Investigating the mechanisms underlying the development of an immunosuppressive microenvironment within colorectal liver metastases (CRLM) is important for identifying synergistic targets for immunotherapy. The regulatory role of tumor-associated macrophage-derived extracellular vesicles (TAM-EVs) in the immune microenvironment of CRLM has not yet been fully explored. Here, we found that TAM-EVs shaped the immunosuppressive microenvironment at the invasive front in murine CRLM models, thus dampening anti-PD-1 immunotherapy. This environment is characterized by an increased tumor stemness potential and abundant neutrophil extracellular traps (NETs) formation. Mechanistically, TAM-EVs-derived fibrinogen-like 2 (FGL2) interacts with the FCGR2B receptor in tumor cells, which further activates a p-STAT3/IL-1β positive feedback loop to increase the stemness potential of cancer cells, whereas IL-1β mediates the communication between cancer cells and neutrophils. The use of an anti-IL-1β monoclonal antibody can reduce NETs production and synergize with anti-PD-1 immunotherapy, which offers clinical translational significance for CRLM therapy. The FGL2/p-STAT3/IL-1β loop correlates with an immunosuppressive microenvironment and poor prognosis in human patients with CRLM. Our results revealed the potential of enhancing the efficacy of immunotherapy via the targeted clearance of NETs using anti-IL-1β monoclonal antibodies, which have significant clinical translational value in the treatment of CRLM.

Flavonoids are a group of polyphenolic compounds distributed in vegetables, fruits and other plants, which have considerable antioxidant, anti‑tumor and anti‑inflammatory activities. Several types of gastrointestinal (GI) cancer are the most common malignant tumors in the world. A large number of studies have shown that flavonoids have inhibitory effects on cancer, and they are recognized as a class of potential anti‑tumor drugs. Therefore, the present review investigated the molecular mechanisms of flavonoids in the treatment of different types of GI cancer and summarized the drug delivery systems commonly used to improve their bioavailability. First, the classification of flavonoids and the therapeutic effects of various flavonoids on human diseases were briefly introduced. Then, to clarify the mechanism of action of flavonoids on different types of GI cancer in the human body, the metabolic process of flavonoids in the human body and the associated signaling pathways causing five common types of GI cancer were discussed, as well as the corresponding therapeutic targets of flavonoids. Finally, in clinical settings, flavonoids have poor water solubility, low permeability and inferior stability, which lead to low absorption efficiency in vivo. Therefore, the three most widely used drug delivery systems were summarized. Suggestions for improving the bioavailability of flavonoids and the focus of the next stage of research were also put forward.

Colorectal cancer (CRC) is a substantial global health concern due to its limited treatment options, especially for oxaliplatin (L-OHP) regimen resistance. This study used organoid-based screening methodologies to evaluate drug responses in CRC while validating the approach with patient-derived CRC organoids and investigating potential biomarkers.

Patient-derived organoids were created from CRC surgical specimens, and drug screening were performed. Selected organoids with high and low L-OHP sensitivity underwent next-generation sequencing (NGS), and in vivo experiments using xenotransplantation were used to validate in vitro results. Moreover, the clinical application of homologous recombination deficiency (HRD) as a biomarker was investigated.

Organoid drug screening revealed differences in L-OHP sensitivity among 34 patient-derived CRC organoids, and NGS deemed HRD as a potential biomarker. In vivo experiments validated the correlation between HRD status and L-OHP sensitivity, and clinical data suggested the potential of HRD as a biomarker for recurrence-free survival in patients treated with L-OHP. Additionally, HRD exhibited potential as a biomarker for other platinum agents and poly (ADP-ribose) polymerase inhibitors in CRC.

The study underscores HRD as a potential biomarker for predicting L-OHP sensitivity, expanding its application to other drugs in CRC. Organoid screening is reliable, providing insights into the intricate association between genetic features and treatment responses.

Vaccinia-Related Kinase 2 (VRK2), a member of the vaccinia virus-related protein kinase family, is crucial in regulating apoptosis and tumor cell growth signaling pathways. Despite its established roles in various cancers, investigations into its functions in colorectal cancer have been relatively limited. Utilizing The Cancer Genome Atlas and Genotype-Tissue Expression databases, this study assesses VRK2 expression across 33 cancer types, highlighting significant upregulation and diagnostic relevance, particularly in colorectal cancer, where it marks poor prognosis. VRK2's influence extends across multiple cancer-related signaling pathways, with focused experiments confirming its vital role in the E2F signaling pathway through transcriptomic sequencing and dual-luciferase reporter assays. Deletion of VRK2 markedly inhibits proliferation, cell cycle progression, migration, and tumorigenesis in colorectal cancer cells, whereas overexpression enhances these oncogenic traits. Additionally, VRK2 expression correlates with genomic instability and the tumor microenvironment, influencing antitumor immunity and response to immunotherapy. Importantly, our analysis reveals that VRK2 modulates the chemosensitivity of tumor cells, specifically enhancing resistance to the chemotherapeutic agent 5-FU. These findings underscore VRK2's multifaceted role in promoting colorectal cancer development and suggest its potential as a therapeutic target.

Colorectal cancer (CRC) is the most common malignancy of the digestive system. Although research into the causes of CRC's origin and progression has advanced over the past few decades, many details are still not fully understood. Circular RNAs (circRNAs), as a novel regulatory molecule, have been found to be closely involved in various key biological processes in CRC. CircRNAs also have been shown to encode proteins, which could offer new possibilities for therapeutic applications. This ability to produce tumor-specific proteins makes circRNA-based vaccines a potentially valuable approach for targeted cancer treatment. In this review, we summarize recent findings on the various roles of circRNAs in CRC and explore their potential in the development of protein-encoding circRNA vaccines for CRC therapy.

The implementation of circulating tumor DNA (ctDNA) in the diagnostic routine may enable non-invasive predictive biomarker testing and treatment optimization in patients who lack a suitable tumor specimen, have failed previous molecular analysis or are clinically ineligible for (re-)biopsy procedures. As the interpretation and reporting are more complex for ctDNA than conventional tissue-based NGS, there is a need for specific guidelines. These will offer support for the reporting of ctDNA test results and will facilitate optimal communication of liquid biopsy findings between diagnostic laboratories and the medical oncology team. Aiming to generate guidelines based on real-world experiences and broad perspectives, we organized a European Liquid Biopsy Society (ELBS) ctDNA workshop, in which forty-four experts and key stakeholders from different molecular diagnostics laboratories, oncology and pathology departments, as well as an IVDR specialist, convened to address significant challenges associated with the reporting of liquid biopsy test results. This report delineates the resulting consensus recommendations for ctDNA test reporting with underlying rationale and background information.

Glycolysis provides growth advantages and leads to drug resistance in colorectal cancer (CRC) cells. SIRT1, an NAD+-dependent deacetylase, regulates various cellular processes, and its upregulation results in antitumor effects. This study investigated the role of SIRT1 in metabolic reprogramming and oxaliplatin resistance in CRC cells.

To investigate the role of SIRT1 in metabolic reprogramming and overcoming oxaliplatin resistance in CRC cells.

We performed transcriptome sequencing of human CRC parental cells and oxaliplatin-resistant cells to identify differentially expressed genes. Key regulators were identified via the LINCS database. NAD+ levels were measured by flow cytometry, and the effects of SIRT1 on oxaliplatin sensitivity were assessed by MTS assays, colony formation assays, and xenograft models. Glycolytic function was measured using Western blot and Seahorse assays.

Salermide, a SIRT1 inhibitor, was identified as a candidate compound that enhances oxaliplatin resistance. In oxaliplatin-resistant cells, SIRT1 was downregulated, whereas γH2AX and PARP were upregulated. PARP activation led to NAD+ depletion and SIRT1 inhibition, which were reversed by PARP inhibitor treatment. The increase in SIRT1 expression overcame oxaliplatin resistance, and while SIRT1 inhibition increased glycolysis, the increase in SIRT1 inhibited glycolysis in resistant CRC cells, which was characterized by reduced expression of the glycolytic enzymes PKM2 and LDHA, as well as a decreased extracellular acidification rate. The PKM2 inhibitor shikonin inhibited glycolysis and reversed oxaliplatin resistance induced by SIRT1 inhibition.

SIRT1 expression is reduced in oxaliplatin-resistant CRC cells due to PARP activation, which in turn increases glycolysis. Restoring SIRT1 expression reverses oxaliplatin resistance in CRC cells, offering a promising therapeutic strategy to overcome drug resistance.

Limited evidence is currently available on the role of liquid biopsy (LBx) in predicting the efficacy of anti-epidermal growth factor receptor (EGFR) therapies in metastatic colorectal cancer (mCRC).

The CAPRI-2 GOIM is a phase II trial investigating the use of LBx-comprehensive genomic profiling (CGP)-guided, cetuximab-based treatment through three subsequent lines of therapy in patients with RAS/BRAF wild-type (WT) mCRC. LBx-CGP is carried out at baseline and at progressive disease to first- and second-line therapies. In case of RAS/BRAF WT circulating tumor DNA at progressive disease, EGFR therapeutic blockade is continued by combining cetuximab with a different chemotherapy backbone. The primary endpoint is overall response rate (ORR) by RECIST 1.1 criteria. Tumor molecular characteristics by LBx-CGP are correlated with treatment efficacy.

One hundred and ninety-two RAS/BRAF WT microsatellite stable mCRC patients treated with FOLFIRI plus cetuximab with baseline LBx-CGP and assessable for response were included in the analysis. One hundred and thirty-seven patients with WT tumors for potential anti-EGFR drug resistance genes (RAS/BRAF/EGFR/PIK3CA/MAP2K1/MET/RET/ALK/ROS1/NTRK/NF1/FGFR, and HER2 amplification; 'negatively hyper-selected' cases) had 78.1% ORR compared with 54.5% ORR for patients with mutations [odds ratio 2.95, 95% confidence interval (CI) 1.44-6.10, P = 0.001]. 'Negatively hyper-selected' patients had median progression-free survival of 12.35 months (95% CI 10.58-15.4 months) compared with 8.68 months (95% CI 4.87-12.1 months) for patients with mutations (hazard ratio 0.64, 95% CI 0.44-0.92, P = 0.017). High cancer cell clonality of pathogenic variants (PVs) correlated with worse median progression-free survival (3.55 months, 95% CI 2.57 months to NE) compared with low cancer cell clonality of PV (9.63 months, 95% CI 7.16 months to NE, P = 0.21). After first-line therapy failure, approximately one out of five patients had acquired PVs of potential anti-EGFR drug resistance genes, whereas RAS/BRAF WT circulating tumor DNA was maintained in most patients (78.5%).

These results support the integration of LBx-CGP for implementing the efficacy and for optimizing the use of anti-EGFR therapies in RAS/BRAF WT mCRC.

Patients with liver metastatic colorectal cancer (mCRC) have a poor prognosis and are the leading cause of death in colorectal cancer (CRC) patients, but the mechanisms associated with CRC metastasis have not been fully elucidated. In this study, we obtained data from the Gene Expression Omnibus database and characterized the single-cell profiles of CRC, mCRC and healthy samples at single-cell resolution, and explored the cells that influence CRC metastasis. We find that AQP1+ CRC identified as highly malignant tumor cells exhibited proliferative and metastatic characteristics. Immunosuppressive properties are present in the tumor microenvironment (TME), while NOTCH3+ Fib is identified to play a facilitating role in the metastatic colonization of CRC. Importantly, we reveal that tumor-associated macrophages (TAM) characterized by SPP1-specific high expression may be involved in TME remodeling through intercellular communication. Specifically, SPP1+ TAM mediates the generation of Fib-derived extracellular vesicle through the APOE-LRP1 axis, which in turn delivers tumor growth-promoting factors in the TME. This study deepens the understanding of the mechanism of TME in mCRC and lays the scientific foundation for the development of therapeutic regimens for mCRC patients.

Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, both in terms of diagnoses and cancer-related mortality. Increasing evidence suggests that an imbalance in intestinal flora can contribute to the progression of CRC, and fecal microbiota may serve as potential biomarkers for its screening and diagnosis. Notably, Porphyromonas gingivalis has been identified in the malignant tissues and feces of CRC patients, establishing it as a significant biomarker for early screening, diagnosis, and prognostic assessment of CRC. Current methods for detecting P. gingivalis face numerous challenges, including high costs, complex procedures, and lengthy implementation times. Therefore, developing rapid, highly specific, and sensitive detection methods for P. gingivalis is of great importance. In this study, we utilized the whole-bacterium systematic evolution of ligands by exponential enrichment method to identify highly specific and high-affinity aptamers targeting P. gingivalis through 15 selection cycles. Subsequently, we developed an aptasensor driven by MoS2 nanoflowers, which integrates strand displacement amplification and CRISPR/Cas12a double amplification for sensitive detection of P. gingivalis, achieving a limit of detection of 10 CFU/mL. Using this aptasensor, we evaluated the abundance of P. gingivalis in clinical fecal samples and observed significantly higher levels in the feces of CRC patients compared to healthy individuals, corroborating the results obtained from quantitative polymerase chain reaction. In summary, we developed a highly specific and sensitive aptasensor for the first time, representing a promising new approach for the identification of P. gingivalis, with significant potential for CRC screening and diagnosis.

Oxaliplatin-based chemotherapy is the first-line treatment for colorectal cancer (CRC). However, oxaliplatin resistance remains a major challenge contributing to treatment failure and poor prognosis. An increased capacity for DNA damage repair is a key mechanism underlying oxaliplatin resistance. Although XPA binding protein 2 (XAB2) is implicated in various DNA damage repair mechanisms, its specific role in mediating oxaliplatin resistance remains unclear.

XAB2 was identified through analysis of public datasets. Western blot analysis and immunohistochemistry were performed to evaluate XAB2 expression, while survival analysis was performed to assess its clinical significance in CRC. Functional experiments were then conducted to assess the impact of XAB2 on proliferation, DNA damage repair, and oxaliplatin resistance in CRC. RNA sequencing (RNA-seq) and Chromatin immunoprecipitation-sequencing (ChIP-seq) were used to identify XAB2 target genes. Co-immunoprecipitation (Co-IP) and mass spectrometry were used to identify the proteins interacting with XAB2. Dual-luciferase reporter assays, ChIP-qPCR, Co-IP, ubiquitination site mass spectrometry, and ubiquitin assays were used to analyse the interactions and potential mechanisms involving XAB2, Annexin A2 (ANXA2), and ubiquitin-specific protease 10 (USP10).

XAB2 was found to be expressed in CRC and was associated with poor prognosis in patients with CRC. XAB2 promoted CRC cell proliferation and enhanced oxaliplatin resistance by promoting DNA damage repair. Mechanistically, CRC cells treated with oxaliplatin exhibited increased USP10 nuclear expression. USP10 bound to XAB2 and deubiquitinated XAB2 K48-linked polyubiquitination at K593, thereby stabilising XAB2 by reducing its degradation via the ubiquitin-proteasome pathway. XAB2 upregulates ANXA2 expression at the transcriptional level by binding to the ANXA2 promoter, thereby promoting DNA damage repair, mitigating oxaliplatin-induced DNA damage, and enhancing oxaliplatin resistance.

In summary, this study demonstrates that the USP10/XAB2/ANXA2 axis promotes proliferation, DNA damage repair, and oxaliplatin resistance in CRC. These findings uncover a novel mechanism of oxaliplatin resistance in CRC and suggest potential therapeutic targets for improving the efficacy of oxaliplatin in CRC treatment.

Colorectal cancer (CRC) is the third most common and second most deadly cancer worldwide. Despite advances in screening and treatment, CRC is heterogeneous and the response to therapy varies significantly, limiting personalized treatment options. Certain molecular biomarkers, including microsatellite instability (MSI), are critical in planning personalized treatment, although only a subset of patients may benefit. Currently, the primary methods for assessing MSI status include immunohistochemistry (IHC) for DNA mismatch repair proteins (MMRs), polymerase chain reaction (PCR)-based molecular testing, or next-generation sequencing (NGS). However, these techniques have limitations, are expensive and time-consuming, and often result in inter-method inconsistencies. Deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) are critical predictive biomarkers of response to immune checkpoint inhibitor (ICI) therapy and MSI testing is recommended to identify patients who may benefit. There is a pressing need for a more robust, reliable, and cost-effective approach that accurately assesses MSI status. Recent advances in computational pathology, in particular the development of technologies that digitally scan whole slide images (WSI) at high resolution, as well as new approaches to artificial intelligence (AI) in medicine, are increasingly gaining ground. This review aims to provide an overview of the latest findings on WSI and advances in AI methods for predicting MSI status, summarize their applications in CRC, and discuss their strengths and limitations in daily clinical practice.

To explore the effective components of Guishao Yigong decoction (GYD) in the treatment of colorectal cancer and reveal its potential mechanism of action.

Through network pharmacology, the main target and signaling pathway of GYD therapy for colorectal cancer (CRC) were found. Subsequently, the effect of GYD was verified by in vitro cell viability measurements, colony formation, and scratch healing tests. The effects of GYD on metabolic pathways in vivo were found through plasma metabolomics. Finally, flow cytometry and qPCR experiments were used to verify the cycle-blocking effect of GYD on CRC cells.

Based on the network pharmacological analysis and molecular docking technology, it was found that GYD could restrain the growth of CRC cells by affecting lipid metabolic pathways and mitogen-activated protein kinase (MAPK) signaling pathways. A series of cell experiments showed that GYD could inhibit the proliferation, migration and clonogenic ability of CRC cells. Furthermore, the plasma metabolomics results showed that GYD could affect the production of unsaturated fatty acids in mice. Flow cytometry and qPCR experiments further proved that GYD blocked the CRC cells in the G1 phase and modulated the expression of cell cycle-related targets, such as AKT, TP53, CDKN1A, and CDK2.

All the results indicated that GYD could regulate the related metabolism of unsaturated fatty acids. Thus, the cell cycle was blocked and the expressions of the key proteins such as AKT and TP53 were regulated, which achieved the purpose of intervention in colorectal cancer.

Early detection of colorectal cancer (CRC) is significantly associated with reduced morbidity and mortality. Virtual colonoscopy (VC) is a minimally invasive, safe and well-tolerated alternative procedure to traditional colonoscopy. Therefore, we aimed to evaluate the findings of VC particularly in supine and prone positions as well as to contribute to the practical challenges of procedure.

Total number of 20 patients who underwent VC were included in this retrospective study. After proper bowel cleansing was achieved, intestinal dilatation was performed by injecting air into the rectum. Two different shots were performed in the supine and prone positions. Additionally, intestinal diameters were measured from the cecum to the rectum at their widest point via 2-dimensional coronal reformat.

Polyps were detected in 3 patients which were confirmed by optical colonoscopy. The mean cecum diameter was detected as the largest diameter in the supine and prone examinations. In both supine and prone examinations, the distal descending colon was the most challenging site. Additionally, the mean descending colon diameter calculated in the prone position (40.9 ± 6.4 mm) was found to be statistically larger than descending colon diameter calculated in the supine position (36.1 ± 5.3 mm) (P = 0.001).

Our findings clearly demonstrated that combination of prone and supine scanning provides clear field of vision on narrow parts of the colon which improves accurate estimation for polyp detection. Furthermore, VC appears to be more comfortable, safe, fast, and cost-efffective procedure for CRC screening with advantages of low radiation exposure, extracolonic findings and lack of sedation requirements.

Photodynamic therapy is an "old" strategy for cancer therapy featuring clinical safety and rapid working, but suitable photosensitizers for colorectal cancer therapy remain lacking. This study synthesized a novel photosensitizer termed Ce6-GFFY based on a self-assembling peptide GFFY and a photo-responsive molecule chlorin e6 (Ce6). Ce6-GFFY forms macroparticles with a diameter of ∼160 nm and possesses a half-life of 10 h, as well as an ideal tumor-targeting ability in mouse models. Ce6-GFFY effectively penetrates cells and generates numerous reactive oxygen species upon 660 nm laser irradiation. The reactive oxygen species promotes the accumulation of cytotoxic T cells and decrease of myeloid-derived suppressor cells in the tumor microenvironment through immunogenic cell death, thus prohibiting the growth of both primary and metastatic tumors after once treatment. This study not only provides a strategy for photosensitizer development but also confirms a promising application of Ce6-GFFY for colorectal cancer therapy.

The Bushen Jiedu Formula (BSJDF) is a traditional and effective chemical prescription of traditional Chinese medicine (TCM) administered due to its anti-cancer properties, particularly in colorectal cancer (CRC).

This study proposes to explore the therapeutic benefits of BSJDF against metastasis in CRC and unravel its regulatory mechanisms related to the tumor microenvironment.

The combination of mass spectrometry and network pharmacology was used to analyze the involvement of BSJDF in anti-tumor progression. In vitro and in vivo experiments were conducted to measure the regulatory effect of BSJDF on tumor-derived extracellular vesicles (EVs), which induce the M2 polarization of macrophages and CRC metastasis. Flow cytometry, immunofluorescence, and RT-qPCR assays were employed to elucidate the mechanisms by which tumor-derived EVs induce macrophage M2-type polarization.

Network pharmacology illuminated that immune and inflammatory response pathways were involved in the beneficial effects of BSJDF on CRC. In vivo experiments indicated that BSJDF suppressed the metastasis of CRC to the liver by modulating macrophage immune infiltration. Mechanically, BSJDF inhibited CRC metastasis via modulating tumor-derived EVs that facilitate the polarization of M2 macrophages. Moreover, BSJDF suppressed the metastasis of CRC and the polarization of M2 macrophages by reducing lncRPPH1 in tumor-derived EVs.

BSJDF blocked the M2-type polarization of macrophages and prevented CRC metastasis by decreasing the expression levels of lncRPPH1 in tumor-derived EVs.

Detection of the BRAF V600E mutation has important genetic, prognostic, and therapeutic implications for patients with metastatic colorectal cancer (mCRC), identifying a subgroup of patients who derive modest benefit from standard treatments and have extremely poor prognosis. The evolution of molecular profiling and the implementation of next generation sequencing in the evaluation of a patient with BRAF-mutated mCRC has currently led to the discovery of actionable alterations. Targeting multiple pathways of resistance in BRAF-mutated mCRC may be the most efficacious route. Then, over a short period of time, the treatment landscape BRAF-mutated mCRC patients has shifted dramatically. Finally, novel treatment strategies are available. This review will discuss on currently approved treatments for BRAF V600E mutated mCRC and will try and portray the changing landscape in this setting in the era of targeted molecular therapy.

Colorectal cancer (CRC) usually creates an immunosuppressive microenvironment, thereby hindering immunotherapy response. Effective treatment options remain elusive. Using scRNA-seq analysis in a tumor-bearing murine model, it is found that lobeline, an alkaloid from the herbal medicine lobelia, promotes polarization of tumor-associated macrophages (TAMs) toward M1-like TAMs while inhibiting their polarization toward M2-like TAMs. Additionally, lobeline upregulates mRNA expression of secreted Ly-6/UPAR-related protein 1 (Slurp1) in cancer cells. The inhibitory effects of lobeline on tumor load and TAM polarization are almost completely eliminated when Slurp1-deficient MC38 cells are subcutaneously injected into mice, suggesting that lobeline exerts an antitumor effect in a Slurp1-dependent manner. Furthermore, using target-responsive accessibility profiling, MAPK14 is identified as the direct target protein of lobeline. Mechanistically, upon binding to MAPK14 in colon cancer cells, lobeline prevents nuclear translocation of MAPK14, resulting in decreased levels of phosphorylated p53. Consequently, negative transcriptional regulation of SLURP1 by p53 is suppressed, leading to enhanced transcription and secretion of SLURP1. Finally, combination therapy using lobeline and anti-PD1 exhibits stronger antitumor effects. Taken together, these findings suggest that remodeling the immunosuppressive microenvironment using small-molecule lobeline may represent a promising therapeutic strategy for CRC.

Precision medicine has revolutionized the treatment of colorectal cancer by enabling a personalized approach tailored to each patient's unique genetic characteristics. Genomic profiling allows for the identification of specific mutations in genes such as KRAS, BRAF, and PIK3CA, which play a crucial role in cell signaling pathways that regulate cell proliferation, apoptosis, and differentiation. This information enables doctors to select targeted therapies that inhibit specific molecular pathways, maximizing treatment effectiveness and minimizing side effects. Precision medicine also facilitates adaptive monitoring of tumor progression, allowing for adjustments in therapy to maintain treatment effectiveness. While challenges such as high costs, limited access to genomic technology, and the need for more representative genomic data for diverse populations remain, collaboration between researchers, medical practitioners, policymakers, and the pharmaceutical industry is crucial to ensure that precision medicine becomes a standard of care accessible to all. With continued advances and support, precision medicine has the potential to improve treatment outcomes, reduce morbidity and mortality rates, and enhance the quality of life for colorectal cancer patients worldwide.

Oligometastatic colorectal cancer (OMCRC) patients can achieve long-term disease control with multidisciplinary treatment. However, the development of extensive metastasis worsens prognosis and restricts treatment options. This study aims to develop a predictive model for extensive metastasis in OMCRC to assist in clinical decision-making.

Clinical and pathological data for OMCRC patients were collected from the Second Affiliated Hospital of Soochow University. Patients were randomly divided into training and testing cohorts. Risk factors for extensive metastasis were identified through LASSO regression analysis and COX regression analysis. Three predictive models were developed in the training cohort and validated in the testing cohort: COX regression analysis, Extreme Gradient Boosting (XGBoost), and Survival Support Vector Machine (SurvSVM). Finally, the optimal model was visualized with the nomogram.

A total of 214 patients with OMCRC were enrolled in the study. Four independent risk factors were identified: whether surgery has been undertaken following oligometastasis (WST), histological type (HT), carcinoembryonic antigen at the last follow-up (CAE at last-FU), and preoperative albumin to globulin ratio (Preop-AGR). In the testing cohort, the COX model (1-year AUC = 0.82, 3-year AUC = 0.72, 5-year AUC = 0.85, mean AUC = 0.80) performed best. Decision curve analysis (DCA) confirmed the net benefit of the Cox model, and the nomogram provided accurate predictions of metastasis risk.

CAE at last-FU, Preop-AGR, HT, and WST are independent risk factors for extensive metastasis in OMCRC. The nomogram model incorporating risk factors can assist clinicians in developing optimal treatment for OMCRC patients.

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide. Currently, irinotecan (CPT-11) is used alone or in combination with other drugs to treat patients with advanced CRC. However, the 5-year survival rate for metastatic CRC remains below 10 %, largely due to chemotherapy resistance. Several genes, including ABCG2, CYP3A4, MCL1, and MLH1 contribute to irinotecan resistance. This study aimed to identify microRNAs that simultaneously regulate the expression of these genes in irinotecan-resistant cell lines and study their effect on resistant colorectal cancer cells.

Irinotecan-resistant colorectal cancer cell lines were developed by intermittently exposing HCT116 and SW480 cell lines to gradually increasing doses of irinotecan over four generations. These resistant cell lines were designated HCT116-R1, HCT116-R2, HCT116-R3, HCT116-R4 and SW480-R1, SW480-R2, SW480-R3, SW480-R4. The induction of resistance was confirmed using MTT assays, by calculating IC50 values for each generation and comparing them to the parental cells. The expression levels of the ABCG2, CYP3A4, MCL1, and MLH1 genes, along with miR-3664-3p, were initially measured in all resistant and parental cell lines using quantitative real-time PCR. Following transfection of HCT116-R3 and SW480-R3 cells with pre-miR-3664-3p, the expression levels of ABCG2, CYP3A4, MCL1, MLH1, and miR-3664-3p were re-evaluated using real-time PCR.

In resistant cell lines derived from HCT116 and SW480, increased expression of the ABCG2, CYP3A4, and MCL1 genes was observed. However, a reduction in CYP3A4 expression was noted in the final resistant lines from both cell lines. Additionally, while MLH1 expression increased in HCT116-derived cell lines, no significant increase was observed in SW480-derived lines. A consistent decrease in miR-3664-3p expression was found across all resistant cell lines. When we transfected HCT116-R3 and SW480-R3 cells with pre-miR-3664-3p, there was an increase in miR-3664-3p expression and a reduction in ABCG2, CYP3A4, MCL1, and MLH1 gene expression. This led to increased sensitivity to irinotecan.

It can be concluded that miR-3664-3p can be considered a regulator of resistance to irinotecan by modulating the expression of ABCG2, CYP3A4, MCL1, and MLH1 genes.

Colorectal cancer (CRC) organoids provide more accurate and tissue-relevant models compared to conventional two-dimensional cultured cell cultures. Mouse CRC organoids, in particular, offer unique advantages over their human counterparts, as they can be transplanted into immunocompetent mice. These syngeneic transplantation models create a robust system for studying cancer biology in the immunocompetent tumor microenvironment (TME). This article discusses the development and applications of these organoid systems, emphasizing their capacity to faithfully recapitulate in vivo tumor progression, metastasis, and the immune landscape.

Colorectal cancer (CRC) is the second leading cause of cancer deaths globally, which poses a heavy burden on our healthcare and economy. In recent years, increasing researches suggest that the tumor microenvironment (TME) influences cancer onset, progression, metastasis, and treatment. This has become a popular direction for researching and attacking cancer. However, to date, there is no bibliometric analysis of colorectal cancer and tumor microenvironment from 2014 to 2024. This study aims to provide a comprehensive picture of the current research status, hotspots, and future trends in this field from a bibliometric perspective.

In this study, the publications about colorectal cancer and tumor microenvironment from 2014 to 2024 were searched based on the Web of Science Core Collection database. Then we analyzed and visualized the data using CiteSpace, VOSviewer, bibliometrix package, and Microsoft Excel 2019.

A total of 748 publications were included in our study, and the number of publications entered a period of rapid growth after 2019. China and the United States are the major research and collaboration centers in this field. Elkord, Eyad is the most prolific author, and Frontiers in Immunology is the journal that published the most papers on the TME of CRC. In addition, keyword and cluster analysis showed that immune checkpoint inhibitors, cancer-associated fibroblasts, macrophage polarization, intestinal microbiota, colorectal cancer liver metastasis, drug resistance, scRNA-seq, etc. may be the research hotspots and trends in this field.

Colorectal cancer and tumor microenvironment research is in the developmental stage, and strengthening international cooperation can help to drive this field forward. The main components and signaling in TME, CRC immunotherapy, colorectal cancer liver metastasis, and new research techniques are the hot research directions in this domain. Our findings will provide scholars with an up-to-date perspective on the current state of research, hotspots, and future trends in this field.

The burden of colorectal cancer (CRC) is high in the Asia-Pacific region, and several countries in this region have among the highest and/or fastest growing rates of CRC in the world. A significant proportion of patients will present with or develop metastatic CRC (mCRC), and BRAFV600E-mutant mCRC represents a particularly aggressive phenotype that is less responsive to standard chemotherapies. In light of recent therapeutic advances, an Asia-Pacific expert consensus panel was convened to develop evidence-based recommendations for the diagnosis, treatment, and management of patients with BRAFV600E-mutant mCRC. The expert panel comprised nine medical oncologists from Australia, Hong Kong, Singapore, and Taiwan (the authors), who met to review current literature and develop eight consensus statements that describe the optimal management of BRAFV600E-mutant mCRC in the Asia-Pacific region. As agreed by the expert panel, the consensus statements recommend molecular testing at diagnosis to guide individualized treatment decisions, propose optimal treatment pathways according to microsatellite stability status, advocate for more frequent monitoring of BRAFV600E-mutant mCRC, and discuss local treatment strategies for oligometastatic disease. Together, these expert consensus statements are intended to optimize treatment and improve outcomes for patients with BRAFV600E-mutant mCRC in the Asia-Pacific region.

Colorectal cancer is a common and fatal disease that affects many people globally. CRC is classified as the third most prevalent cancer among males and the second most frequent cancer among females worldwide. The purpose of this article is to examine how personalized medicine might be used to treat colorectal cancer. The classification of colorectal cancer based on molecular profiling, including the detection of significant gene mutations, genomic instability, and gene dysregulation, is the main topic of this discussion. Advanced technologies and biomarkers are among the detection methods that are explored, demonstrating their potential for early diagnosis and precise prognosis. In addition, the essay explores the world of treatment possibilities by providing light on FDA-approved personalized medicine solutions that provide individualized and precise interventions based on patient characteristics. This article assesses targeted treatments like cetuximab and nivolumab, looks at the therapeutic usefulness of biomarkers like microsatellite instability (MSI) and circulating tumor DNA (ctDNA), and investigates new approaches to combat resistance. Through this, our review provides a thorough overview of personalized medicine in the context of colorectal cancer, ultimately highlighting its potential to revolutionize the field and improve patient care.

Telomeric repeat-containing RNAs (TERRA) and telomerase RNA component (TERC) regulate telomerase activity (TA) and thereby contribute to telomere homeostasis by influencing telomere length (TL) and the cell immortality hallmark of cancer cells. Additionally, the non-canonical functions of telomerase reverse transcriptase (TERT) and TERRA appear to be involved in the epithelial-mesenchymal transition (EMT), which is important for cancer progression. However, the relationship between TERRA and patient prognosis has not been fully characterized. In this small-scale study, 68 patients with colorectal cancer (CRC) were evaluated for correlations between telomere biology, proliferation, and EMT gene transcripts and disease outcome. The proliferating cell nuclear antigen (PCNA) and the epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) showed a positive correlation with TERRA, while TA and TERRA exhibited an inverse correlation. Consistent with previous findings, the present study revealed higher expression levels of TERT and TERC, and increased TA and TL in CRC tumor tissue compared to adjacent non-tumor tissue. In contrast, lower expression levels of TERRA were observed in tumor tissue. Patients with high TERRA expression and low PCNA levels exhibited favorable overall survival rates compared to individuals with the inverse pattern. Furthermore, TERRA suppressed CRC tumor growth in severe combined immunodeficiency disease (SCID) mice. In conclusion, our study extends previously published research on TERRA suggesting its potential therapeutic role in telomerase-positive CRC.

Efforts have been made to leverage technology to accurately identify tumor characteristics and predict how each cancer patient may respond to medications. This involves collecting data from various sources such as genomic data, histological information, functional drug profiling, and drug metabolism using techniques like polymerase chain reaction, sanger sequencing, next-generation sequencing, fluorescence in situ hybridization, immunohistochemistry staining, patient-derived tumor xenograft models, patient-derived organoid models, and therapeutic drug monitoring. The utilization of diverse detection technologies in clinical practice has made "individualized treatment" possible, but the desired level of accuracy has not been fully attained yet. Here, we briefly summarize the conventional and state-of-the-art technologies contributing to individualized medication in clinical settings, aiming to explore therapy options enhancing clinical outcomes.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Due to the poor therapeutic efficacy of CRC treatments and poor prognosis of the disease, effective treatment strategies are urgently needed. As long-term proteotoxic stress is a major cause of cell death, agents that induce proteotoxic stress offer a promising strategy for cancer intervention. Thiostrepton is a natural antibiotic derived from the Streptomyces genus. In the present study, we found that thiostrepton triggered apoptosis, reduced the migration of CRC cells, and inhibited xenograft tumour growth in vivo. Mechanistically, thiostrepton reduced proteasome activity; induced the aggregation of ubiquitinated proteins; caused endoplasmic reticulum (ER) stress, which was characterized by increased protein levels of GRP78, ATF4, P-eIF2α, and CHOP and cytosolic calcium release; and ultimately resulted in cell death. Thiostrepton-related changes in cell survival and cell migration, as well as mechanistical processes, were almost completely reversed by treatment with the antioxidant N-acetylcysteine (NAC), suggesting that the mechanism is dependent on reactive oxygen species (ROS). These results demonstrated that thiostrepton induced apoptosis and inhibited migration through ROS-induced ER stress and proteotoxic stress in colorectal cancer.

Kirsten rat sarcoma viral oncogene homolog (KRAS) somatic mutations occur in 30% to 40% of patients with colorectal cancer (CRC). These were thought to equally affect prognosis and resistance to anti-epidermal growth factor receptor agents; however, recent data show the activity of KRAS-G12C and pan-RAS inhibitors. The effects of uncommon KRAS (uKRAS) variants are largely unexplored. The distribution and pathogenicity of uKRAS mutations and their relationship with patients' clinicopathologic features were assessed. A total of 2427 CRCs were profiled for KRAS using next-generation sequencing (NGS). The study and control groups included patients with uKRAS (<1% frequency in CRC data sets on cBioPortal) and canonical KRAS mutations, respectively. In silico protein structure modifications and prediction analyses were performed by using PyMOL, trRosetta, and PolyPhen-2. uKRAS mutations affected 35 cases (1.5%), with G13C (28.6%), G12R (20%), and V14I (8.6%) being most common. Missense mutations (D33E, G12W, G12F, Q22H, Q61L, and L19F) occurred in nine cases (25.7%). Duplications (G10dup and L52_G60dup) affected two cases. Pathogenicity analyses showed that G12W, Q22R, L56V, and A130I mutations are probably damaging, with scores between 0.928 and 1.000. No differences were seen in clinicopathologic features. uKRAS mutants had lower event-free survival but no difference in overall survival compared with controls. Although these data are hypothesis generating and need further confirmation, they highlight the importance of NGS-based profiling to identify CRC patients with uKRAS mutations as candidates for personalized therapy.

Saffron is one of the traditional medicinal herbs, which contains various active ingredients, such as safranal, crocin, saffron acid, etc. It has anti-inflammatory, antioxidant, and anti-cancer properties, and is widely used in clinical practice. The anti-cancer efficacy of saffron has been previously confirmed, but its anti-cancer mechanism in colorectal cancer remains unclear.

We investigated the effect of active compounds of saffron on the efficacy of immunotherapy for colorectal cancer.

TCMSP and liquid chromatography-mass spectrometry analysis (LC-MS), GeneCards, and DisGeNET databases were used to identify the active compounds of saffron, drug targets and the disease targets of colorectal cancer. They were then subjected to Gene Ontology Enrichment (GO) and Signalling Pathway Enrichment (KEGG) analyses. The core targets and corresponding compounds were selected for molecular docking. The effect of active components of saffron on the proliferation of CT26 and HCT116 cells was investigated using the cell counting kit-8 (CCK-8). In vitro experiments were conducted by subcutaneous injection of CT26 cells to establish a colon cancer model. Enzyme-linked immunosorbent assay (ELISA), western blotting (WB), real-time polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and flow cytometry (FCM) were employed to validate the effects of saffron on colorectal cancer immunotherapy.

1. LC-MS analysis revealed that the main active component of saffron extract was crocin. The active chemicals of saffron intersected with 170 colorectal cancer targets, with 17 predicting targets for saffron treatment. GO and KEGG enrichment analyses revealed that the active components of saffron can prevent colorectal cancer development by enhancing Th17 cell differentiation and the IL-17 signaling pathway. 2. In vitro studies revealed that saffron alcohol extract, crocin, and safranal can suppress the proliferation of CT26 and HCT116 cells. 3. In vivo studies showed that crocin and safranal can increase the body mass and decrease the tumor mass of loaded mice, decrease the serum level of IL-17, and lower the mRNA expression level of IL-17, IL-6, TNF-α, TGF-β, and PD-L1 and IL-17, PD-L1 protein in tumors. This inhibitory effect was strengthened after combined immunotherapy. In addition, saffron modulated CD4+ and CD8+ T cells and the CD4+/CD8+T ratio in mouse spleens.

The active components of saffron can reduce the expression of inflammatory factors and ameliorate the immunological microenvironment of tumors via the IL-17 signaling pathway, thereby improving the efficacy of immunotherapy for colorectal cancer. This study provides pharmacological support for the application of saffron in enhancing the efficacy of immunotherapy for colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with adenocarcinoma as the most common subtype. While metastasis typically occurs in the liver, lungs, and peritoneal cavity, metastasis to the brain, particularly the cerebellum, is exceedingly rare.

This report discusses the case of a 50-year-old woman diagnosed with mucinous adenocarcinoma of the descending colon. Over six years, the patient experienced multiple common metastatic sites, including the liver and lungs, before developing a rare cerebellar metastasis. Despite extensive treatment, including surgery and chemotherapy, the disease progressed, ultimately leading to the patient's demise. This case represents the first documented cerebellar metastasis from CRC in Mexico.

This case highlights the altered metastatic patterns in CRC due to advanced therapies that extend survival. Clinicians should remain vigilant for metastasis to uncommon sites, such as the cerebellum, especially in patients with prolonged survival. Further research is needed to understand the mechanisms underlying such metastatic behavior and optimize treatment strategies.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality around the world. Despite advances in surgery, chemotherapy, and targeted therapies, the prognosis for patients with metastatic or advanced CRC remains poor. Immunotherapies comprising immune checkpoint inhibitors showed disappointing responses in metastatic CRC (mCRC). However, cellular immunotherapy, specifically using classical dendritic cells (cDCs), may hold unique promise in immune recognition for CRC antigens. cDCs are substantial players in immune recognition and are instrumental in orchestrating innate and adaptive immune responses by processing and presenting tumor antigens to effector cells. Natural killer T (NKT) cells are insufficiently studied but unique effector cells because of their ability to bridge innate and adaptive immune reactions and the crosstalk with dendritic cells in cancer. This review explores the therapeutic potential of using both cDCs and NKT cells as a synergistic therapy in CRC, focusing on their biological roles, strategies for harnessing their capabilities, clinical applications, and the challenges within the tumor microenvironment. Both cDCs and NKT cells can be used as a new effective approach for cell-based therapies in cancers to provide a new hope for CRC patients that are challenging to treat.

The prolongation of survival along with the preservation of quality of life, possibly avoiding harmful cumulative toxicities, is the primary therapeutic aim for patients with metastatic colorectal cancer (mCRC) in the third-line setting. Several therapeutic options are now available, although some differences across countries in drug approval and the optimal therapeutic sequencing associated with each peculiar patient subgroup represent a clinical challenge for oncologists. Among various options, the SUNLIGHT trial showed how the combination of trifluridine/tipiracil (FTD/TPI) with bevacizumab is effective with an easily manageable toxicity profile compared to FTD/TPI alone. Of note, the efficacy is confirmed independently from KRAS mutational status and also for patients who had breaks in anti-vascular endothelial growth factor (anti-VEGF) therapy. Herein, we describe the current state of the art in the landscape of treatments after the second progression in mCRC. Based on a critical review of the literature aimed to guide clinicians in their daily decision-making, we point out that the combination of FTD/TPI with bevacizumab produces a clinical benefit in unselected mCRC patients. Therefore, the FTD/TPI plus bevacizumab regimen can represent a new standard of care for the treatment of patients with refractory mCRC who have progressed after two lines of therapy.

The aim of this study is to derive and validate a reliable indicator for predicting an increased risk of postoperative mortality in elderly patients undergoing curative resection for colorectal cancer (CRC).

This study is of multicentre retrospective design.

A total of 1227 CRC patients undergoing curative resection (age ≥65 years) from three distinct cohorts were retrospective enrolled. Participant cohorts consisted of the derivation (n=845), external validation (n=95) and localised validation (n=287) groups. The carcinoembryonic antigen (CEA) to lymphocyte ratio (CLR) was derived from the derivation cohort and subsequently validated in two additional cohorts. The observed end point was all-cause death during the follow-up period postoperation.

In the derivation cohort, CLR demonstrated an independent association with all-cause mortality. In the two validation cohorts, CLR also presented a strong discriminatory ability in predicting postoperative all-cause death, with the area under the curve (AUC) of 0.68 in the external cohort and 0.78 in the localised cohort. Survival analyses revealed that CRC patients with CLR ≤2.53 tended to have better overall survival than those with CLR >2.53 (p<0.05 for all cohorts). Multivariate Cox proportional hazard models indicated that CLR ≤2.53 was significantly associated with reduced mortality risk in the derivation (HR: 0.405, p<0.001), external validation (HR: 0.519, p=0.039) and localised validation cohorts (HR: 0.167, p<0.001).

Preoperative CLR serves as a reliable predictor of all-cause death following curative resection in elderly patients with CRC. Individuals with CLR exceeding 2.53 are inclined to a lower overall survival probability.