Search Results (617)

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

Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10⁻⁵). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. Full article

Background/Objectives: Subcutaneous tumor models are widely used in colorectal cancer (CRC) research due to their experimental accessibility; however, the spatial organization and regulatory mechanisms of their tumor microenvironment remain poorly understood. Methods: Here, we applied spatial transcriptomics to systematically characterize spatial heterogeneity within MC38 subcutaneous tumors in a syngeneic mouse model. Results: We identified two spatially distinct tumor zones, partitioned by cancer-associated fibroblasts (CAFs), that differ markedly in cellular composition, oncogenic signaling, immune infiltration, and metabolic states. One zone exhibited features of TGF-β-driven extracellular matrix remodeling, immune exclusion, and hyperproliferative metabolism, while the other was enriched for immunosuppressive macrophages, metabolic reprogramming via PPAR and AMPK pathways, and high-risk cell populations. Spatially resolved cell–cell communication networks further revealed zone-specific ligand–receptor interactions—such as ANGPTL4–SDC2 and PROS1–AXL—that underpin stromal remodeling and immune evasion and are associated with patient prognosis. Conclusions: Collectively, our study uncovers how region-specific cellular ecosystems and intercellular crosstalk establish prognostically divergent niches within subcutaneous CRC tumors, offering insights into spatially guided therapeutic strategies. Full article

Background: Epigenomic instability accelerates mutations in tumor suppressor genes and oncogenes, contributing to malignant transformation. Histone modifications, particularly methylation and acetylation, significantly influence tumor biology, with chromo-, bromo-, and Tudor domain-containing proteins mediating these changes. This study investigates how genes encoding these domain-containing proteins affect colorectal cancer (CRC) prognosis. Methods: Using CRC data from the GSE39582 and TCGA datasets, we identified domain-related genes via GeneCards and developed a prognostic signature using LASSO-COX regression. Patients were classified into high- and low-risk groups, and comparisons were made across survival, clinical features, immune cell infiltration, immunotherapy responses, and drug sensitivity predictions. Single-cell analysis assessed gene expression in different cell subsets. Results: Four domain-related genes (AKAP1, ORC1, CHAF1A, and UHRF2) were identified as a prognostic signature. Validation confirmed their prognostic value, with significant differences in survival, clinical features, immune patterns, and immunotherapy responses between the high- and low-risk groups. Drug sensitivity analysis revealed top candidates for CRC treatment. Single-cell analysis showed varied expression of these genes across cell subsets. Conclusions: This study presents a novel prognostic signature based on domain-related genes that can predict CRC severity and offer insights into immune dynamics, providing a promising tool for personalized risk assessment in CRC. Full article

Background/Objectives: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Even though the screening programs have decreased the incidence rates, the prognosis for CRC varies depending on the stage at diagnosis. Thus, early diagnosis is still a big challenge due to screening methods, and subsequent diagnosis is not very sensitive. Methods: In this work, LC-MS-based metabolomics, a powerful and sensitive tool to study complex dynamic changes, was used to analyze 211 human fecal samples from control individuals (CTRL), adenoma (AA), and CRC patients. Results: Multivariate and univariate statistical analysis highlighted cholesteryl esters (CEs) and fecal haemoglobin, quantified by fecal immunochemical test (FIT), as relevant biomarkers that clearly differentiate CRC from AA and CTRL. Predictive models based on random forest and the area under the curve (AUC) of the receiver operating characteristic curve (ROC) demonstrate that CEs, together with FIT measurement, improved the CRC and CTRL classification, but not AA. This study revealed that the AA group is a transitional stage with high heterogeneity. The increased tendency observed in CEs from CTRL to CRC might be related to the imbalance of cholesterol homeostasis due to cancer cells requiring a high cholesterol level for cell development and proliferation. The free cholesterol is probably obtained from CEs, as it is the most cost/effective way to obtain the needed cholesterol. Conclusions: The accumulation of CEs is produced by two possible approaches: (1) dysfunction of cholesterol absorption in the small intestine and/or (2) transported inside exosomes from cell to cell to promote proliferation. Full article

Colorectal cancer (CRC) is one of the most prevalent and deadly neoplasms globally; this fact puts emphasis on the need for accurate molecular biomarkers for early detection and accurate prognosis. Circular RNAs (circRNAs) have recently emerged as very promising cancer biomarkers. In this study, we thoroughly examined whether the expression levels of circular transcripts of the protein arginine methyltransferase 1 (PRMT1) gene can predict the prognosis of patients diagnosed with colorectal adenocarcinoma, the most frequent type of CRC. Hence, a highly sensitive quantitative PCR (qPCR) assay was developed and applied to quantify circ-PRMT1 expression in cDNAs from 210 primary colorectal adenocarcinoma tissue specimens and 86 paired normal colorectal mucosae. Extensive biostatistical analysis was then performed to assess the potential prognostic power of circ-PRMT1. Significant overexpression of this molecule was observed in colorectal adenocarcinoma tissue samples in contrast to their non-cancerous counterparts. Moreover, higher circ-PRMT1 expression was correlated with poorer disease-free survival (DFS) and worse overall survival (OS) in colorectal adenocarcinoma patients. Interestingly, multivariate Cox regression analysis revealed that the prognostic value of the expression of this circRNA does not depend on other established prognostic factors included in the prognostic model. Furthermore, the stratification of patients based on TNM staging revealed that higher circ-PRMT1 levels were significantly related to shorter DFS and OS intervals, particularly in patients with colorectal adenocarcinoma of TNM stage II or III. In summary, this original research study provides evidence that circ-PRMT1 overexpression represents a promising molecular biomarker of poor prognosis in colorectal adenocarcinoma, not depending on other established prognostic factors such as TNM staging. Full article

Purpose: Previous studies have reported that blood-based inflammatory markers are associated with prognosis in patients with various solid tumors, including colorectal cancer (CRC). The pan-immune inflammation value (PIV) is a novel prognostic biomarker based on blood count. Here, we aimed to study the association between PIV and survival following transarterial radioembolization (TARE) in patients with liver-dominant metastatic colorectal cancer (CLM). Methods: A total of 49 patients with CLM who underwent TARE at the Ankara University Department of Medical Oncology were retrospectively analyzed. The relationship between clinical and laboratory parameters with post-TARE overall survival (OS) was analyzed by multivariate analyses. Results: The median age was 60 years and 71.4% of patients had received at least two lines of chemotherapy. The objective response rate (ORR) was 59.1% following TARE. Patients with hepatic response after TARE treatment demonstrated significantly longer survival compared to non-responders (p: 0.033). The optimal PIV threshold value was calculated as 629 in ROC analyses. This PIV value had 81% sensitivity and 80% specificity for OS prediction (AUC 0.86; 95% CI: 0.75–0.98, p = 0.008). Patients with elevated PIV > 629 had significantly shorter OS (p = 0.002). In the multivariate analysis, adjusted for ECOG PS, TARE response, presence of extrahepatic disease, number of chemotherapy lines, CEA levels and post-TARE NLR and PIV, only low PIV level was associated with longer OS (>629 vs. ≤629; HR: 4.87; 95% CI: 1.32–17.92; p = 0.017). Conclusions: PIV, a blood-based inflammatory score, may reflect the host’s immune response following TARE and serve as a novel predictor of survival. Full article

Background: Colorectal cancer (CRC) is a prevalent global malignancy with particularly challenging treatment outcomes in advanced stages. Oxaliplatin (OXA) is a frontline chemotherapeutic agent for CRC. However, 15% to 50% of stage III patients experience recurrence due to drug resistance. Elucidating the molecular mechanisms underlying OXA resistance is, therefore, crucial for improving CRC prognosis. The role of DIRAS1, a RAS superfamily member with reported tumor-suppressive functions in various cancers, remains poorly defined in CRC. Methods: The effects of DIRAS1 on CRC cell proliferation and migration were evaluated using MTT, wound healing, and colony formation assays. Stable cell lines with knockdown or overexpression of DIRAS1 and PHB1 were established via plasmid and lentiviral systems. Drug sensitivity to OXA was assessed through cytotoxicity assays and IC₅₀ determination. Clinical relevance was validated through immunohistochemical analysis of CRC tissue samples. Transcriptomic sequencing was performed to explore downstream regulatory mechanisms. Results: DIRAS1 expression was positively correlated with OXA resistance and was significantly upregulated following prolonged chemotherapy exposure. Silencing DIRAS1 reduced the IC₅₀ of OXA in vitro and increased tumor sensitivity to OXA in vivo. Transcriptome analysis identified PHB1 as a downstream effector of DIRAS1. Functional studies revealed that PHB1 contributes to chemoresistance by maintaining mitochondrial stability. Conclusions: This study identifies DIRAS1 as a key contributor to OXA resistance in CRC by modulating PHB1 expression and mitochondrial function. Targeting the DIRAS1–PHB1 axis may offer a novel therapeutic strategy to overcome chemoresistance in CRC. Full article

Circulating cell-free RNAs (cfRNAs) have emerged as promising non-invasive biomarkers for colorectal cancer (CRC), offering insights into the disease’s prognosis. This study investigates the prognostic significance of the specific cfRNA biomarkers HPGD, PACS1, and TDP2 by employing the Taqman quantitative PCR (qPCR) to evaluate their expression levels in a cohort of 52 CRC patients. The methodology involved a robust statistical analysis to assess correlations between cfRNA levels and clinical parameters, including survival rates and recurrence incidences. Findings revealed a significant upregulation in the expression of HPGD and PACS1, while TDP2 displayed varying results, indicating a complex role in disease dynamics. Notably, lower expression levels of HPGD were associated with reduced survival, suggesting its potential as a negative prognostic indicator. Conversely, TDP2 levels correlated strongly with increased risks of recurrence, highlighting its clinical relevance in monitoring disease progression. Overall, this study elucidates the intricate interplay between these cfRNAs in the CRC prognosis. The results advocate for further exploratory studies to validate PACS1’s potential as a prognostic marker and reinforce the clinical significance of HPGD and TDP2 in the context of CRC management, positioning them as vital elements in the landscape of molecular oncology. Full article

Background: Frailty is common in colorectal cancer (CRC) patients and is associated with poor prognosis and increased mortality. Anti-inflammatory dietary education is a promising and cost-effective strategy for frailty improvement. Methods: A prospective, assessor-blinded, two-arm randomized controlled trial was conducted to assess the effects of a 12-week dietary inflammatory index (DII)-based anti-inflammatory dietary education program on frailty in frail CRC patients. Participants in the intervention group received a DII-based anti-inflammatory dietary education, while the control group received a routine health education. Outcome measurements included the Fried frailty phenotype (FP), DII, plasma inflammatory biomarkers, body mass index (BMI), nutritional status, and quality of life (QoL), which were all assessed at baseline and post-intervention. Results: A total of 86.4% (57/66) of participants completed the follow-up. No statistically significant baseline differences were observed between groups. After the intervention, the intervention group showed significant improvements in DII (p = 0.029), BMI (p = 0.012), mini nutritional assessment (MNA) scores (p = 0.027), and QoL (p = 0.014) compared with the control group. Within-group comparisons revealed significant decreases in frailty status (p = 0.031), DII (p = 0.008), and interleukin (IL)-6 (p = 0.003), and significant increases in IL-10 (p = 0.021), MNA scores (p = 0.010), and QoL (p < 0.001) in the intervention group, with no significant changes in the control group. Conclusions: DII-based anti-inflammatory dietary education can improve the frailty, nutritional status, and QoL of frail CRC patients by modulating systemic inflammation. Given its acceptability and utility, this strategy may be incorporated into routine cancer health education. Full article

Background: Colorectal cancer (CRC) remains a significant global health burden, with early detection and intervention crucial for improving patient outcomes. This study aims to develop and evaluate a novel proof-of-concept ensemble framework combining transformer-based language models and decision tree-based models for early-stage CRC screening, diagnosis, and prognosis. Methods: The ensemble framework consists of four key components: (1) GastroGPT, a transformer-based language model for extracting relevant data points from patient histories; (2) a decision tree-based model for assessing CRC risk and recommending colonoscopy; (3) GastroGPT for extracting data points from early CRC patients’ histories; and (4) a suite of decision tree-based models for predicting survival outcomes in early-stage CRC patients. The study employed a retrospective, observational, methodological design using simulated patient cases. Results: GastroGPT demonstrated high accuracy in extracting relevant data points from patient histories. The decision tree-based model for CRC risk assessment achieved an area under the receiver operating characteristic curve (AUC-ROC) of 0.85 (95% CI: 0.78–0.92) in predicting the need for colonoscopy. The decision tree-based models for survival prediction showed strong performance, with C-indices ranging from 0.71 to 0.75 for overall survival and disease-free survival at 24, 36, and 48 months. Conclusions: The novel ensemble framework demonstrates promising performance in early-stage CRC screening, diagnosis, and prognosis. Further research is needed to validate the models using larger, real-world datasets and to assess their clinical utility in prospective studies. 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

Expression patterns and underlying mechanisms of metabolism-related genes SMOX and SUCLG2 in pan-cancer remain unclear. We conducted a comprehensive pan-cancer analysis of SMOX and SUCLG2, to explore their potential roles and mechanisms of action. Comprehensive analysis of SMOX and SUCLG2 was performed through UCSC, TCGA, GEO, and other databases. We validated the expression levels, diagnostic value, and prognostic significance of SMOX and SUCLG2 in CRC using external databases and qPCR. Then, CCK-8 is used to detect proliferation of RKO and HCT116 after silencing or overexpressing of SUCLG2. The expression of SMOX was upregulated and that of SUCLG2 was downregulated in most cancers. Both SMOX and SUCLG2 exhibited significant correlations with cancer prognosis, tumor microenvironment, immune infiltration, stemness scores, tumor mutational burden, and microsatellite instability. The diagnostic and prognostic value of SMOX and SUCLG2 in CRC was confirmed through TCGA, GEO, and HPA, as well as qPCR. SUCLG2 overexpression inhibited the proliferation of RKO and HCT116, whereas SUCLG2 silence promoted their proliferation. Our data provide insights into the role of SMOX and SUCLG2 in pan-cancer, highlighting their association with prognosis, cancer immunity, and other cancer characteristics and also revealing their significance in cancer progression. SUCLG2 may inhibit the proliferation of CRC. Full article

Lifestyle, diet, and genetics are established risk factors for developing colorectal cancer (CRC). In recent years, the role of the gut microbiota (GM) has been increasingly highlighted in several studies, suggesting an effect on both the disease’s pathogenesis and the efficacy and tolerability of treatments. We conducted a search on Medline, aiming to identify published studies exploring the role of the GM in the development and treatment of CRC. Dysbiosis, an imbalance in GM, is common in CRC patients and is associated with precancerous lesions, aggressive tumors, and varied therapy outcomes. Restoring GM balance can reduce treatment complications and may improve prognosis. The review details how GM influences CRC through metabolite production, inflammation modulation, and immune response alteration. Diet significantly impacts GM composition, with processed meats and high-fat diets increasing CRC risk, while fiber-rich diets are protective. The role of the GM in CRC treatments like surgery, chemotherapy, radiotherapy, and immunotherapy is also explored, noting its influence on complications, chemoresistance, and treatment efficacy. Future strategies involving GM modulation through diet, probiotics, and fecal microbiota transplantation (FMT) show promise for CRC prevention and treatment, warranting further research. Full article

The prognosis of advanced (UICC IIb-IV) primary colorectal cancer (pCRC) remains poor. More effective targeted therapies are needed. Heat shock protein 90 alpha/beta (Hsp90α/β) expression was immunohistologically quantified in 89 pCRCs and multivariately correlated with survival. Pimitespib (Pim, TAS-116), a Hsp90α/β-specific inhibitor, was tested in pCRC cell lines and patient-derived cancer spheroids (PDCS) and referenced to the pan-Hsp90 inhibitor ganetespib (Gan, STA-9090) and standard-of-care therapies. A total of 26.97% pCRCs showed strong tumoral Hsp90α/β expression (Hsp90α/β > 40%), which correlated with reduced PFS (HR: 3.785, 95%CI: 1.578–9.078, p = 0.003) and OS (HR: 3.502, 95%CI: 1.292–9.494, p = 0.014). Co-expression of Hsp90α/β > 40% with its clients BRAF-V600E and Her2/neu aggravated the prognosis (BRAF-V600E mutated: PFS, p = 0.002; OS, p = 0.012; Her2/neu score3: PFS, p = 0.029). The prognostic cut-off Hsp90α/β > 40% was also a predictor for response to Pim-based therapy. Pim efficacy was increased in combination with 5-FU, 5-FU + oxaliplatin, and 5-FU + irinotecan (all p < 0.001). Pim induced sensitization to all chemotherapies in HT-29 (p < 0.001), Caco-2 (p < 0.01), and HCT116 (p < 0.05) cells. Pim combined with encorafenib in HT-29 and with trastuzumab in Caco-2 cells was most effective in dual-target inhibition approaches (HT-29: p < 0.005; Caco-2: p < 0.05). The anti-cancer effect and chemosensitization of Pim-based therapy were prospectively confirmed in PDCS directly generated from Hsp90α/β > 40% pCRCs. Protein profiling combined with functional drug testing stratifies Hsp90α/β > 40% pCRC patients diagnosed with UICC IIb-IV for effective Pim-based therapy. Full article