Search Results (293)

CD26 (dipeptidyl peptidase-4) is a marker of colorectal cancer stem cells with high metastatic potential and resistance to therapy. Although CD26 expression is known to be associated with tumor progression, its functional involvement in epithelial-mesenchymal transition (EMT) and metastasis remains to be fully elucidated. In this study, we aimed to investigate the effects of a monoclonal anti-CD26 antibody on EMT-related phenotypes and metastatic behavior in colorectal cancer cells. We evaluated changes in EMT markers by quantitative PCR and Western blotting, assessed cell motility and invasion using scratch wound-healing and Transwell assays, and examined metastatic potential in vivo using a splenic injection mouse model. Treatment with the anti-CD26 antibody significantly increased the expression of the epithelial marker E-cadherin and reduced levels of EMT-inducing transcription factors, including ZEB1, Twist1, and Snail1, at the mRNA and protein levels. Functional assays revealed that the antibody markedly inhibited cell migration and invasion in vitro without exerting cytotoxic effects. Furthermore, systemic administration of the anti-CD26 antibody significantly suppressed the formation of liver metastases in vivo. These findings suggest that CD26 may contribute to the regulation of EMT and metastatic behavior in colorectal cancer. Our data highlight the potential therapeutic utility of CD26-targeted antibody therapy for suppressing EMT-associated phenotypes and metastatic progression. Full article

Background: Colorectal liver metastasis (CRLM) represents a major clinical challenge in oncology, affecting 25–50% of colorectal cancer patients and significantly impacting survival. While multimodal therapies—including surgical resection, systemic chemotherapy, and local ablative techniques—have improved outcomes, prognosis remains heterogeneous due to variations in tumor biology, patient factors, and institutional practices. Methods: This review synthesizes current evidence on prognostic factors influencing CRLM management, encompassing clinical (e.g., tumor burden, anatomic distribution, timing of metastases), biological (e.g., CEA levels, inflammatory markers), and molecular (e.g., RAS/BRAF mutations, MSI status, HER2 alterations) determinants. Results: Key findings highlight the critical role of molecular profiling in guiding therapeutic decisions, with RAS/BRAF mutations predicting resistance to anti-EGFR therapies and MSI-H status indicating potential responsiveness to immunotherapy. Emerging tools like circulating tumor DNA (ctDNA) and radiomics offer promise for dynamic risk stratification and early recurrence detection, while the gut microbiome is increasingly recognized as a modulator of treatment response. Conclusions: Despite advancements, challenges persist in standardizing resectability criteria and integrating multidisciplinary approaches. Current guidelines (NCCN, ESMO, ASCO) emphasize personalized strategies but lack granularity in terms of incorporating novel biomarkers. This exhaustive review underscores the imperative for the development of a unified, biomarker-integrated framework to refine CRLM management and improve long-term outcomes. Full article

Purpose: Predicting colorectal cancer liver metastasis (CRLM) is essential for prognostic assessment. This study aims to develop and validate an interpretable multimodal machine learning framework based on multiparametric MRI for predicting CRLM, and to enhance the clinical interpretability of the model through SHapley Additive exPlanations (SHAP) analysis and deep learning visualization. Methods: This multicenter retrospective study included 463 patients with pathologically confirmed colorectal cancer from two institutions, divided into training (n = 256), internal testing (n = 111), and external validation (n = 96) sets. Radiomics features were extracted from manually segmented regions on axial T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI). Deep learning features were obtained from a pretrained ResNet101 network using the same MRI inputs. A least absolute shrinkage and selection operator (LASSO) logistic regression classifier was developed for clinical, radiomics, deep learning, and combined models. Model performance was evaluated by AUC, sensitivity, specificity, and F1-score. SHAP was used to assess feature contributions, and Grad-CAM was applied to visualize deep feature attention. Results: The combined model integrating features across the three modalities achieved the highest performance across all datasets, with AUCs of 0.889 (training), 0.838 (internal test), and 0.822 (external validation), outperforming single-modality models. Decision curve analysis (DCA) revealed enhanced clinical net benefit from the integrated model, while calibration curves confirmed its good predictive consistency. SHAP analysis revealed that radiomic features related to T2WI texture (e.g., LargeDependenceLowGrayLevelEmphasis) and clinical biomarkers (e.g., CA19-9) were among the most predictive for CRLM. Grad-CAM visualizations confirmed that the deep learning model focused on tumor regions consistent with radiological interpretation. Conclusions: This study presents a robust and interpretable multiparametric MRI-based model for noninvasively predicting liver metastasis in colorectal cancer patients. By integrating handcrafted radiomics and deep learning features, and enhancing transparency through SHAP and Grad-CAM, the model provides both high predictive performance and clinically meaningful explanations. These findings highlight its potential value as a decision-support tool for individualized risk assessment and treatment planning in the management of colorectal cancer. Full article

Background: Peritoneal dissemination in colorectal cancer (CRC) is associated with poor prognosis due to limited efficacy of current therapeutic strategies. The cholinergic receptor nicotinic beta 2 subunit (CHRNB2), a component of the acetylcholine receptor, has been implicated in other malignancies, but its role in CRC remains unknown. Methods: This study evaluated the expression and function of CHRNB2 in CRC. CHRNB2 mRNA levels were quantified by qRT-PCR in cell lines and clinical specimens. Functional assays were conducted using CRC cell lines with high CHRNB2 expression, in which CHRNB2 was knocked down by shRNA. Cell proliferation, migration, and invasion were assessed in vitro. In vivo effects were evaluated using subcutaneous and peritoneal xenograft models. The impact of CHRNB2 monoclonal antibody (mAb) treatment on CRC cell proliferation was also examined. Clinical correlations were assessed between CHRNB2 expression and clinicopathological features, including recurrence patterns. Results: CHRNB2 expression varied among CRC cell lines, with the highest levels observed in LOVO cells. CHRNB2 knockdown significantly inhibited proliferation, migration, and invasion in vitro and suppressed tumor growth in vivo. CHRNB2 mAb treatment reduced cell proliferation. Clinically, high CHRNB2 expression correlated with a significantly higher cumulative rate of peritoneal recurrence, but not with recurrence in the liver, lungs, or lymph nodes. Multivariate analysis identified high CHRNB2 expression and T4 tumor depth as independent predictors of peritoneal recurrence. Conclusions: CHRNB2 promotes the malignant phenotype of CRC, particularly in peritoneal dissemination. These findings suggest that CHRNB2 may serve as a novel diagnostic biomarker and therapeutic target for CRC with peritoneal metastasis. Full article

Colorectal liver metastasis (CRLM) poses a significant challenge in oncology due to its high incidence and poor prognosis in unresectable cases. Current treatments, including surgical resection, systemic chemotherapy, and liver-directed therapies, often fail to effectively target hypoxic tumor regions, which are inherently more resistant to these interventions. This review examines the potential of a novel therapeutic strategy combining irreversible electroporation (IRE) ablation and Clostridium novyi-nontoxic (C. novyi-NT) bacterial therapy. IRE is a non-thermal tumor ablation technique that uses high-voltage electric pulses to create permanent nanopores in cell membranes, leading to cell death while preserving surrounding structures, and is often associated with temporary tumor hypoxia due to disrupted perfusion. C. novyi-NT is an attenuated, anaerobic bacterium engineered to selectively germinate and proliferate in hypoxic tumor regions, resulting in localized tumor cell lysis while sparing healthy, oxygenated tissue. The synergy between IRE-induced hypoxia and hypoxia-sensitive C. novyi-NT may enhance tumor destruction and stimulate systemic antitumor immunity. Furthermore, the integration of advanced imaging and artificial intelligence can support precise treatment planning and real-time monitoring. This integrated approach holds promise for improving outcomes in patients with CRLM, though further preclinical and clinical validation is needed. Full article

Colorectal cancer (CRC) diagnosed in an advanced stage has an increased predisposition for invasion and metastasis, requiring upgraded prognostic markers. CDH17, a liver-intestine cadherin, is an adhesion molecule implicated in tumor progression. This retrospective study assessed the immunohistochemical expression of CDH17 in 84 CRC cases with lymphovascular invasion (LVI), analyzing its correlation with clinicopathological features and survival outcomes. CDH17 expression was evaluated in the tumor core, invasive front, tumor emboli, and lymph node metastases. Statistical analyses showed significant associations between high CDH17 expression and favorable histological types, as well as low-grade differentiation. However, high CDH17 levels in tumor emboli correlated with advanced T stage and poorer overall survival. Multivariable Cox regression confirmed CDH17 expression in tumor emboli as an independent prognostic factor, indicating an approximately twofold risk of death. These findings suggest that CDH17 may have a dual role—maintaining adhesion in low-grade tumors while facilitating tumor emboli-related dissemination. CDH17 expression, particularly in the tumor emboli, could serve as a valuable prognostic biomarker in CRC with LVI. Full article

Background: Huang Qin Decoction (HQD) is a well-established Traditional Chinese Medicine (TCM) formulation recognized for its application in the treatment of colorectal cancer (CRC). However, the precise therapeutic mechanisms remain inadequately defined. Methods: This study integrates metabolomics from a mouse model and network pharmacology to screen potential targets and bio-active ingredients of HQD. The pharmacological activity of HQD for CRC was evidenced via single-cell RNA sequencing (scRNA-seq), molecular docking, and molecular dynamics simulations. Atomic force microscopy (AFM) assays and cellular experimental validation were used to confirm the relative mechanisms. Results: The metabolite profile undergoes significant alterations, with metabolic reprogramming evident during the malignant progression of CRC liver metastasis. Network pharmacology analysis identified that HQD regulates several metabolic pathways, including arginine biosynthesis, alanine, aspartate, and glutamate metabolism, nitrogen metabolism, phenylalanine metabolism, and linoleic acid metabolism, by targeting key proteins such as aspartate aminotransferase (GOT1), cytochrome P450 1A2 (CYP1A2), and carbonic anhydrase 2 (CA2). ScRNA-seq analysis indicated that HQD may enhance the functionality of cytotoxic T cells, thereby reversing the immunosuppressive microenvironment. Virtual verification revealed a strong binding affinity between the identified hub targets and active constituents of HQD, a finding subsequently corroborated by AFM assays. Cellular experiments confirmed that naringenin treatment inhibits the proliferation, migration, and invasion of CRC cells by downregulating GOT1 expression and disrupting glutamine metabolism. Conclusions: Computational prediction and in vitro validation reveal the active ingredients, potential targets, and molecular mechanisms of HQD against CRC liver metastasis, thereby providing a scientific foundation for the application of TCM in CRC treatment. Full article

Objective: Tumor progression is regulated by systemic immune status, nutritional metabolism, and the inflammatory microenvironment. This study aims to investigate inflammatory–nutritional biomarkers associated with metachronous liver metastasis (MLM) in colorectal cancer (CRC) and develop a machine learning model for accurate prediction. Methods: This study enrolled 680 patients with CRC who underwent curative resection, randomly allocated into a training set (n = 477) and a validation set (n = 203) in a 7:3 ratio. Feature selection was performed using Boruta and Lasso algorithms, identifying nine core prognostic factors through variable intersection. Seven machine learning (ML) models were constructed using the training set, with the optimal predictive model selected based on comprehensive evaluation metrics. An interactive visualization tool was developed to interpret the dynamic impact of key features on individual predictions. The partial dependence plots (PDPs) revealed a potential dose–response relationship between inflammatory–nutritional markers and MLM risk. Results: Among 680 patients with CRC, the cumulative incidence of MLM at 6 months postoperatively was 39.1%. Multimodal feature selection identified nine key predictors, including the N stage, vascular invasion, carcinoembryonic antigen (CEA), systemic immune–inflammation index (SII), albumin–bilirubin index (ALBI), differentiation grade, prognostic nutritional index (PNI), fatty liver, and T stage. The gradient boosting machine (GBM) demonstrated the best overall performance (AUROC: 0.916, sensitivity: 0.772, specificity: 0.871). The generalized additive model (GAM)-fitted SHAP analysis established, for the first time, risk thresholds for four continuous variables (CEA > 8.14 μg/L, PNI < 44.46, SII > 856.36, ALBI > −2.67), confirming their significant association with MLM development. Conclusions: This study developed a GBM model incorporating inflammatory-nutritional biomarkers and clinical features to accurately predict MLM in colorectal cancer. Integrated with dynamic visualization tools, the model enables real-time risk stratification via a freely accessible web calculator, guiding individualized surveillance planning and optimizing clinical decision-making for precision postoperative care. Full article

Background: To overcome the limitations of conventional CRC (colorectal cancer) mouse models in replicating metastasis and enabling efficient therapeutic evaluation, we developed a novel implantation method using tissue adhesive to establish reproducible orthotopic and metastatic tumors. Conventional models using injection or suturing techniques often suffer from technical complexity, inconsistent tumor establishment, and limited metastatic reliability. Methods: We developed and validated a novel orthotopic and metastatic CRC model utilizing tissue adhesive for tumor transplantation. Uniform tumor fragments derived from bioluminescent HCT116/Luc xenografts were affixed to the cecum of nude mice. Tumor growth and metastasis were monitored through bioluminescence imaging and confirmed by the results of histological analysis of metastatic lesions. The model’s utility for therapeutic testing was evaluated using MK801, an NMDA receptor antagonist. Results: The biological-based model demonstrated rapid and reproducible tumor implantation (<5 min), consistent primary tumor growth, and robust metastasis to the liver and lungs. The biological-based approach achieved 80% tumor engraftment (4/5), with consistent metastasis to the liver and lungs in all mice, compared with lower and variable metastasis rates in injection (0%, 0/5) and suturing (20%, 1/5) methods. MK801 treatment significantly suppressed both primary tumor growth and metastasis, validating the model’s suitability for preclinical drug evaluation. Conclusions: By enabling rapid, reproducible, and spontaneous formation of metastatic lesions using a minimally invasive tissue adhesive technique, our model represents a significant methodological advancement that supports high-throughput therapeutic screening and bridges the gap between experimental modeling and clinical relevance in colorectal cancer research. Full article

Colorectal cancer (CRC) is a leading global malignancy with a poor prognosis in advanced stages. Early and accurate diagnosis remains challenging due to the overlapping of clinical manifestations between early-stage CRC and inflammatory bowel diseases. Although dynamic contrast-enhanced MRI (DCE-MRI) is a critical imaging modality for the diagnosis of CRC and colorectal cancer liver metastasis (CRLM), conventional gadolinium-based contrast agents (GBCAs) have the limitations of rapid clearance and potential toxicity risks. In this study, we report a gadolinium-free T1-weighted nanocontrast agent based on Fe(III)-coordinated poly(α-amino acid)s (Fe@POS) nanomicelles. Fe@POS nanomicelles exhibit a high longitudinal relaxivity (r₁ = 5.56 mM⁻¹s⁻¹) and prolonged blood circulation time with selective CRC tumor accumulation via enhanced permeability and retention (EPR) effect. In vivo MRI studies revealed long-period MRI of CRC. In CRLM lesions, normal hepatic tissue demonstrates greater Fe@POS uptake compared to tumor tissue, which enables clear delineation of tumor margins on MRI. Histological and biochemical analysis confirmed the biocompatibility of Fe@POS nanomicelles, with no acute toxicity observed, highlighting their potential as alternatives to GBCAs for clinical diagnostic applications. Full article

Background: Colorectal cancer (CRC) is among the most prevalent and lethal cancers globally, with liver metastasis representing the leading cause of CRC-related mortality. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has recently gained attention due to its overexpression in colorectal tumor tissues and its potential role in driving metastatic progression. This aims to investigate the involvement of PCSK9 in the liver metastatic niche, focusing on its effects on liver sinusoidal endothelial cells (LSECs), key components of the liver microenvironment. Methods: LSECs were stimulated with conditioned media derived from differentiated colorectal cancer cells and cancer stem cells (CSCs), the latter generated by reprogramming SW620 and CT26 cell lines. RNA sequencing was used to profile gene expression in LSECs. PCSK9 mRNA and protein levels were quantified by qPCR and Western blotting, respectively. PCSK9 expression in CRC liver metastases was evaluated by immunofluorescent staining. Results: PCSK9 was detected in both human and murine LSECs and significantly upregulated following exposure to CSC-conditioned media. Immunofluorescent staining confirmed PCSK9 expression in LSECs within CRC liver metastases. Total RNA sequencing revealed that a pre-treatment of LSECs with the PCSK9 inhibitor PF-06446864 prior to CSC stimulation seems to reduce the expression of microRNAs linked to cell migration and proliferation. Functional assays demonstrated that CSC-conditioned media enhanced LSEC proliferation and migration, effects reversed by PCSK9 inhibition. Conclusions: PCSK9 promotes the activation of LSECs in response to colorectal CSCs, contributing to a pro-metastatic phenotype. These findings highlight PCSK9 as a potential therapeutic target in colorectal liver metastasis. Full article

Transplant oncology is a rapidly evolving discipline that incorporates oncology, transplant medicine, and surgery. As the field continues to grow, there remains an opportunity to enhance patient selection, detect recurrence after liver transplantation, and optimize treatment after recurrence. Liquid biopsies are an emerging resource to improve patient care. In this review, we evaluate the most recent available data on circulating tumor DNA and how it pertains to primary and metastatic hepatobiliary malignancies. We discuss the opportunities and current limitations to clinical practice, especially in relation to total hepatectomy and liver transplantation. We conclude that as both transplant oncology and our understanding of circulating tumor DNA continue to evolve, rigorous, prospective study is required to integrate this technology into a clinical paradigm. Full article

Background: Hepatic resection is performed for liver lesions and requires careful preoperative planning to minimize bleeding. Blood type O, associated with lower von Willebrand factor (vWF) levels, may increase bleeding risk. This study investigates the relationship between the ABO blood type and perioperative bleeding in partial hepatectomy for colorectal liver metastases (CRLMs). Methods: Out of 563 patients who underwent hepatectomy, 135 cases were analyzed for CRLM at Carmel Medical Center (2013–2023). Patients were categorized into blood type O (61 patients) and non-O (74 patients) groups. Data on perioperative hemoglobin levels, blood loss, coagulation parameters, transfusion needs, and complications were assessed using χ², t-tests, and ANOVA (p < 0.05). Results: No significant differences were observed for estimated blood loss (474.3 ± 696 mL for O vs. 527.8 ± 599 mL for non-O; p = 0.29), intraoperative hemoglobin drop (p = 0.613), or transfusion rates (24.59% for O vs. 28.37% for non-O; p = 0.698). Although non-O patients had a higher postoperative INR (p = 0.035), this did not correlate with increased bleeding or transfusion needs. Conclusions: Blood type O does not significantly affect perioperative bleeding or transfusion requirements in partial hepatectomy for CRLM. Further research is needed to better understand the significance of the ABO blood type. Full article

Surgery is one of the most effective treatment methods for liver metastases developing from primary colorectal cancer (CRC). Despite the widespread application of surgical approaches, recurrence rates remain substantial. Although chemotherapy is frequently employed, the supporting evidence for its efficacy in this context remains inconclusive. In the present study, we aimed to identify potential predictors of post-metastasectomy recurrence by analyzing clinical, pathological, and molecular features of both primary colorectal tumors and their corresponding hepatic metastases. Specifically, we evaluated the expression of epithelial–mesenchymal transition (EMT) markers, cancer stem cell (CSC) markers, and selected oncogenic mRNAs (RAS, mTOR, and CMYC) in tissue samples from 84 patients. RAS and CMYC are well-known proto-oncogenes involved in cell proliferation and survival, while mTOR functions as a central regulator of cell growth and metabolism. Following liver metastasectomy, intra-hepatic recurrence was observed in 40.5% of the cases. Among the molecular markers analyzed, the EMT transcription factor SNAIL—which plays a critical role in cancer cell invasion and metastasis—and mTOR exhibited significantly elevated expression in metastatic lesions from patients who experienced recurrence. While SNAIL expression did not show a clear association with the time to recurrence, increased mTOR expression in metastatic liver tissue was significantly associated with both shorter recurrence-free survival and diminished overall survival (p < 0.001). Results showed that mTOR expression levels could be a clinically relevant predictive indicator of remnant liver recurrence. In patients with liver metastases, the use of mTOR inhibitors may be considered after hepatic metastasectomy. Full article

Gastrointestinal (GI) cancers, including esophageal, gastric, pancreatic, liver, and colorectal malignancies, represent a major global health burden due to their high incidence, aggressive nature, and limited treatment outcomes. This review explores the therapeutic potential of carvacrol, a naturally occurring monoterpenoid phenol predominantly found in oregano and other aromatic plants. Carvacrol has demonstrated strong anticancer properties by modulating multiple molecular pathways governing apoptosis, inflammation, angiogenesis, and metastasis. Preclinical studies have revealed its ability to selectively target cancer cells while sparing healthy tissue. Advances in nanotechnology have further enhanced its pharmacological profile by improving solubility, stability, and tumor-targeted delivery. Additionally, carvacrol shows synergistic effects when used in combination with conventional chemotherapeutics. While the evidence is promising, clinical studies are needed to validate its translational potential. This review aims to consolidate current findings and encourage further investigation into carvacrol’s application as an adjunct or alternative therapeutic agent in GI cancer management. Full article