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Colorectal cancer liver metastases (CRLM) represent most of the causes of death in patients with colorectal cancer. Surgical resection is the only treatment that can provide the possibility of prolonged survival, or even cure, for patients with CRLM. Over the last few decades, survival of these patients has improved dramatically thanks to more effective chemotherapy, extension of surgical indications, and development of new surgical procedures. In particular, patients with initially unresectable CRLM can achieve downsizing of the tumor by using various chemotherapies and the tumor can become resectable. It has been shown that such patients have a 33% 5‐year survival and a 23% 10‐year survival rate after surgery, which is a little bit lower than that of patents with resectable CRLM but significantly higher than patients without surgery. However, a decision‐making strategy for patients with CRLM is difficult because there is a wide variety of treatments and no definitive consensus. As an example, much variation among institutions exists on the resectability rate in patients with unresectable CRLM. Also, it is recommended that all patients with CRLM be managed by a multidisciplinary approach (MDA) to select the best strategy. In the future, new treatment procedures (e.g. immune checkpoint blockade, liver transplantation) may contribute to improve prognosis; hence, the necessity for MDA for the treatment of CRLM will further increase.

Introduction Selected patients with colorectal cancer liver metastases (CRLM) and synchronous extrahepatic disease (EHD) are considered for surgery. Objectives To evaluate the change in surgical management and long-term survival (disease-free survival [DFS] and overall survival [OS]) for patients with CRLM and EHD who undergo positron emission tomography combined with computed tomography (PET-CT) vs no PET-CT. Methods Patients with CRLM were enrolled in a trial evaluating the effect of PET-CT (vs no PET-CT) on surgical management, DFS, and OS. This is a sub-study of the trial, including only patients with synchronous EHD. Cox proportional hazard models were used to calculate risks for recurrence and death. Survival were described by Kaplan-Meier method and compared with log-rank test. Results Of 25 patients with EHD (PET-CT arm: 14/270 (5%) and no PET-CT arm: 11/134 (8%)), PET-CT changed surgical management in 14%, all of which avoided liver resection due to more extensive disease. Complete metastasectomy was achieved in 36% (5/14) and 72% (8/11), respectively. Respectively, PET-CT vs no PET-CT had statistically similar median DFS, 5.6 months (95% confidence interval (CI) 3.6-18) vs 7.6 months (95% CI 2.9-15) and median OS, 42 months (95% CI 25-48) vs 29 months (95% CI 17-41). EHD was associated with worse DFS (hazard ratio HR = 1.89, 95% CI 1.41-2.52) and OS (HR = 2.47, 95% CI 1.6-3.83). Conclusions Preoperative PET-CT for the management of resectable CRLM did not improve long-term outcomes among patients who had synchronous EHD; however, it changed surgical management in a relatively significant proportion of patients.

Background Peroxisome proliferator-activated receptor gamma (PPARG) is a member of the nuclear receptor family. It is involved in the regulation of adipogenesis, lipid metabolism, insulin sensitivity, vascular homeostasis and inflammation. In addition, PPARG agonists, known as thiazolidinediones, are well established in the treatment of type 2 diabetes mellitus. PPARGs role in cancer is a matter of debate, as pro- and anti-tumour properties have been described in various tumour entities. Currently, the specific role of PPARG in patients with colorectal cancer (CRC) is not fully understood. Material and methods The prognostic impact of PPARG expression was investigated by immunohistochemistry in a case-control study using a matched pair selection of CRC tumours ( n  = 246) with either distant metastases to the liver ( n  = 82), lung ( n  = 82) or without distant metastases ( n  = 82). Its effect on proliferation as well as the sensitivity to the chemotherapeutic drug 5-fluorouracil (5-FU) was examined after activation, inhibition, and transient gene knockdown of PPARG in the CRC cell lines SW403 and HT29. Results High PPARG expression was significantly associated with pulmonary metastasis ( p  = 0.019). Patients without distant metastases had a significantly longer overall survival with low PPARG expression in their tumours compared to patients with high PPARG expression ( p  = 0.045). In the pulmonary metastasis cohort instead, a trend towards longer survival was observed for patients with high PPARG expression in their tumour ( p  = 0.059). Activation of PPARG by pioglitazone and rosiglitazone resulted in a significant dose-dependent increase in proliferation of CRC cell lines. Inhibition of PPARG by its specific inhibitor GW9662 and siRNA-mediated knockdown of PPARG significantly decreased proliferation. Activating PPARG significantly increased the CRC cell lines sensitivity to 5-FU while its inhibition decreased it. Conclusion The prognostic effect of PPARG expression depends on the metastasis localization in advanced CRC patients. Activation of PPARG increased malignancy associated traits such as proliferation in CRC cell lines but also increases sensitivity towards the chemotherapeutic agent 5-FU. Based on this finding, a combination therapy of PPARG agonists and 5-FU-based chemotherapy constitutes a promising strategy which should be further investigated.

Background Mounting evidence has demonstrated the vital importance of tumor-associated macrophages (TAMs) and exosomes in the formation of the premetastatic niche. However, the molecular mechanisms by which tumor-derived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown. Methods Transmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify roles of exosomal miR-934. RNA pull-down assay, dual-luciferase reporter assay, etc. were applied to clarify the mechanism of exosomal miR-934 regulated the crosstalk between CRC cells and M2 macrophages. Results In the present study, we first demonstrated the aberrant overexpression of miR-934 in colorectal cancer (CRC), especially in CRLM, and its correlation with the poor prognosis of CRC patients. Then, we verified that CRC cell-derived exosomal miR-934 induced M2 macrophage polarization by downregulating PTEN expression and activating the PI3K/AKT signaling pathway. Moreover, we revealed that hnRNPA2B1 mediated miR-934 packaging into exosomes of CRC cells and then transferred exosomal miR-934 into macrophages. Interestingly, polarized M2 macrophages could induce premetastatic niche formation and promote CRLM by secreting CXCL13, which activated a CXCL13/CXCR5/NFκB/p65/miR-934 positive feedback loop in CRC cells. Conclusions These findings indicate that tumor-derived exosomal miR-934 can promote CRLM by regulating the crosstalk between CRC cells and TAMs. These findings reveal a tumor and TAM interaction in the metastatic microenvironment mediated by tumor-derived exosomes that affects CRLM. The present study also provides a theoretical basis for secondary liver cancer.

Colorectal cancer (CRC) is a major global health issue. Despite advancements in treatment, CRC patients still face challenges of metastasis and variable prognosis. Circulating tumor cells (CTCs) shed from the primary tumor into the peripheral blood circulation provide new insights into the potential molecular mechanisms driving tumor progression and metastasis.In this study, we comprehensively analyzed CTC data, primary tumor tissue data, and metastatic tumor tissue data from CRC patients to identify pathways associated with CRC metastasis, with a specific focus on the transport processes of vitamins, nucleosides, and related molecules. Using machine learning techniques, we identified Solute Carrier Family 27 Member 1 (SLC27A1) as the biomarker most closely associated with CRC metastasis. SLC27A1 is responsible for transporting extracellular long-chain fatty acids (LCFAs) into cells, and the model constructed based on the expression level of this gene achieved an accuracy of over 95% in assisting the assessment of patients’ metastatic risk across different datasets.Further studies revealed that the process of intracellular LCFAs being catalyzed to synthesize diacylglycerol-3-phosphate (DAG-3P) is closely related to CRC metastasis. Laboratory experiments confirmed that downregulation of SLC27A1 expression in colorectal cancer cell lines (Caco-2 and T84) significantly inhibited cell migration and invasion abilities, directly validating the functional role of this gene in promoting tumor metastasis. Additionally, statistical analysis using data from the National Health and Nutrition Examination Survey database (2017–2020) showed a slightly higher incidence of cancer in populations with high-fat intake.These findings, integrating computational predictions and experimental validation, deepen our understanding of the biological mechanisms of colorectal cancer and provide potential targets for therapeutic interventions and personalized treatment strategies.

In current studies, the role of serum Cytokeratin-19 fragments (CYFRA 21-1) in colorectal cancer (CRC) remains unclear. This study aimed to clarify the diagnostic and prognostic value of CYFRA 21-1 in CRC. Data were collected for 196 stage I-III CRC patients and 50 colorectal liver metastases (CRLM) patients between January 2018 and December 2019. The serum CYFRA 21-1 levels were measured using the chemiluminescent particle immunoassay (CMIA) kit in all objects and common biomarkers such as CA19-9, CEA, HSP90α, and AFP were measured in all colorectal cancer patients. We investigated the association between CYFRA 21-1 level and clinicopathological features. In addition, we evaluated the ability of serum CRFRA21-1 to differentiate CRLM from CRC. To assess the potential prognostic value, we used Cox proportional hazard model for univariate or multivariate analyses. Serum CYFRA 21-1 was significantly elevated in CRLM patients compared to stage I-III CRC patients (5.85 ng/mL vs 2.29 ng/mL, p < 0.001). For all CRC patients cohort, stage I-III CRC patients cohort and CRLM patients cohort, the optimal cutoff levels of CYFRA 21-1 for overall survival (OS) were 3.47 ng/mL, 2.14 ng/mL and 7.63 ng/mL, respectively, and the optimal cutoff levels for progression-free survival (PFS) were 3.47 ng/mL, 2.56 ng/mL and 7.63 ng/mL, respectively. For CRLM patients, Kaplan-Meier analysis showed that patients with high CYFRA 21-1 level had poor OS. Multivariate analysis indicated that the CYFRA 21-1 level was an independent prognostic factor for PFS in stage I-III patients. And CYFRA 21-1 levels and age were independent prognostic factors for OS and PFS in CRLM patients. CYFRA 21-1 can better differentiate CRLM patients from the whole CRC patients and has unique prognostic value for CRLM patients.

Colorectal cancer (CRC) is one of the most common malignancies, and the main cause of death from CRC is tumor metastasis. m1A RNA modification plays critical role in many biological processes. However, the role of m1A modification in CRC remains unclear. Here, we find that the m1A demethylase alkB homolog 1, histone H2A dioxygenase (ALKBH1) is overexpressed in CRC and is associated with metastasis and poor prognosis. Upregulation of ALKBH1 expression promotes CRC metastasis in vitro and in vivo. Mechanistically, knockdown of ALKBH1 results in a decrease in methyltransferase 3, N6‐adenosine‐methyltransferase complex catalytic subunit (METTL3) expression, probably due to m1A modification of METTL3 mRNA, followed by m6A demethylation of SMAD family member 7 (SMAD7) mRNA. In addition, downregulation of SMAD7 establishes an aggressive phenotype. More importantly, the cell migration and invasion defects caused by ALKBH1 depletion or METTL3 depletion are significantly reversed by SMAD7 silencing. Considering these results collectively, we propose that ALKBH1 promotes CRC metastasis by destabilizing SMAD7 through METTL3. Colorectal cancer (CRC) is one of the most common malignancies, and the main cause of death from CRC is tumor metastasis. Here, we identified the important role of ALKBH1‐catalyzed m1A modification in CRC metastasis. ALKBH1‐mediated m1A demethylation of METTL3 mRNA promotes the metastasis of colorectal cancer by downregulating SMAD7 expression.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, and detecting circulating tumor cells (CTCs) is crucial for early diagnosis and metastasis monitoring. Conventional staining-based cytology is costly, time-consuming, and often compromises sample integrity. In this study, we employed a combined digital holography (DH) and fluorescence imaging approach to develop a virtual staining framework for transforming quantitative phase imaging (QPI) data into interpretable pseudo-stained images. To the best of our knowledge, this is the first application of such a framework to colorectal cancer CTC detection. In our experiments, green fluorescent protein (GFP)-labeled HCT116 cells-generated through lentiviral transfection-were mixed with peripheral blood mononuclear cells (PBMCs) to create training datasets. The trained network achieved 99% classification accuracy and demonstrated strong generalization to unseen donors. This DH-fluorescence-based virtual staining method preserves cell integrity while enabling rapid, label-free, and low-cost liquid cytology diagnostics, highlighting its potential for non-invasive cancer detection and monitoring.

Tumors are a major global health problem. As economic development and material standards increase, the incidence and mortality of digestive system tumors have shown an overall rising trend. Among them, colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer death worldwide. Despite advances in molecular biology and therapeutic strategies, tumor metastasis remains the main driver of cancer-related deaths (about 90%). Especially in CRC, the progression of metastasis greatly limits clinical intervention options. Circulating tumor cells (CTCs), a key mediator of hematogenous metastasis, have emerged as a key target for unravelling metastatic mechanisms and developing therapeutic strategies, and are gradually gaining prominence in tumor biology and precision medicine. Therefore, a comprehensive understanding of CTC-mediated mechanisms, especially in the invasion-metastasis cascade of CRC and other cancers of the digestive system, is crucial for early metastasis detection, prevention and identification of new therapeutic targets.

Background Colorectal cancer liver metastasis (CRLM) is associated with poor survival, primarily due to acquired therapy resistance. While novel therapies arise, translation is limited by the lack of tumor models accurately representing dynamic microenvironmental interplay. Here, we show that ex vivo normothermic machine perfusion (NMP) offers a novel preclinical framework to study the intratumoral dynamics of CRLM biology. Methods Six resected metastatic human livers were preserved for two days and subjected to multi-omic profiling of serially sampled adjacent liver and metastatic tissue using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST). Tissue integrity was assessed and cross-validated by immunofluorescence (IF), high-resolution respirometry (HRR) and flow-cytometry. Results NMP was successfuly applied to metastatic livers with minimal surgical adaptations, preserving both intrinsic hepatic properties and tissue viability over an extended duration. Single-cell and spatial mapping confirmed preservation of CRLM phenotypic properties and demonstrated high clinical translatability by applicability of the intrinsic epithelial consensus molecular subtypes to metastasis. Spatially deconvoluted pathway activities reflected functional tissue-microenvironments. Transcriptomic profiles – including those of tumor-associated myeloid cells – were preserved during NMP. Finally, we demonstrate tumor-associated myeloid cell persistence as a driver of disease progression and poor survival in colorectal cancer. Conclusion Our findings represent the basis for future innovative applications adopting NMP in the context of CRLM, providing a new preclinical tumor model avenue. Graphical Abstract