Survival Of Colorectal Cancer Patients Research Articles

Immunotherapy outcomes in dMMR/MSI-H and/or TMB-H metastatic colorectal cancer (CRC) with peritoneal metastases (PM).

163 Background: CRC with PM has a poor prognosis and limited treatment options. Immunotherapy has shown promise in improving outcomes for patients with microsatellite instability-high (MSI-H), mismatch repair-deficient (dMMR), and high tumor mutational burden (TMB-H) tumors. However the peritoneal niche has a unique microenvironment, which can influence the effectiveness of immune check point inhibitors (ICIs). We assessed the impact of ICI on progression-free survival (PFS) and overall survival (OS) in CRC patients (pts) and PM, considering key clinical and molecular characteristics. Methods: A retrospective review aiming to identify CRC pts with MSI-H/dMMR and PM treated with immunotherapy between 2015 and 2023 was performed. Data collected included pt demographics, tumor characteristics, and treatment details. Responses were evaluated using RECIST v1.1 criteria. Results: 37 pts were included, 9 (24%) had Lynch syndrome. The median age of diagnosis was 61 years and most pts were females (65%). Most pts had MSI-H/dMMR tumors, while one pt was treated based on ultra-hypermutated phenotype (TMB 202) and POLE mutation. Among those with available TMB data, the median TMB was 52 mutations/Mb (0-202). Common mutations were PMS2 (51%), MLH1 (38%), MSH6 (16.2%), and MSH2 (16.2%). Right-sided tumors were in 54%, mucinous histology in 62%, and ascites in 54%. Pts received a median of 11 cycles of ICI (2-52). Pembrolizumab was the most frequently used ICI (78%), while Nivolumab was used either alone (11%) or in combination with Ipilimumab (11%). Median PFS in our cohort was 7.8 months and median OS was 29.9 months. The disease control rate (DCR) was 81%, with an objective response rate (ORR) of 51.3% (9 complete responses, 12 partial responses). At the time of data collection, 30% of pts were off systemic therapy and 5-FU-based chemotherapy combined with a biologic agent was the most common subsequent treatment in 32% who had PD. Univariate analysis showed no significant differences in PFS or OS based on tumor sidedness, isolated PM, liver metastases, mucinous vs. non mucinous histology or BRAF / RAS status (WT vs mutant). Malignant ascites was associated with worse OS(HR 0.3; p= 0.03). Conclusions: Treatment with ICIs in pts with MSI-H/dMMR and/or TMB-H CRC and PM improved disease control in CRC pts with PM, however, as compared to historical controls for patients with MSI-H/d-MMR disease treated with ICI, this group showed less favorable outcomes. Malignant ascites was associated with poorer overall survival. Further research of the immune response and tumor microenvironment in the peritoneal cavity is warranted.

Patients with colorectal cancer combined with HIV had a worse overall survival after surgery: a meta-analysis

PurposeThe purpose of this current study was to find out whether human immunodeficiency virus (HIV) affected overall survival (OS) of colorectal cancer (CRC) patients after surgery.MethodsPubMed, Embase, the Cochrane Library, and CNKI were searched from inception to March 27, 2023 to find eligible studies. Eligible studies included CRC patients grouped by HIV status (HIV-positive and HIV-negative). Stata SE 16 was used for data analysis.ResultsA total of eight studies involving 2180 patients were enrolled in this study. After data analysis, there were significant differences in sex (OR=0.69, 95% CI=0.49 to 0.98, I2 = 22.6%, P=0.04<0.1), tumor grade (OR=6.61, 95% CI=2.36 to 18.49, I2 = 0.00%, P=0.00<0.1), and tumor location (OR=2.19, 95% CI=1.74 to 2.77, I2 = 0.04%, P=0.00<0.1) between the HIV and non-HIV groups. Furthermore, we found that HIV was associated with worse OS in CRC patients after surgery (HR=3.12, 95% CI=2.07 to 4.69, I2 = 52.51%, P=0.00<0.1).ConclusionThis study highlights that HIV is associated with significantly poorer OS in CRC patients after surgery, emphasizing the need for tailored postoperative management strategies for this vulnerable population. Future research should explore underlying mechanisms and potential interventions to improve outcomes for HIV-positive CRC patients.

Integrating E-cadherin expression levels with TNM staging for enhanced prognostic prediction in colorectal cancer patients

PurposeThis study aimed to investigate the clinical significance of E-cadherin expression levels in colorectal cancer tissues and explore the relationship between E-cadherin expression and tumor node metastasis (TNM) stage. The goal was to establish a more accurate prognostic prediction for colorectal cancer patients by analyzing E-cadherin expression levels alongside TNM staging.MethodsThe study examined colorectal cancer patients by dividing them into groups based on E-cadherin expression levels. It then assessed their 5-year event-free survival (EFS) and disease-specific survival (DSS) hazard ratios (HRs). Additionally, the prognosis of patients was analyzed by combining E-cadherin expression levels with TNM staging, particularly focusing on patients in stages III and IV.ResultsThe E-cadherinLow group had significantly worse outcomes, with HRs of 2.30 for EFS and 2.76 for DSS compared to the E-cadherinHigh group. When combined with TNM stage III/IV, patients with E-cadherinLow expression showed a poor prognosis, with HRs of 1.93 for EFS and 2.35 for DSS compared to those with E-cadherinHigh expression at the same TNM stage.ConclusionsLow levels of E-cadherin expression are associated with a poor prognosis and decreased survival in colorectal cancer patients. Combining E-cadherin expression levels with TNM staging provides a more precise prediction of patient prognosis and survival, potentially guiding personalized treatment strategies.

Increased nerve density adversely affects outcome in colorectal cancer and denervation suppresses tumor growth

BackgroundThe colon and rectum are highly innervated, with neural components within the tumor microenvironment playing a significant role in colorectal cancer (CRC) progression. While perineural invasion (PNI) is associated with poor prognosis in CRC, the impact of nerve density and diameter on tumor behavior remains unclear. This study aims to evaluate the prognostic value of nerve characteristics in CRC and to verify the impact of nerves on tumor growth.MethodsTissue samples from 129 CRC patients were stained with immunofluorescent markers NF-L and S100B to detect nerves. Nerve diameter and density were measured and normalized. Kaplan-Meier survival analysis and Cox regression models were used to identify prognostic factors. Prognostic models were established using receiver operating characteristic (ROC) curve analysis to assess the predictive value of neural factors. A murine chemical denervation model was employed to disrupt sympathetic nerves using 6-hydroxydopamine, inhibit muscarinic receptor 3 with darifenacin, and ablate sensory neurons with capsaicin.ResultsThe total nerve density was 0.72 ± 0.59/mm², with intratumoral (0.42 ± 0.40/mm²) being significantly lower than extratumoral regions (1.00 ± 0.75/mm²). The average nerve diameter was 28.14 ± 6.04 μm, with no significant difference between intratumoral (28.2 ± 7.65 μm) and extratumoral regions (27.86 ± 6.72 μm). PNI was observed in 65 patients (50.4%). PNI and high normalized nerve density (NND) were associated with shorter overall survival and disease-free survival in CRC patients, with PNI identified as an independent prognostic factor. Patients with PNI exhibit higher NND. Incorporating PNI and NND into ROC curve analysis improved the sensitivity and specificity of survival predictions. In the murine model, chemical denervation of sympathetic, parasympathetic, and sensory nerves significantly reduced rectal tumor volume.ConclusionsPNI and NND are critical factors influencing CRC patient survival and enhance the accuracy of survival prediction models. Moreover, chemical denervation effectively inhibits rectal tumor growth in vivo, highlighting the potential of neural targeting as a therapeutic strategy in CRC.

Hypoxia Promotes Malignant Progression of Colorectal Cancer by Inducing POSTN+ Cancer-Associated Fibroblast Formation.

Colorectal cancer (CRC) is one of the most common malignancies. Hypoxia can promote the occurrence and development of CRC. However, how hypoxia regulates the CRC immune microenvironment needs to be further explored. The bulk RNA sequencing data and clinicopathological information of CRC patients were enrolled from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. The single-cell RNA sequencing (scRNA-seq) datasets of CRC were collected from and analyzed from the GEO database and the ArrayExpress database. The score of the hypoxia gene set was estimated using the "ssGSEA" algorithm in the "GSVA" R package. The functional characteristics of CAF subtypes were studied by bioinformatics analysis and in vitro experiments, and a prognostic model was constructed based on machine learning correlation. Hypoxia is associated with poor prognosis in CRC patients. Periostin (POSTN) + Fib is a cancer-associated fibroblast (CAF) closely associated with hypoxia, and high infiltration of POSTN + Fib is associated with adverse outcomes in overall survival (OS) and relapse-free survival (RFS) in CRC patients. Hypoxia can induce POSTN expression and secretion in CAFs. Hypoxia-induced increase of POSTN expression in CAFs can significantly promote the migration and proliferation of CRC cells. Hypoxia-induced increase of POSTN expression in CAFs can significantly promote the proliferation and migration of CRC cells. The POSTN+Fib Hypoxia-Related Risk Model (PFHRM) can predict the survival and immunotherapy response of CRC patients. Our study identified a POSTN+Fib cell subpopulation closely associated with hypoxia, which promotes the malignant progression of CRC. The development of PFHRM provides a theoretical basis for improving patient survival and prognosis.

MiRNA-155: A double-edged sword in colorectal cancer progression and drug resistance mechanisms.

Colorectal cancer (CRC) is a leading cause of death worldwide due to its aggressive nature and drug resistance, which limit traditional treatment effectiveness. Recent studies highlight the role of microRNAs (miRNAs) in tumorigenesis, metastasis, and chemotherapy resistance, with miRNA-155 emerging as a key player in CRC. miRNA-155 exerts dual effects, inducing drug resistance while serving as a potential therapeutic target. It regulates a wide array of mRNA transcripts associated with apoptosis, cell cycle regulation, and DNA repair, impacting various cellular pathways. Overexpression of miRNA-155 is linked to resistance against multiple chemotherapeutic drugs, promoting tumor cell survival, proliferation, and the epithelial-mesenchymal transition (EMT) process by repressing tumor suppressors and activating oncogenes. Additionally, miRNA-155 holds promise as a diagnostic and prognostic marker due to its association with CRC patient survival rates. However, its regulatory mechanisms across CRC subtypes remain unclear. This study provides insights into miRNA-155's role in CRC, focusing on its involvement in therapeutic resistance and potential as a therapeutic target. We also explore its significance as a prognostic biomarker and emphasize its therapeutic applications based on evidence from human, in vivo, in vitro, and clinical studies.

Identification of Immune Infiltration-Associated CC Motif Chemokine Ligands as Biomarkers and Targets for Colorectal Cancer Prevention and Immunotherapy.

Colorectal cancer (CRC) is the third most common cancer globally, with limited effective biomarkers and sensitive therapeutic targets. An increasing number of studies have highlighted the critical role of tumor microenvironment (TME) imbalances, particularly immune escape due to impaired chemokine-mediated trafficking, in tumorigenesis and progression. Notably, CC chemokines (CCLs) have been shown to either promote or inhibit angiogenesis, metastasis, and immune responses in tumors, thereby influencing cancer development and patient outcomes. However, the diagnostic and prognostic significance of CCLs in CRC remains unclear. In this study, multiple online tools for bioinformatics analyses were utilized. The findings revealed that the mRNA expression levels of CCL3, CCL4, and CCL26 were significantly elevated in CRC tissues compared to normal tissues, whereas CCL2, CCL5, CCL11, CCL21, and CCL28 mRNA levels were markedly downregulated. Additionally, dysregulation of CCL4, CCL5, and CCL21 was strongly associated with clinical staging, and elevated levels of CCL4, CCL11, and CCL28 were linked to significantly prolonged survival in CRC patients. Functional enrichment analysis indicated that the cellular roles of CCLs were predominantly associated with the chemokine, Wnt, and Toll-like receptor signaling pathways, as well as protein kinase activity. Furthermore, transcriptional regulation of most CCLs involved RELA and NFKB1. Key downstream targets included members of the SRC family of tyrosine kinases (HCK, LYN, and LCK), serine/threonine kinases (ATR and ATM), and others such as CSNK1G2, NEK2, and CDK2. Moreover, CCLs (CCL2, CCL3, CCL4, CCL5, CCL11, CCL21, and CCL28) exhibited strong correlations with major infiltration-related immune cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. In conclusion, our study provides novel insights into the potential utility of CCLs as biomarkers and therapeutic targets for CRC prevention and immunotherapy.

Single-cell transcriptomics reveals intratumor heterogeneity and the potential roles of cancer stem cells and myCAFs in colorectal cancer liver metastasis and recurrence.

Metastasis and recurrence are the primary obstacles to long-term survival in colorectal cancer (CRC) patients. In this study, we employed single-cell RNA sequencing (scRNA-seq) to comprehensively delineate the transcriptomic landscape of primary and liver metastatic CRCs, and revealed novel cellular crosstalk between cancer cell subpopulation and myofibroblastic CAFs (myCAFs) at single-cell resolution. We identified a cancer cell subpopulation termed stem/transient amplifying-like (stem/TA-like) cells, which expressed genes associated with stem cell-like characteristics and metastatic potential. MyCAFs in their microenvironment showed the potential to remodel the extracellular matrix (ECM), regulate angiogenesis, and support a pro-metastatic microenvironment through paracrine signaling involving FN1, BGN, and other ECM components. Notably, we found that they may communicate through the ligand-receptor pairs FN1-CD44 and GDF15-TGFBR2, which may be linked to the liver metastatic process. Additionally, our findings suggest that both stem/TA-like cells and myCAFs could be involved in CRC recurrence following chemotherapy. A unique gene signature generated using the gene expression characteristics of stem/TA-like cells and myCAFs (SM signature) can be used to assess recurrence risk in CRC patients. Collectively, these findings highlight the intratumor heterogeneity and the potential roles of cancer stem cells and myCAFs in CRC liver metastasis and recurrence, providing new targets and insights for the prognostic assessment of CRC patients and the improved selection of effective treatment options.

CYP24A1 DNA Methylation in Colorectal Cancer as Potential Prognostic and Predictive Markers.

The DNA methylation of CYP24A1 can regulate its gene expression and may play a role in the occurrence and progression of colorectal cancer (CRC). However, the association between CYP24A1 DNA methylation and the prognosis of CRC patients has not yet been reported. In this study, differential methylation analysis was conducted in both blood and tissue cohorts, and differential expression analysis was performed in the tissue cohort with in vitro validation. GO and KEGG enrichment analyses were performed on CYP24A1-related genes. A correlation between CYP24A1 promoter methylation and its gene expression was explored. Kaplan-Meier survival and Cox regression analyses were performed to investigate the impact of CYP24A1 DNA methylation on the prognosis of CRC patients. Prognostic risk scores were constructed for survival prediction. Immune infiltration analysis was also conducted. Our results showed that the hypermethylation of cg02712555 in tumor tissues (hazard ratio, 0.48; 95% confidence interval, 0.24-0.94; p = 0.032) and CpG site 41 in peripheral leukocytes (HR, 0.35; 95%CI, 0.14-0.84; p = 0.019) were both associated with decreased overall mortality in CRC patients. Prognostic risk scores showed robust predictive capabilities of these two CpG loci for the prognosis of CRC patients. CYP24A1 hypermethylation was positively correlated with infiltration levels of activated CD4 + T cells, activated CD8 + T cells, activated B cells, activated dendritic cells, and macrophages. Taken together, our findings indicate that the methylation levels of specific CpG sites within the CYP24A1 promoter region in blood leukocytes and tumors are potential prognostic and predictive markers for overall survival in CRC patients.

Chemokine family significance and prognostic value in colorectal cancer.

Colorectal cancer (CRC) poses a substantial global health concern, exhibits inconspicuous early symptoms, and is typically diagnosed at advanced stages leading to unfavorable outcomes. The intricate tumor microenvironment plays a crucial role in CRC development and progression, where chemokines contribute significantly. These chemokines exhibit widespread expression within tumor cells, facilitating immune cell infiltration, angiogenesis, and the establishment of distant metastases. The dysregulation of various chemokines in the context of CRC has emerged as a pivotal factor in the disease's pathogenesis. To explore the relationship between chemokine gene expression and CRC patient survival, as well as to clarify their biological roles,We conducted RNA-sequencing (RNA-seq) analysis on a cohort of 88 CRC patients with tumor samples, thereby enabling a detailed exploration of chemokine involvement in CRC. This study was rigorously augmented using comprehensive datasets from The Cancer Genome Atlas (TCGA), ensuring a robust analysis of gene expression patterns associated with clinical outcomes. Through data analysis, we identified key genes from the chemokine family thought pertinent to CRC outcomes. Consequently, we constructed a novel prognostic model based on the risk score derived from these chemokine expressions. Validation against clinical metadata, executed through immunohistochemistry analysis, affirmed the relevance and accuracy of our model in predicting patient survival. Our findings illuminate the critical role of chemokines in shaping the immune microenvironment of CRC, thereby highlighting potential therapeutic targets for future treatment strategies. Our new prognostic model could provide important information for the development of targeted therapies for CRC, enhancing personalized treatment approaches andultimately improving survival for CRC patients.

MiR-424-5p Promotes Proliferation, Migration and Invasion of Colorectal Cancer Cells via the Targeting TXNIP/Hippo Axi.

Aggressive biological behavior leads to unfavorable survival of colorectal cancer (CRC) patients. Dysregulation of TXNIP has been reported to be associated with the occurrence, proliferation and metastasis of malignancies such as liver cancer, lung cancer, kidney cancer, gastric cancer, and pancreatic cancer. MiR-424-5p has been reported as a negative regulator of TXNIP involved in lipopolysaccharide-induced acute kidney injury. And disordered Hippo pathway and YAP/TAZ-TEAD activity are related to tumor progression. The study was designed to clarify the function of miR-424-5p and thioredoxin interacting protein (TXNIP) in the progression of CRC. The expression pattern of TXNIP and miR-424-5p was detected by immunohistochemistry, qRT-PCR and/or Western blotting. CCK-8 assays and transwell assays were applied to investigate the effect of TXNIP and miR-424-5p on cell proliferation, invasion and migration. Luciferase reporter assays were used to verify the transcriptional regulation among TXNIP, miR-424-5p and Hippo signaling pathway. TXNIP was poorly expressed whereas miR-424-5p was highly expressed in CRC tissues and cells. TXNIP overexpression suppressed proliferation, invasion and migration of CRC cells. It also suppressed the malignant behavior of the CRC cells promoted by miR-424-5p. Mechanically, TXNIP overexpression significantly inhibited YAP/TAZ transcriptional activity, and the highly expressed miR-424-5p in CRC targeted TXNIP mRNA. The study clarify a novel miR-424-5p/TXNIP/Hippo signaling pathway that facilitated CRC cells proliferation, migration and invasion. The above findings suggested that miR-424-5p and TXNIP might serve as the potential therapeutic targets for CRC patients.

Prognostic value of combined systemic inflammation response index and prognostic nutritional index in colorectal cancer patients.

The prognosis of colorectal cancer (CRC) patients is notably influenced by both inflammation and nutritional status. The prognostic nutritional index (PNI) and systemic inflammatory response index (SIRI) have been reported in prognostic studies of various tumors. However, the efficacy of the combination of the two in predicting the prognosis of CRC patients has not been studied. To evaluate the effectiveness of PNI and SIRI in predicting the prognosis of patients with CRC. We retrospectively gathered data from 470 CRC patients who underwent feasible radical surgery at Xinjiang Cancer Hospital. The optimal cut-off values for SIRI and PNI, along with their predictive power for survival, were determined through area under the receiver operating characteristic curve using time-dependent receiver operating characteristic analysis. The Kaplan-Meier method and log-rank test were applied to assess prognostic impact, and a multifactorial Cox proportional hazards model was employed for analysis. Additionally, a new model, PSIRI, was developed and assessed for its survival prediction capability. The optimal cutoff values for PNI and SIRI were determined to be 47.80 and 1.38, respectively. Based on these values, patients were categorized into high PNI and low PNI groups, as well as high SIRI and low SIRI groups. Significant differences in age, T stage, neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) subgroups were observed between the PNI groups in the baseline profile. In the SIRI group, notable differences were found in gender, T stage, nerve invasion, intravascular tumor emboli, NLR, MLR, and PLR subgroups. Both low PNI and high SIRI were identified as independent risk factors for poor prognosis in CRC patients. When combined into the PSIRI model, it was shown that patients with a PSIRI ≤ 1 had a higher risk of death compared to those with a PSIRI of 2. We assessed the impact of PNI and SIRI on the prognostic survival of CRC patients and developed a new model, PSIRI. This model demonstrated superior predictive accuracy, with a concordance index of 0.767.

Multiomics Approach Identifies Key Proteins and Regulatory Pathways in Colorectal Cancer.

The prevalence rate of colorectal cancer (CRC) has dramatically increased in recent decades. However, robust CRC biomarkers with therapeutic value for early diagnosis are still lacking. To comprehensively reveal the molecular characteristics of CRC development, we employed a multiomics strategy to investigate eight different types of CRC samples. Proteomic analysis revealed 2022 and 599 differentially expressed tissue proteins between CRC and control groups in CRC patients and CRC mice, respectively. In patients with colorectal precancerous lesions, 25 and 34 significantly changed proteins were found between patients and healthy controls in plasma and white blood cells, respectively. Notably, vesicle-associated membrane protein-associated protein A (VAPA) was found to be consistently and significantly decreased in most types of CRC samples, and its level was also significantly correlated with increased overall survival of CRC patients. Furthermore, 37 significantly enriched pathways in CRC were further validated via metabolomics analysis. Ten VAPA-related pathways were found to be significantly enriched in CRC samples, among which PI3K-Akt signaling, central carbon metabolism in cancer, cholesterol metabolism, and ABC transporter pathways were also enriched in the premalignant stage. Our study identified VAPA and its associated pathways as key regulators, suggesting their potential applications in the early diagnosis and prognosis of CRC.

TCF12 and LncRNA MALAT1 Cooperatively Harness High Cyclin D1 but Low β-Catenin Gene Expression to Exacerbate Colorectal Cancer Prognosis Independently of Metastasis.

Metastasis is a well-known factor worsening colorectal cancer (CRC) prognosis, but mortality mechanisms in non-metastatic patients with poor outcomes are less understood. TCF12 is a transcription factor that can be physically associated with the long non-coding RNA MALAT1, creating an alliance with correlated expression levels in CRC patients. This TCF12-MALAT1 alliance is linked to poorer prognosis independently of age and metastasis. To identify the downstream effects responsible for this outcome, we analyzed 2312 common target genes of TCF12 and MALAT1, finding involvement in pathways like Aurora B, ATM, PLK1, and non-canonical WNT. We investigated the impact of WNT downstream genes CTNNB1 and CCND1, encoding β-catenin and cyclin D1, respectively, on survival in CRC patients with this alliance. Tumors with higher TCF12 and MALAT1 gene expressions alongside increased β-catenin gene expressions were classified as having a "Pan-CMS-2 pattern", showing relatively better prognoses. Conversely, tumors with high TCF12, MALAT1, and cyclin D1 gene expressions but low β-catenin expression were categorized as "TMBC pattern", associated with poor survival, with survival rates dropping sharply from 60% at one year to 30% at three years. This suggests that targeting cyclin D1-associated CDK4/6 could potentially reduce early mortality risks in TMBC patients, supporting personalized medicine approaches.

Effectiveness of hyperthermic intraperitoneal chemotherapy during primary curative resection for colorectal carcinoma

PurposePeritoneal metastasis (PM) is the life-threatening cause of colorectal cancer patients (CRC). Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) plus cytoreductive surgery exhibited promising effects in preventing recurrence and increasing the survival of CRC patients. However, the outcomes of HIPEC on treating advanced CRC with risk of PM are still controversial. Here, we retrospectively examined the impact of HIPEC on preventing PM and its overall effects on patients with locally advanced CRC who underwent primary curative resection at our center.MethodsWe retrospectively analyzed 45 patients diagnosed with locally advanced colorectal cancer (CRC) who underwent primary curative laparoscopic surgery with proactive hyperthermic intraperitoneal chemotherapy (HIPEC), in conjunction with adjuvant systemic chemotherapy at our center between 2019 and 2022. An additional 55 patients with locally advanced CRC who underwent similar surgery and received adjuvant systemic chemotherapy but did not undergo HIPEC during the same period were selected as the control group. Disease-free survival (DFS), overall survival (OS), and PM incidence were compared between patients with and without HIPEC.Results and conclusionsThe cumulative PM incidence was 2.2% in the HIPEC group and 14.5% in the control group(P = 0.0347). No significant adverse effects were observed in the HIPEC group. Furthermore, Kaplan–Meier survival analysis showed that the HIPEC correlated to better DFS [hazard ratio (HR) 0.4670, 95% confidence interval (CI) 0.2305–0.9462; P = 0.0345] and extended the overall survival of CRC patients [hazard ratio (HR) 0.3978, 95% confidence interval (CI) 0.1684–0.9395; P = 0.0355]. Therefore, our data supports that adjuvant HIPEC can prevent peritoneal failure in CRC patients and improve both PFS and OS survival following primary curative resection.

DUSP6 regulates Notch1 signalling in colorectal cancer

Notch1 plays various roles in cancer development, and Notch1-induced transactivation is controlled by phosphorylation of its cleaved intracellular domain. However, it is unclear whether there are phosphatases capable of dephosphorylating the cleaved Notch1 transmembrane/intracellular region (NTM) to regulate its function. Here, we show that DUSP6 can function as a phosphatase for Notch1, thereby regulating NTM stability and transcriptional activity, thus influencing colorectal cancer (CRC) development. In human CRC cells, elevated DUSP6 expression correlates with increased NTM levels, leading to enhanced CRC cell proliferation both in vitro and in vivo. High tumoral DUSP6 protein expression is associated with poorer overall CRC patient survival. In mice, DUSP6 deficiency results in reduced CRC development. Mechanistically, DUSP6 dephosphorylates phospho-Y2116, which in turn reduces NTM ubiquitination, leading to increased NTM stability and transcriptional activity. As a result, the expression of Notch1-targeted proliferation genes is increased to promote tumour cell growth.

Machine learning-driven estimation of mutational burden highlights DNAH5 as a prognostic marker in colorectal cancer

BackgroundTumor Mutational Burden (TMB) have emerged as pivotal predictive biomarkers in determining prognosis and response to immunotherapy in colorectal cancer (CRC) patients. While Whole Exome Sequencing (WES) stands as the gold standard for TMB assessment, carry substantial costs and demand considerable time commitments. Additionally, the heterogeneity among high-TMB patients remains poorly characterized.MethodsWe employed eight advanced machine learning algorithms to develop gene-panel-based models for TMB estimation. To rigorously compare and validate these TMB estimation models, four external cohorts, involving 1,956 patients, were used. Furthermore, we computed the Pearson correlation coefficient between the estimated TMB and tumor neoantigen levels to elucidate their association. CD8+ tumor-infiltrating lymphocyte (TIL) density was assessed via immunohistochemistry.ResultsThe TMB estimation model based on the Lasso algorithm, incorporating 20 genes, exhibiting satisfactory performance across multiple independent cohorts (R2 ≥ 0.859). This 20-gene TMB model proved to be an independent prognostic indicator for the progression-free survival (PFS) of CRC patients (p = 0.001). DNAH5 mutations were associated with a more favorable prognosis in high-TMB CRC patients, and correlated strongly with tumor neoantigen levels and CD8+ TIL density.ConclusionsThe 20-gene model offers a cost-efficient approach to precisely estimating TMB, providing prognosis in patients with CRC. Incorporating DNAH5 within this model further refines the categorization of patients with elevated TMB. Utilizing the 20-gene model facilitates the stratification of patients with CRC, enabling more precise treatment planning.

Identifying colorectal cancer subtypes and establishing a prognostic model using metabolic plasticity and ferroptosis genes

Metabolic plasticity and ferroptosis are essential for colorectal cancer (CRC) progression. The effects and prognostic value of metabolic plasticity- and ferroptosis-related genes (MPFRGs) in CRC remain unclear. We established a prognostic model for CRC patients by identifying important genes in metabolic plasticity and ferroptosis. Data of CRC patients were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus; MPFRG data were obtained from GeneCards and FerrDb. We performed functional (to explore differences between the two metabolic subtypes) and single-sample gene set (to assess the immune environment) enrichment analyses. Immunophenotype, tumor immunological dysfunction, and exclusion scores were assessed to determine patient immune responses. A least absolute shrinkage and selection operator-Cox regression model comprising 10 significant differentially expressed genes of metabolic plasticity and ferroptosis (MPFDEGs) was constructed using TCGA training cohort and validated using the GSE17536 and GSE39582 datasets. We established a nomogram comprising metabolic plasticity- and ferroptosis-based signatures, revealing the clinical application and potential molecular mechanisms underlying the role of MPFRGs in CRC. Our model (developed based on 10 MPFDEGs) is efficient for calculating the overall survival of CRC patients. Our findings provide new strategies for the clinical management and individualized treatment of these patients.

Targeting SLITRK4 Restrains Proliferation and Liver Metastasis in Colorectal Cancer via Regulating PI3K/AKT/NFκB Pathway and Tumor-Associated Macrophage.

Liver metastasis is the major cause of death in colorectal cancer (CRC) due to the lack of effective treatment. To explore novel drivers of CRC liver metastasis, the transcriptomes of primary paracancerous, colorectal tumors and metastases from human patients are profiled. It is found that SLIT- and NTRK-like family member 4 (SLITRK4) is the top upregulated gene in liver metastases and is associated with worse overall survival of CRC patients. Multiple in vitro and in vivo models suggested SLITRK4 promoted CRC tumorigenesis, invasion, migration, and angiogenesis, and inhibition of it restrained CRC tumor growth and liver metastasis with a more profound effect on the tumor microenvironment (TME). Mechanistically, SLITRK4 overexpression significantly activated the PI3K/AKT/NFκB pathway, regulated extracellular matrix organization, and multiple cytokines expression. Furthermore, the results from coculture models and single-cell RNA sequencing analyses suggested SLITRK4 promoted tumor-associated macrophages (TAMs) infiltration and polarization. In addition, macrophage depletion significantly inhibited SLITRK4-induced liver metastasis in CRC. Finally, pharmacological inhibition of SLITRK4 by using lipid-polymer hybrid nanoparticles (NPs) for systemic siRNA delivery can effectively inhibit CRC liver metastasis. Taken together, these results pinpoint that SLITRK4 regulates CRC tumorigenesis and liver metastasis, and siRNA delivering NPs agents validate the therapeutic potential of targeting SLITRK4 in CRC.

Establishment and Validation of a Prognostic Nomogram for Predicting Postoperative Overall Survival in Advanced Stage III-IV Colorectal Cancer Patients.

Most colorectal cancer (CRC) patients are at an advanced stage when they are first diagnosed. Risk factors for predicting overall survival (OS) in advanced stage CRC patients are crucial, and constructing a prognostic nomogram model is a scientific method for survival analysis. A total of 2956 advanced stage CRC patients were randomised into training and validation groups at a 7:3 ratio. Univariate and multivariate Cox proportional hazards regression analyses were used to screen risk factors for OS and subsequently construct a prognostic nomogram model for predicting 1-, 3-, 5-, 8- and 10-year OS of advanced stage CRC patients. The performance of the model was demonstrated by the area under the curve (AUC) values, calibration curves and decision curve analysis (DCA). Kaplan-Meier curves were used to plot the survival probabilities for different strata of each risk factor. There was no statistically significant difference (p > 0.05) in the 32 clinical variables between patients in the training and validation groups. Univariate and multivariate Cox proportional hazards regression analyses demonstrated that age, location, TNM, chemotherapy, liver metastasis, lung metastasis, MSH6, CEA, CA199, CA125 and CA724 were risk factors for OS. We estimated the AUC values for the nomogram model to predict 1-, 3-, 5-, 8- and 10-year OS, which in the training group were 0.826 (95% CI: 0.807-0.845), 0.836 (0.819-0.853), 0.839 (0.820-0.859), 0.835 (0.809-0.862) and 0.825 (0.779-0.870) respectively; in the validation group, the corresponding AUC values were 0.819 (0.786-0.852), 0.831 (0.804-0.858), 0.830 (0.799-0.861), 0.815 (0.774-0.857) and 0.802 (0.723-0.882) respectively. Finally, the 1-, 3-, 5-, 8- and 10-year OS rates for advanced stage CRC patients were 73.4 (71.8-75.0), 49.5 (47.8-51.4), 43.3 (41.5-45.2), 40.1 (38.1-41.9) and 38.6 (36.6-40.8) respectively. We constructed and validated an original nomogram for predicting the postoperative OS of advanced stage CRC patients, which can help facilitates physicians to accurately assess the individual survival of postoperative patients and identify high-risk patients.