of-life-related factors appearing more relevant in women, whereas lifestyle and clinical factors appeared more prominent in men. Conclusions: Long-term mortality in CRC reflects the interplay between tumor-related factors and patient vulnerability. Competing risk models allow a more accurate characterization of cause-specific outcomes and may help identify high-risk subgroups for tailored follow-up and management strategies. Full article

Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related mortality worldwide. A consistent and epidemiologically well-documented feature of CRC is its sexual dimorphism: age-standardized incidence rates are 33–45% higher in men than in women, and mortality rates differ by 43–50%. Beyond epidemiology, biological sex influences tumor location, molecular subtype, and clinical outcome. Women more frequently develop right-sided, microsatellite-unstable tumors driven by the CpG island methylator phenotype pathway, whereas men predominantly present with left-sided, chromosomally unstable tumors harboring APC, KRAS, and TP53 mutations. Sex steroid hormones play a central modulatory role: estrogens, primarily via estrogen receptor β (ERβ), exert tumor-suppressive effects on colonic epithelium, whereas androgens promote pro-inflammatory and pro-tumorigenic signaling through androgen receptor (AR)-dependent pathways. The gut microbiome displays sex-specific compositional profiles (‘microgenderome’) and contributes to sex-specific CRC susceptibility through bidirectional interactions with sex hormones, shaping distinct immunological and metabolic microenvironments. Finally, sex influences the pharmacokinetics of fluoropyrimidines, the toxicity of targeted agents, and the response to immune checkpoint inhibitors. This review summarizes current evidence on sex-related differences in CRC epidemiology, molecular pathology, hormonal regulation, gut microbiota composition, and treatment outcomes, highlighting the need to systematically incorporate sex as a biological variable in CRC research and clinical practice. Full article

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy and the second leading cause of cancer-related mortality worldwide, underscoring the need for the development of more effective and durable therapeutic strategies. A key mechanism of tumor immune evasion involves activation of immune checkpoint pathways through the upregulation of inhibitory ligand expression within the tumor microenvironment, leading to lymphocyte exhaustion and impaired antitumor immunity. Consequently, immune checkpoints have emerged as important targets for immunotherapeutic intervention, with significant advances over the past decade. Nevertheless, despite demonstrated clinical benefits in selected patient subpopulations, the overall therapeutic efficacy of immune checkpoint inhibitors remains limited, particularly in the context of CRC. In this review, we provide a comprehensive overview of currently approved immune checkpoint-based immunotherapies for cancer treatment, with a specific focus on CRC, as well as ongoing clinical trials and evolving trends in this area. Furthermore, we discuss emerging targets and novel therapeutic strategies, with particular emphasis on innovative small-molecule inhibitors as potential alternatives to monoclonal antibody-based approaches. Finally, we outline future perspectives and potential directions for advancing immune checkpoint-targeted therapies in CRC. Full article

Background: Colorectal cancer (CRC) represents a major global health burden, accounting for roughly 10% of all newly diagnosed cancers and cancer-related deaths worldwide. According to the World Health Organization, it is the third most diagnosed malignancy and the second leading cause of cancer mortality. Postoperative complications remain a significant concern after CRC resection, occurring in up to 50% of patients and contributing to increased morbidity, mortality, prolonged hospitalization, and substantial healthcare expenditure. Artificial intelligence (AI) has emerged as a transformative tool in modern healthcare, offering advanced capabilities in predictive analytics, clinical decision support, and personalized perioperative management. Methods: This review systematically evaluates the application of AI, specifically machine learning (ML) and deep learning (DL) algorithms, in the prediction of anastomotic leak (AL) and other major postoperative complications. In this context, AI models are generally used to refine risk stratification and enhance surgical decision-making. Results: A total of 13 studies were included, encompassing 15,105 patients. Across these studies, ML and DL algorithms consistently outperformed conventional statistical models in forecasting postoperative outcomes. Conclussions: Current evidence suggests that AI has substantial potential to improve perioperative risk prediction, support intraoperative decision-making, and personalize postoperative surveillance in patients undergoing CRC surgery. Methodological limitations, including a high risk of bias, limited external validation, heterogeneous outcome definitions, and inconsistent reporting, necessitate more robust, prospective, multicenter research before widespread clinical adoption can be realized. Full article

Colorectal cancer (CRC) remains a major global health burden and a leading cause of cancer-related morbidity and mortality. Current blood-based biomarkers lack sufficient sensitivity and specificity, particularly for early detection. In this context, circulating immune-cell transcriptomic profiling has emerged as a promising minimally invasive approach. This systematic review was conducted following a PROSPERO-registered protocol (CRD42024604757) and PRISMA 2020 guidelines to evaluate the diagnostic and prognostic potential of circulating monocyte-related transcriptomic profiles in CRC. Of 295 records identified, six studies met the inclusion criteria. The available evidence consistently supports the diagnostic value of circulating transcriptomic profiles in distinguishing patients with CRC from healthy individuals and in reflecting tumour-associated immune alterations. Monocyte-related signatures, including CXCR2⁺ monocytes, were associated with disease stage and metastatic features. Epitranscriptomic modifications, such as m6A and m5C, further reinforced their diagnostic relevance, with some studies reporting higher diagnostic accuracy than classical biomarkers. In contrast, evidence for prognostic value remains limited, heterogeneous, and often indirect, largely due to small sample sizes, methodological variability, and reliance on public datasets. Overall, circulating immune-cell transcriptomic profiles are promising non-invasive biomarkers for CRC detection and characterization, although their prognostic utility remains unclear. Methodological heterogeneity limits clinical applicability, highlighting the need for standardized, CRC-specific studies with cell-type-resolved approaches. Full article