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Abstract Cancer‐associated cachexia is a multifactorial wasting disorder characterized by anorexia, unintentional weight loss (skeletal muscle mass with or without loss of fat mass), progressive functional impairment, and poor prognosis. This systematic literature review (SLR) examined the relationship between cachexia and survival in patients with colorectal or pancreatic cancer in recent literature. The SLR was conducted following PRISMA guidelines. Embase® and PubMed were searched to identify articles published in English between 1 January 2016 and 10 October 2021 reporting survival in adults with cancer and cachexia or at risk of cachexia, defined by international consensus (IC) diagnostic criteria or a broader definition of any weight loss. Included publications were studies in ≥100 patients with colorectal or pancreatic cancer. Thirteen publications in patients with colorectal cancer and 13 with pancreatic cancer met eligibility criteria. Included studies were observational and primarily from Europe and the United States. Eleven studies (42%) reported cachexia using IC criteria and 15 (58%) reported any weight loss. An association between survival and cachexia or weight loss was assessed across studies using multivariate (n = 23) or univariate (n = 3) analyses and within each study across multiple weight loss categories. Cachexia/weight loss was associated with a statistically significantly poorer survival in at least one weight loss category in 16 of 23 studies that used multivariate analyses and in 1 of 3 studies (33%) that used univariate analyses. Of the 17 studies demonstrating a significant association, 9 were in patients with colorectal cancer and 8 were in patients with pancreatic cancer. Cachexia or weight loss was associated with significantly poorer survival in patients with colorectal or pancreatic cancer in nearly two‐thirds of the studies. The classification of weight loss varied across and within studies (multiple categories were evaluated) and may have contributed to variability. Nonetheless, awareness of cachexia and routine assessment of weight change in clinical practice in patients with colorectal or pancreatic cancer could help inform prognosis and influence early disease management strategies.

Casein kinase 1ε (CK1ε) and axis inhibitor 1 (AXIN1) are crucial components of the β‐catenin destruction complex in canonical Wnt signaling. CK1ε has been shown to interact with AXIN1, but its physiological function and role in tumorigenesis remain unknown. In this study, we found that CK1δ/ε inhibitors significantly enhanced AXIN1 protein level in colorectal cancer (CRC) cells through targeting CK1ε. Mechanistically, CK1ε promoted AXIN1 degradation by the ubiquitin–proteasome pathway by promoting the interaction of E3 ubiquitin‐protein ligase SIAH1 with AXIN1. Genetic or pharmacological inhibition of CK1ε and knockdown of SIAH1 downregulated the expression of Wnt/β‐catenin‐dependent genes, suppressed the viability of CRC cells, and restrained tumorigenesis and progression of CRC in vitro and in vivo. In summary, our results demonstrate that CK1ε exerted its oncogenic role in CRC occurrence and progression by regulating the stability of AXIN1. These findings reveal a novel mechanism by which CK1ε regulates the Wnt/β‐catenin signaling pathway and highlight the therapeutic potential of targeting the CK1ε/SIAH1 axis in CRC.

Abstract As one of the most prevalent tumors, colorectal cancer (CRC) owns complex pathogenesis and the high recurrence rate significantly influence the prognosis of patients with KRAS mutant CRC, to discovery the crosstalk among KEAP1‐NFE2L2 and oncogenic KRAS as the potential prognostic biomarkers in CRC, which might be used to develop novel and effective therapeutics. By using bioinformatics analysis, we explored and identified key genes as the predicted targets in the crosstalk among KEAP1 oncogenic signatures of KRAS mutation that were linked with development, metastasis, and poor prognosis in CRC. We further investigated the correlations between the clinical characteristics and expressions of prognostic genes among the KRAS and KEAP1‐related key hub genes in CRC, which as predicted targets to find the potential herbal ingredients in HERB database, further to verify the active herbal ingredients could regulate the key targets that related to KEAP1‐NFE2L2 in KRAS mutant CRC. The newest TCGA data reveals that the mutation of KRAS is found in 44% of CRC patients. In total, 28 genes were identified as differentially expressed genes (DEGs), and the hub genes such as CDKN2A, SPP1, FOS, BCL2L11, and HPSE were verified. Results indicated that key genes (SOX9, SPP1) significant correlation with the target prediction of the active herbal ingredients by molecular docking analysis. Furthermore, KEAP1, NFE2L2, SOX9 expression were decreased significantly with the treatment of potential ingredients. Furthermore, cyclopamine could enhance the sensitivity of HCT116 cells, downregulated the expression of SPP1, and induced activation of KEAP1‐NFE2L2 pathway, which cell death are characteristic features of apoptosis, and enhanced anticancer effect. Therefore, KEAP1‐related genes might be important oncogenic signatures in KRAS mutant CRC cells and cyclopamine was identified as a potential ingredient and regulated the predict targets of SOX9 and SPP1, may be expand the efficacy and range of novel and effective therapeutics.

Abstract Background Aberrant TGF‐β signaling pathway can lead to invasive phenotype of colorectal cancer (CRC), resulting in poor prognosis. It is pivotal to develop an effective prognostic factor on the basis of TGF‐β‐related genes to accurately identify risk of CRC patients. Methods We performed differential analysis of TGF‐β‐related genes in CRC patients from databases and previous literature to obtain TGF‐β‐related differentially expressed genes (TRDEGs). LASSO‐Cox regression was utilized to build a CRC prognostic feature model based on TRDEGs. The model was validated using two GEO validation sets. Wilcoxon rank‐sum test was utilized to test correlation of model with clinical factors. ESTIMATE algorithm and ssGSEA and tumor mutation burden (TMB) analysis were used to analyze immune landscape and mutation burden of high‐risk (HR) and low‐risk (LR) groups. CellMiner database was utilized to identify therapeutic drugs with high sensitivity to the feature genes. Results We established a six‐gene risk prognostic model with good predictive accuracy, which independently predicted CRC patients' prognoses. The HR group was more likely to experience immunotherapy benefits due to higher immune infiltration and TMB. The feature gene TGFB2 could inhibit the efficacy of drugs such as XAV‐939, Staurosporine, and Dasatinib, but promote the efficacy of drugs such as CUDC‐305 and by‐product of CUDC‐305. Similarly, RBL1 could inhibit the drug action of Fluphenazine and Imiquimod but promote that of Irofulven. Conclusion A CRC risk prognostic signature was developed on basis of TGF‐β‐related genes, which provides a reference for risk and further therapeutic selection of CRC patients.

Abstract Aims The prognosis of colorectal cancer (CRC) has been historically reliant on the Tumor Node Metastasis (TNM) staging system, but there is variability in outcomes among patients at similar stages. Therefore, there is an urgent need for more robust biomarkers. The aim of this study was to assess the clinical feasibility of the recently reported Inflammatory Burden Index (IBI) for predicting short‐ and long‐term outcomes in patients with CRC. Methods This was a retrospective observational study of 555 CRC patients undergoing surgery for primary tumor resection. We determined the prognostic value of preoperative IBI for disease‐free and overall survival, and its predictive value for perioperative risk of infectious complications, including surgical site infection. Results Increased preoperative IBI was significantly associated with advanced disease stage and poor oncological outcome in CRC patients. Higher IBI was independently linked to poorer disease‐free and overall survival. Similar outcomes were observed in a subanalysis focused on high‐risk stage II and stage III CRC patients. Elevated preoperative IBI was significantly correlated with an increased risk of surgical site infection and other postoperative infectious complications. Propensity score‐matching analysis validated the impact of IBI on the prognosis in CRC patients. Conclusion We established preoperative IBI as a valuable predictive biomarker for perioperative risks and oncological outcomes in CRC patients. Preoperative IBI is useful for designing effective perioperative management and postoperative oncological follow‐up.

Abstract Aim To clarify the usefulness of intraoperative lavage cytology in patients undergoing curative resection for pStage II‐III colorectal cancer in a prospective multicenter study. Methods Patients preoperatively diagnosed with stage II‐III colorectal cancer between 2013 and 2017 from 20 hospitals were enrolled. Lavage cytology was performed twice during the surgery. The primary endpoint was the effect of lavage cytology on the 5‐year relapse‐free survival (RFS) in patients with pStage II‐III colorectal cancer. The secondary endpoint was the effect of lavage cytology on the 5‐year overall survival (OS) and peritoneal recurrence. Results A total of 1378 patients were eligible for analysis. The number of patients with pStage II‐III colorectal cancer was 670 and 708, respectively. Fifty‐four patients (3.9%) had positive cytological results. In pStage II patients, the 5‐year RFS rates with positive and negative cytology were 61.1% and 81.6%, respectively (p = 0.023). The 5‐year OS rates were 67.1% and 91.7%, respectively (p = 0.0083). However, there was no difference in RFS or OS between pStage III patients with positive and negative cytology results. The peritoneal recurrence rates were 11.8% and 1.5% in pStage II patients with positive and negative cytology results, respectively (p = 0.032). These rates were 10.5% and 2.5% in patients with stage III disease, respectively (p = 0.022). Conclusion Stage II colorectal cancer patients with negative cytology had better outcomes than those with positive cytology. Peritoneal lavage cytology is useful for predicting peritoneal recurrence after curative resection of stage II‐III colorectal cancer.

Abstract Aim To assess the impact of perioperative prognostic nutritional index (PNI) changes on prognosis and recurrence after colorectal cancer surgery. Methods A total of 475 patients who underwent curative resection for primary colorectal adenocarcinoma and were diagnosed with pathological stage (pStage) II/III were retrospectively reviewed. The patients were divided into two groups: the high group (preoperative PNI ≤ postoperative PNI, n = 290) and the low group (preoperative PNI > postoperative PNI, n = 185). Results The low group exhibited significantly higher recurrence and mortality rates (all p

Abstract Colorectal cancer (CRC) is notable for its high mortality and high metastatic characteristics. The shear force generated by bloodstream provides mechanical signals regulating multiple responses of cells, including metastatic cancer cells, dispersing in blood vessels. We, therefore, studied the effect of shear flow on circulating CRC cells in the present study. The CRC cell line SW620 was subjected to shear flow of 12.5 dynes/cm2 for 1 and 2 h separately. Resulting elevated caspase‐9 and ‐3 indicated that shear flow initiated the apoptosis of SW620. Enlarged cell size associated with a higher level of cyclin D1 was coincident with the flow cytometric results indicating that the cell cycle was arrested at the G1 phase. An elevated phosphor‐eNOSS1177 increased the production of nitric oxide and led to reactive oxygen species‐mediated oxidative stress. Shear flow also regulated epithelial–mesenchymal transition (EMT) by increasing E‐cadherin and ZO‐1 while decreasing Snail and Twist1. The migration and invasion of sheared SW620 were also substantially decreased. Further investigations showed that mitochondrial membrane potential was significantly decreased, whereas mitochondrial mass and ATP production were not changed. In addition to the shear flow of 12.5 dynes/cm2, the expressions of EMT were compared at lower (6.25 dynes/cm2) and at higher (25 dynes/cm2) shear flow. The results showed that lower shear flow increased mesenchymal characteristics and higher shear flow increased epithelial characteristics. Shear flow reduces the malignancy of CRC in their metastatic dispersal that opens up new ways to improve cancer therapies by applying a mechanical shear flow device.

Abstract Aim Serum cholinesterase (ChE) levels are considered to reflect nutritional status. Although ChE has been well documented as a prognostic factor for some cancers, no clear consensus on its use for colorectal cancer (CRC) has been reached. The aim of this study was to investigate the relationship between preoperative serum ChE and postoperative long‐term prognosis in CRC patients. Methods A total of 1053 CRC patients who underwent curative surgery were included in this study. The correlations between the preoperative ChE value and overall survival (OS) or cancer‐specific survival (CSS) were assessed. By dividing patients into two groups according to their ChE value, OS and CSS were compared between the groups. Results Multivariate analysis revealed that the continuous ChE value was a significant predictor of OS (hazard ratio, 0.996; 95% CI, 0.993–0.998; p = 0.002) and CSS (hazard ratio, 0.994; 95% CI, 0.991–0.998; p = 0.001), independent of other variables. The low‐ChE (≤234 U/L) group had a significantly poorer prognosis than the high‐ChE (>234 U/L) group for both OS (5‐year OS for low ChE and high ChE: 79.8% and 93.3%, respectively; p

Abstract Aim To evaluate the potential role of serum and tissue hsa_circ_0008621 as a prognostic biomarker for CRC patients. Focused on the functional role of hsa_circ_0008621 in colorectal cancer (CRC). Methods Serum and tissue hsa_circ_0008621 expression were quantified by qRT‐PCR in 157 CRC patients, as well as 100 serums from healthy controls. Serum and tissue hsa_circ_0008621 expression was evaluated for their prognostic role in CRC patients using Kaplan–Meier curves and Multivariate Cox proportional hazards analysis. To further characterize the biological role of hsa_circ_0008621 expression in CRC, in vitro hsa_circ_0008621 inhibition was performed and the effects on cellular growth, migration, invasion, apoptosis, and glycolysis were explored. Next, the downstream molecules for hsa_circ_0008621 were predicted. Results Hsa_circ_0008621 expression was significantly upregulated in CRC tissues and serums. Serum hsa_circ_0008621 levels were significantly up‐regulated in advanced‐staged samples. High serum hsa_circ_0008621 expression was associated with shorter overall survival and recurrence‐free survival in CRC patients. Multivariate Cox regression analysis identified a high level of serum hsa_circ_0008621 expression as an independent prognostic factor with respect to overall survival and recurrence‐free survival. Loss of function assays for hsa_circ_0008621 in vitro led to a significant decrease in cell proliferation, migration, invasion, and glycolysis, but an increase in cell apoptosis. Hsa_circ_0008621 can sponge miR‐532‐5p, which targets SLC16A3. Conclusion High level of serum hsa_circ_0008621 is associated with poor survival in CRC and promotes CRC progression, suggesting it to be a promising non‐invasive prognostic biomarker and novel therapeutic target in CRC patients.

Multiple strategies are continuously being explored to expand the drug target repertoire in solid tumors. We devised a novel computational workflow for transcriptome‐wide gene expression outlier analysis that allows the systematic identification of both overexpression and underexpression events in cancer cells. Here, it was applied to expression values obtained through RNA sequencing in 226 colorectal cancer (CRC) cell lines that were also characterized by whole‐exome sequencing and microarray‐based DNA methylation profiling. We found cell models displaying an abnormally high or low expression level for 3533 and 965 genes, respectively. Gene expression abnormalities that have been previously associated with clinically relevant features of CRC cell lines were confirmed. Moreover, by integrating multi‐omics data, we identified both genetic and epigenetic alternations underlying outlier expression values. Importantly, our atlas of CRC gene expression outliers can guide the discovery of novel drug targets and biomarkers. As a proof of concept, we found that CRC cell lines lacking expression of the MTAP gene are sensitive to treatment with a PRMT5‐MTA inhibitor (MRTX1719). Finally, other tumor types may also benefit from this approach.

The transcription factor receptor‐interacting protein 140 (RIP140) regulates intestinal homeostasis and tumorigenesis through Wnt signaling. In this study, we investigated its effect on the Notch/HES1 signaling pathway. In colorectal cancer (CRC) cell lines, RIP140 positively regulated HES1 gene expression at the transcriptional level via a recombining binding protein suppressor of hairless (RBPJ)/neurogenic locus notch homolog protein 1 (NICD)‐mediated mechanism. In support of these in vitro data, RIP140 and HES1 expression significantly correlated in mouse intestine and in a cohort of CRC samples, thus supporting the positive regulation of HES1 gene expression by RIP140. Interestingly, when the Notch pathway is fully activated, RIP140 exerted a strong inhibition of HES1 gene transcription controlled by the level of HES1 itself. Moreover, RIP140 directly interacts with HES1 and reversed its mitogenic activity in human CRC cells. In line with this observation, HES1 levels were associated with a better patient survival only when tumors expressed high levels of RIP140. Our data identify RIP140 as a key regulator of the Notch/HES1 signaling pathway, with a dual effect on HES1 gene expression at the transcriptional level and a strong impact on colon cancer cell proliferation.

Store‐operated Ca2+ entry (SOCE) is a major mechanism for Ca2+ influx in colorectal cancer (CRC) cells. This mechanism, regulated by the filling state of the intracellular Ca2+ stores, is mediated by the endoplasmic reticulum Ca2+ sensors of the stromal interaction molecules (STIM) family [stromal interaction molecule 1 (STIM1) and STIM2] and the Ca2+‐release‐activated Ca2+ channels constituted by Orai family members, with predominance of calcium release‐activated calcium channel protein 1 (Orai1). CRC cells exhibit enhanced SOCE due to remodeling of the expression of the key SOCE molecular components. The enhanced SOCE supports a variety of cancer hallmarks. Here, we show that treatment of the colorectal adenocarcinoma cell lines HT‐29 and Caco‐2 with inanimate Lacticaseibacillus paracasei (CECT9610) and Lactiplantibacillus plantarum (CECT9608) attenuates SOCE, although no detectable effect is seen on SOCE in normal colon mucosa cells. The effect of Lacticaseibacillus paracasei and Lactiplantibacillus plantarum postbiotics was mediated by downregulation of Orai1 and STIM1, while the expression levels of Orai3 and STIM2 remained unaltered. Treatment of HT‐29 and Caco‐2 cells with inanimate Lacticaseibacillus paracasei and Lactiplantibacillus plantarum impairs in vitro migration by a mechanism likely involving attenuation of focal adhesion kinase (FAK) tyrosine phosphorylation. Cell treatment with the Orai1 inhibitor synta‐66 attenuates SOCE and prevents any further effect of Lacticaseibacillus paracasei and Lactiplantibacillus plantarum postbiotics. Together, our results indicate for the first time that Lacticaseibacillus paracasei and Lactiplantibacillus plantarum postbiotics selectively exert negative effects on Ca2+ influx through SOCE in colorectal adenocarcinoma cell lines, providing evidence for an attractive strategy against CRC.

Bovine milk and meat factors (BMMFs) are plasmid‐like DNA molecules isolated from bovine milk and serum, as well as the peritumor of colorectal cancer (CRC) patients. BMMFs have been proposed as zoonotic infectious agents and drivers of indirect carcinogenesis of CRC, inducing chronic tissue inflammation, radical formation and increased levels of DNA damage. Data on expression of BMMFs in large clinical cohorts to test an association with co‐markers and clinical parameters were not previously available and were therefore assessed in this study. Tissue sections with paired tumor‐adjacent mucosa and tumor tissues of CRC patients [individual cohorts and tissue microarrays (TMAs) (n = 246)], low‐/high‐grade dysplasia (LGD/HGD) and mucosa of healthy donors were used for immunohistochemical quantification of the expression of BMMF replication protein (Rep) and CD68/CD163 (macrophages) by co‐immunofluorescence microscopy and immunohistochemical scoring (TMA). Rep was expressed in the tumor‐adjacent mucosa of 99% of CRC patients (TMA), was histologically associated with CD68+/CD163+ macrophages and was increased in CRC patients when compared to healthy controls. Tumor tissues showed only low stromal Rep expression. Rep was expressed in LGD and less in HGD but was strongly expressed in LGD/HGD‐adjacent tissues. Albeit not reaching statistical significance, incidence curves for CRC‐specific death were increased for higher Rep expression (TMA), with high tumor‐adjacent Rep expression being linked to the highest incidence of death. BMMF Rep expression might represent a marker and early risk factor for CRC. The correlation between Rep and CD68 expression supports a previous hypothesis that BMMF‐specific inflammatory regulations, including macrophages, are involved in the pathogenesis of CRC.

The incidence of colorectal cancer (CRC) has increased worldwide, and early diagnosis is crucial to reduce mortality rates. Therefore, new noninvasive biomarkers for CRC are required. Recent studies have revealed an imbalance in the oral and gut microbiomes of patients with CRC, as well as impaired gut vascular barrier function. In the present study, the microbiomes of saliva, crevicular fluid, feces, and non‐neoplastic and tumor intestinal tissue samples of 93 CRC patients and 30 healthy individuals without digestive disorders (non‐CRC) were analyzed by 16S rRNA metabarcoding procedures. The data revealed that Parvimonas, Fusobacterium, and Bacteroides fragilis were significantly over‐represented in stool samples of CRC patients, whereas Faecalibacterium and Blautia were significantly over‐abundant in the non‐CRC group. Moreover, the tumor samples were enriched in well‐known periodontal anaerobes, including Fusobacterium, Parvimonas, Peptostreptococcus, Porphyromonas, and Prevotella. Co‐occurrence patterns of these oral microorganisms were observed in the subgingival pocket and in the tumor tissues of CRC patients, where they also correlated with other gut microbes, such as Hungatella. This study provides new evidence that oral pathobionts, normally located in subgingival pockets, can migrate to the colon and probably aggregate with aerobic bacteria, forming synergistic consortia. Furthermore, we suggest that the group composed of Fusobacterium, Parvimonas, Bacteroides, and Faecalibacterium could be used to design an excellent noninvasive fecal test for the early diagnosis of CRC. The combination of these four genera would significantly improve the reliability of a discriminatory test with respect to others that use a single species as a unique CRC biomarker.

The incidence and mortality rates of colorectal cancer have elevated its status as a significant public health concern. Recent research has elucidated the crucial role of mitochondrial fusion–fission dynamics in the initiation and progression of colorectal cancer. Elevated mitochondrial fission or fusion activity can contribute to the metabolic reprogramming of tumor cells, thereby activating oncogenic pathways that drive cell proliferation, invasion, migration, and drug resistance. Nevertheless, excessive mitochondrial fission can induce apoptosis, whereas moderate mitochondrial fusion can protect cells from oxidative stress. This imbalance in mitochondrial dynamics can exert dual roles as both promoters and inhibitors of colorectal cancer progression. This review provides an in‐depth analysis of the fusion–fission dynamics and the underlying pathological mechanisms in colorectal cancer cells. Additionally, it offers partial insights into the mitochondrial kinetics in colorectal cancer‐associated cells, such as immune and endothelial cells. This review is aimed at identifying key molecular events involved in colorectal cancer progression and highlighting the potential of mitochondrial dynamic proteins as emerging targets for pharmacological intervention.

Oral and intestinal samples from a cohort of 93 colorectal cancer (CRC) patients and 30 healthy controls (non‐CRC) were collected for microbiome analysis. Saliva (28 non‐CRC and 94 CRC), feces (30 non‐CRC and 97 CRC), subgingival fluid (20 CRC), and tumor tissue samples (20 CRC) were used for 16S metabarcoding and/or RNA sequencing (RNAseq) approaches. A differential analysis of the abundance, performed with the ANCOM‐BC package, adjusting the P‐values by the Holm‐Bonferroni method, revealed that Parvimonas was significantly over‐represented in feces from CRC patients (P‐value

Abstract Cronkhite–Canada syndrome (CCS) can be difficult to diagnose. To diagnose CCS, it is important to perform endoscopic examination for patients with chronic diarrhea, check for the presence or absence of polyposis, and evaluate inflammation in the mucosa between the polyps. This study reported seven cases of CCS. The age of the patients, which included four men and three women, ranged 48–72 years, and all patients were Asian. The most common symptom among these patients was chronic diarrhea. Three of the patients had rectal cancer. In two patients, the lesions were detected at an early stage and resected via endoscopic treatment. CCS is associated with a high risk of malignant gastrointestinal lesions, especially rectal cancers, and periodic surveillance endoscopy and careful observation are required.

Abstract Background and aims Colorectal cancer is the third most common cancer worldwide, accounting for 10% of cancer deaths. Therefore, this study was performed with the aim of spatial analysis of risk factors for colorectal cancer in Iran. Method This study was conducted ecologically using STEPS information (The WHO Stepwise Approach to NCD Risk Factor Surveillance) in Iran. To analyze the data, the researcher used cluster analysis and Geographically Weighted Regression methods with the help of ArcGIS version 10. Results The results of OLS analysis showed that there was a significant relationship between tobacco consumption (B = 0.571, p‐value = 0.044) and smoking (B = 0.772, p‐value = 0.010) and the incidence of colon cancer (CC). There was also a significant relationship between abdominal obesity and the incidence of rectal cancer (RC) (B = 0.061, p‐value = 0.027). Conclusion This study showed that (CC) high‐risk areas are located in central and northern parts of Iran, and the significant risk factors related to CC and RC were found to be tobacco use, cigarette smoking, and abdominal obesity. These findings are helpful to inform policymakers to plan screening services to reduce CC and RC, especially in high‐risk populations.

Abstract Purpose The prognostic and predictive value of RAS mutations in patients with colorectal liver metastases (CRLM) who have undergone hepatectomy holds substantial importance. The present study aimed to investigate the impact of different RAS codon mutations on long‐term survival in CRLM patients. Methods A retrospective analysis was conducted on clinicopathological data from 399 CRLM patients with RAS mutations who underwent hepatectomy between January 2000 and December 2020. The RAS mutation gene status was assessed in KRAS codons (G12, G13, Q61, and A146) and NRAS codons (G12, G13, and Q61). Survival curves were generated using the Kaplan–Meier plotter and compared using the log‐rank test. Univariate and multivariate analyses were performed to analyze the clinicopathological data. Results In the entire cohort, patients with KRAS G12 mutations exhibited the most favorable prognosis (p = 0.018). Comparatively, patients harboring KRAS Q61 mutations experienced poorer overall survival (OS) with a median of 15 months versus 33 months (p = 0.011) when compared to those with KRAS G12 mutations. Moreover, patients with NRAS Q61 mutations also showed decreased OS with a median of 26 months versus 33 months (p = 0.020) in comparison to KRAS G12 mutation patients. The results of multivariate analysis showed that both KRAS Q61 mutation (HR 2.130; 95% CI 1.088–4.168; p = 0.027) and NRAS Q61 mutation (HR 2.877; 95% CI 1.398–5.922; p = 0.004) were independent influencing factors of OS. Based on all identified risk factors, patients with RAS mutation were divided into high‐risk and low‐risk groups. Notably, in the high‐risk group, the incorporation of postoperative chemotherapy was associated with longer OS, while it did not improve the survival of patients in the low‐risk group. Conclusions KRAS Q61 and NRAS Q61 mutations are promising predictors for OS in CRLM patients after hepatectomy. Postoperative chemotherapy may significantly benefit CRLM patients with RAS mutations, particularly those identified as high‐risk.

Abstract Background Colorectal cancer (CRC) is a malignancy that arises within the gastrointestinal tract. Despite ongoing research, the etiology and pathogenesis of CRC remain elusive; particularly, the distribution and characteristics of tumor‐associated macrophages is currently an active area of investigation in understanding the pathological progression and prevention of CRC. Methods This study utilized CRC patient surgical samples, mouse models of colitis‐associated cancer, colonic organoid, and co‐culture cell line to examine the changes in CD11b/CD86 at different pathological region and detect the Wnt signaling pathway activity. Results Our findings revealed a sensitive and increased expression of CD11b from the early to the advanced CRC tissues and correlated with poor prognosis, while CD86 expression was reduced in advanced CRC tissues. CD133 expression was also elevated in advanced CRC tissues and mainly co‐localized with CD11b, suggesting a positive regulatory effect of CD11b and CD133 expression that may contribute to CRC progression. In AOM/DSS mouse models, activation of the Wnt signaling pathway was associated with increased CD133 and CD11b expression. In vitro, THP‐1 cell was induced to high expression of CD11b, and the above conditional cultural medium enhanced HCT116 cell colony number and CD133 protein expression. Furthermore, colonic crypts from AOM/DSS mouse models were isolated to culture, and the colonic organoids exhibited dilation and significant increases expression of CD133 and β‐Catenin/N‐P‐B‐Catenin. Conclusions CD11b might be an important factor to participate the progress of CRC. And the high CD11b of CRC microenviroment might potentially promote CD133 expression and associate with Wnt signal activation.

Abstract Background Investigating the molecular mechanism of colorectal cancer (CRC), a common lethal malignancies worldwide, is of great clinical significance. Solute carrier family 25 member 19 (SLC25A19) is a member of the solute carrier family that contribute to cellular functions, including tumor biology. Recently, many studies have attention on uncovering the relationship of SLC25A19 with malignant cancers, but its precise involvement in the regulation of CRC has not been thoroughly understood. This study sought to uncover the role and mechanism of SLC25A19 in CRC development. Methods The GEPIA database and immunohistochemical staining were utilized to detect the expression of SLC25A19 in CRC tissues. The functional influences of SLC25A19 on CRC cell phenotypes were evaluated through a series of assays including celigo cell count, colony formation, CCK‐8, flow cytometry, wound healing, and transwell assays following knocking down SLC25A19. Subsequently, the xenograft tumor model was constructed to evaluate the effect of SLC25A19 on tumor growth in vivo. The underlying mechanisms of SLC25A19 silencing were investigated using the human phospho‐kinase array. Results This study demonstrated the upregulation of SLC25A19 in CRC and its significant correlation with unfavorable prognosis in CRC patients. Suppression of SLC25A19 resulted in significant inhibition of cell proliferation, colony formation, and cell migration, alongside a boost in cell apoptosis. In vivo experiments revealed that silenced SLC25A19 displayed reduced growth rates and formed smaller xenografts. Mechanistically, the p53 pathway was found to be upregulated by SLC25A19 knockdown and mediated the function of SLC25A19. Conclusions Consequently, SLC25A19 was identified as a novel molecule with key regulatory ability in CRC development.

Abstract Introduction Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Surveillance colonoscopy is recommended 1‐year after surgical resection for patients with stage I‐III CRC; however, only 18%–61% of CRC survivors complete this test. This study describes clinician‐identified barriers and facilitators to surveillance colonoscopy among CRC survivors. Methods We conducted semi‐structured interviews with clinicians until thematic saturation was achieved. Interviews were analyzed using the social cognitive theory. Results Thirteen clinicians were interviewed, and all identified health system‐level barriers to surveillance colonoscopy completion; the most common being fragmented care due to patients receiving care across many health systems. Clinicians also identified social determinants of health barriers (e.g., geographical distance between patients and health systems) to 1‐year surveillance colonoscopy completion. Conclusions Clinicians identified several potentially modifiable barriers to 1‐year surveillance colonoscopy completion which, if addressed, could improve post‐treatment care and outcomes among stage I‐III CRC survivors.

Abstract The treatment of colorectal cancer is always a major challenge in the field of cancer research. The number of estimated new cases of colorectal cancer worldwide in 2020 is 1 148 515, and the estimated number of deaths is 576 858, revealing that mortality accounted for approximately half of the disease incidence. The development of new drugs and strategies for colorectal cancer treatment is urgently needed. Thermosensitive injectable hydrogel PDLLA‐PEG‐PDLLA (PLEL) loaded with cabazitaxel (CTX) is used to explore its anti‐tumor effect on mice with orthotopic colorectal cancer. CTX/PLEL is characterized by a solution state at room temperature and a hydrogel state at physiologic temperature. The excipients MPEG‐PCL and PDLLA‐PEG‐PDLLA have good biocompatibility and biodegradability. The simple material synthesis and preparation process renders this system cost‐effective and more conducive to clinical transformation. An orthotopic colorectal cancer model is established by transplantation subcutaneous tumors onto the cecum of mice. According to the results of experiments in vivo, CTX/PLEL significantly inhibits orthotopic colorectal cancer and liver metastasis in mice. The results indicate that CTX/PLEL nanoparticle preparations have high security and excellent anti‐tumor effects, and have great application potential in colorectal cancer therapy.

Abstract Programmed death‐ligand 1 (PD‐L1) is overexpressed in multiple cancers and critical for their immune escape. It has previously shown that the nuclear coactivator SRC‐1 promoted colorectal cancer (CRC) progression by enhancing CRC cell viability, yet its role in CRC immune escape is unclear. Here, we demonstrate that SRC‐1 is positively correlated with PD‐L1 in human CRC specimens. SRC‐1 deficiency significantly inhibits PD‐L1 expression in CRC cells and retards murine CRC growth in subcutaneous grafts by enhancing CRC immune escape via increasing tumor infiltration of CD8+ T cells. Genetic ablation of SRC‐1 in mice also decreases PD‐L1 expression in AOM/DSS‐induced murine CRC. These results suggest that tumor‐derived SRC‐1 promotes CRC immune escape by enhancing PD‐L1 expression. Mechanistically, SRC‐1 activated JAK‐STAT signaling by inhibiting SOCS1 expression and coactivated STAT3 and IRF1 to enhance PD‐L1 transcription as well as stabilized PD‐L1 protein by inhibiting proteasome‐dependent degradation mediated by speckle type POZ protein (SPOP). Pharmacological inhibition of SRC‐1 improved the antitumor effect of PD‐L1 antibody in both subcutaneous graft and AOM/DSS‐induced murine CRC models. Taken together, these findings highlight a crucial role of SRC‐1 in regulating PD‐L1 expression and targeting SRC‐1 in combination with PD‐L1 antibody immunotherapy may be an attractive strategy for CRC treatment.

Abstract Due to its decade‐long progression, colorectal cancer (CRC) is most suitable for population screening to achieve a significant reduction in its incidence and mortality. DNA methylation has emerged as a potential marker for the early detection of CRC. However, the current mainstream methylation detection method represented by bisulfite conversion has issues such as tedious operation, DNA damage, and unsatisfactory sensitivity. Herein, a new high‐performance CRC screening tool based on the promising specific terminal‐mediated polymerase chain reaction (STEM‐PCR) strategy is developed. CRC‐related methylation‐specific candidate CpG sites are first prescreened through The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases using self‐developed bioinformatics. Next, 9 homebrew colorectal cancer DNA methylated STEM‒PCR assays (ColoC‐mSTEM) with high sensitivity (0.1%) and high specificity are established to identify candidate sites. The clinical diagnostic performance of these selected methylation sites is confirmed and validated by a case‐control study. The optimized diagnostic model has an overall sensitivity of 94.8% and a specificity of 95.0% for detecting early‐stage CRC. Taken together, ColoC‐mSTEM, based on a single methylation‐specific site, is a promising diagnostic approach for the early detection of CRC which is perfectly suitable for the screening needs of CRC in primary healthcare institutions.

Abstract Colorectal cancer (CRC) and inflammatory bowel disease (IBD) are escalating global health concerns. Despite their distinct clinical presentations, both disorders share intricate genetic and molecular interactions. The Hippo signaling pathway plays a crucial role in regulating cell processes and is implicated in the pathogenesis of IBD and CRC. Circular RNAs (circRNAs) have gained attention for their roles in various diseases, including IBD and CRC. However, a comprehensive understanding of specific circRNAs involved in both IBD and CRC, and their functional roles is lacking. Here, it is found that circHIPK2 (hsa_circRNA_104507) is a bona fide circRNA consistently upregulated in both IBD and CRC suggesting its potential as a biomarker. Furthermore, silencing of circHIPK2 suppressed the growth of CRC cells in vitro and in vivo. Interestingly, decreased circHipk2 potentiated dextran sulfate sodium (DSS)‐induced colitis but alleviated colitis‐associated tumorigenesis. Most significantly, mechanistic investigations further unveil that circHIPK2, mediated by FUS, interacting with EIF4A3 to promote the translation of TAZ, ultimately increasing the transcription of downstream target genes CCN1 and CCN2. Taken together, circHIPK2 emerges as a key player in the shared mechanisms of IBD and CRC, modulating the Hippo signaling pathway. CircHIPK2‐EIF4A3 axis contributes to cell growth in intestinal epithelial of colitis and CRC by enhancing TAZ translation.

Abstract Background With the burden of colorectal cancer in Canada, there is a need to address the psycho‐oncologic challenges, including mental health. This study aims to explore the lived mental health experiences in patients with CRC across the phases of the CRC care continuum. Methods We employed a patient‐oriented constructivist grounded theory design and recruited English speaking participants ≥18 years, diagnosed with CRC within the last 10 years, residing in Canada. We collected data through semi‐structured individual interviews using a guide co‐constructed with patient research partners. Data collection and analysis were iterative, employed theoretical sampling, and culminated in a theoretical model. Results Twenty‐eight participants diagnosed with CRC (18 females, 10 males), aged 18–63 years at time of diagnosis were interviewed, with representation across all CRC stages. There were 10 participants (36%) in treatment, 12 participants (43%) in follow‐up, and 6 participants (21%) in the beyond phase. We constructed a patient‐oriented theory illustrating the dynamic nature between one's self‐identity and their mental health experiences across the CRC care continuum. Mental health experiences encompass emotional and cognitive‐behavioral responses, expressed differently across phases. Mental health care experiences are also shaped by barriers, facilitators, and individual contextual factors, all of which influence their access to care. Conclusion Our theory provides insight into the mental health experiences of patients with CRC across phases of the CRC care continuum. Understanding patients' emotional and cognitive‐behavioral responses and care experiences can help identify opportunities to integrate mental health into CRC care.

Abstract Purpose Therapeutic management of colorectal cancer (CRC) does not yet yield promising long‐term results. Therefore, there is a need for further investigation of possible therapeutic options. Various experiments have studied the effects of apigenin on CRC and have shown conflicting results. This systematic review and meta‐analysis investigates the currently existing evidence on the effect of apigenin on CRC. Methods Medline, Embase, Scopus, and Web of Science databases were searched for articles related to apigenin and its effect on CRC in the preclinical setting. Cell viability, growth inhibition, apoptosis, and cell cycle arrest for in‐vitro, and body weight, tumor size, and mortality in in‐vivo studies were extracted as outcomes. Results Thirty‐nine articles investigating colorectal adenocarcinoma were included in this meta‐analysis. Thirty‐seven of these studies had data for in vitro experiments, with eight studies having data for in vivo experiments. Six articles had both in vitro and in vivo assessments. Our analysis showed apigenin reduces cell viability and induces growth inhibition, apoptosis, and cell cycle arrest in in vitro studies. The few in vivo studies indicate that apigenin decreases tumor size while showing no effects on the body weight of animal colorectal adenocarcinoma models. Conclusion Our results demonstrated that apigenin, through reducing cell viability, inducing growth inhibition, apoptosis, and cell cycle arrest, and also by decreasing the tumor size, can be considered as a possible adjuvant agent in the management of colorectal adenocarcinoma. However, further in vivo studies are needed before any efforts to translate the current evidence into clinical studies.

Abstract Background Colorectal cancer (CRC) is a prevalent and lethal tumor, with metastasis being the leading cause of mortality. Previous research has indicated that the long non‐coding RNA (lncRNA) CCAT2 is involved in the regulation of various tumor progression mechanisms. However, the precise role of CCAT2 in CRC proliferation and metastasis remains ambiguous. This study seeks to elucidate the mechanisms through which CCAT2 influences CRC. Methods High‐throughput sequencing and RT‐qPCR were used to detect CCAT2 expression in CRC. Functional analyses including CCK8, colony formation, wound healing migration, transwell chamber, and Muse® Cell Analyzer assays were performed to study the effects of CCAT2 gene deletion on CRC cells. RNA‐pulldown and protein mass spectrometry were employed to identify the interaction between CCAT2 and GNB2 protein. Results Increased CCAT2 expression was found in CRC, especially in metastatic CRC. Deletion of CCAT2 gene inhibited CRC cell proliferation, migration, and invasion while promoting apoptosis. The interaction between CCAT2 and GNB2 protein was shown to modulate GNB2 protein alterations and affect the ERK and Wnt signaling pathways, thereby promoting CRC proliferation and metastasis. Conclusion CCAT2 plays a crucial role in CRC progression by modulating the ERK and Wnt signaling pathways through its interaction with GNB2. These findings highlight the importance of CCAT2 as a key regulatory element in the mechanisms underlying CRC proliferation and metastasis.

Abstract Background Gut bacteria are related to colorectal cancer (CRC) and its clinicopathologic characteristics. Objective To develop gut bacterial subtypes and explore potential microbial targets for CRC. Methods Stool samples from 914 volunteers (376 CRCs, 363 advanced adenomas, and 175 normal controls) were included for 16S rRNA sequencing. Unsupervised learning was used to generate gut microbial subtypes. Gut bacterial community composition and clustering effects were plotted. Differences of gut bacterial abundance were analyzed. Then, the association of CRC‐associated bacteria with subtypes and the association of gut bacteria with clinical information were assessed. The CatBoost models based on gut differential bacteria were constructed to identify the diseases including CRC and advanced adenoma (AA). Results Four gut microbial subtypes (A, B, C, D) were finally obtained via unsupervised learning. The characteristic bacteria of each subtype were Escherichia‐Shigella in subtype A, Streptococcus in subtype B, Blautia in subtype C, and Bacteroides in subtype D. Clinical information (e.g., free fatty acids and total cholesterol) and CRC pathological information (e.g., tumor depth) varied among gut microbial subtypes. Bacilli, Lactobacillales, etc., were positively correlated with subtype B. Positive correlation of Blautia, Lachnospiraceae, etc., with subtype C and negative correlation of Coriobacteriia, Coriobacteriales, etc., with subtype D were found. Finally, the predictive ability of CatBoost models for CRC identification was improved based on gut microbial subtypes. Conclusion Gut microbial subtypes provide characteristic gut bacteria and are expected to contribute to the diagnosis of CRC.

Abstract Background Determining the effect of dietary factors on cancer is a crucial issue when accounting for the effect of other major risks, such as smoking and drinking. Method A total of 15,563 adults from the Korean National Cancer Center Community Cohort were analyzed to determine and to compare the effect of dietary factors on stomach and colorectal cancer in overall and in the subgroup of non‐smokers (or urinary cotinine concentrations

Abstract Background and Aim Adequate bowel preparation is necessary for optimal colonoscopy. Inadequate bowel preparation results in increased costs and imprecise colonoscopy results. This study aims to determine the incidence and risk factors of inadequate bowel preparation. Methods In this study, 604 consecutive patients were observed prospectively who underwent colonoscopy examination. The patient's clinical and demographic data were obtained on the day of the procedure. Bowel preparation was evaluated by Boston Bowel Preparation Scale (BBPS) and was divided into two groups; adequate and inadequate. Univariate and multivariate analyses were performed. Results Inadequate bowel preparation incidence was 17.9%. In the univariate analysis, education level (P value = 0.009), body mass index (P value = 0.03), admission type (P value = 0.038), previous history of colonoscopy (P value = 0.03), color and consistency of the last feces (P value = 0.03), diabetes (P value = 0.004), and smoking (P value = 0.03) were significantly related with the incidence of inadequate bowel preparation. While ischemic heart disease (IHD) decreased the level of inadequate bowel preparation (P value = 0.047). Multivariate analysis showed that diabetes mellitus (odds ratio [OR] = 2.18), smoking (OR = 2.10), inpatient status of admission type (OR = 3.32), last stool that was non‐watery (OR = 1.60), and ischemic heart disease (OR = 0.032) were independent factors associated with inadequate bowel preparation. Conclusion Diabetic patients, smokers, inpatients and who defecated a non‐watery and colory stool as the last defecation are at risk of inadequate bowel preparation and need more potent regimens. It is important to inform patients about preventable factors that affect bowel preparation to improve their preparation outcomes.

Abstract Radiotherapy is essential for treating colorectal cancer (CRC), especially in advanced rectal cancer. However, the low radiosensitivity of CRC cells greatly limits radiotherapy efficacy. Small nucleolar RNAs (snoRNAs) are a class of noncoding RNA that primarily direct post‐transcriptional modifications of ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs), and other cellular RNAs. While snoRNAs are involved in tumor progression and chemoresistance, their association with radiosensitivity remains largely unknown. Herein, SNORA28 is shown highly expressed in CRC and is positively associated with poor prognosis. Furthermore, SNORA28 overexpression enhances the growth and radioresistance of CRC cells in vitro and in vivo. Mechanistically, SNORA28 acts as a molecular decoy that recruits bromodomain‐containing protein 4 (BRD4), which increases the level of H3K9 acetylation at the LIFR promoter region. This stimulates LIFR transcription, which in turn triggers the JAK1/STAT3 pathway, enhancing the proliferation and radioresistance of CRC cells. Overall, these results highlight the ability of snoRNAs to regulate radiosensitivity in tumor cells and affect histone acetylation modification in the promoter region of target genes, thus broadening the current knowledge of snoRNA biological functions and the mechanism underlying target gene regulation.

Abstract The process of drug discovery and pre‐clinical testing is currently inefficient, expensive, and time‐consuming. Most importantly, the success rate is unsatisfactory, as only a small percentage of tested drugs are made available to oncological patients. This is largely due to the lack of reliable models that accurately predict drug efficacy and safety. Even animal models often fail to replicate human‐specific pathologies and human body's complexity. These factors, along with ethical concerns regarding animal use, urge the development of suitable human‐relevant, translational in vitro models.

ABSTRACT Introduction Qualitative research on the perceptions of healthcare professionals involved in cancer care about their respective roles in the patient care pathway is limited. Therefore, the aim of this qualitative study was to document these perceptions. Methods A multidisciplinary team that included patient researchers constructed a semi‐structured interview guide on the perceptions of the colorectal cancer care pathway by professionals. Interviews were conducted with healthcare professionals from two French hospitals that manage patients with colorectal cancer. Then, the interviews were fully transcribed and analysed by the whole multidisciplinary team. Results Thirteen healthcare professionals were interviewed (six nurses, four physicians, one psychologist, one social worker and one secretary). They described the colorectal care pathway using a great lexical diversity and listed a significant number of professionals as taking part in this pathway. Among the people mentioned were healthcare professionals working inside and outside the hospital, family members and non‐conventional medicine practitioners. However, they did not spontaneously mention the patient. Their views on the role of the referring physician, the general practitioner and the patient were further explored. The interviews highlighted the coordination difficulties among the various professionals, particularly between general practitioners and hospital teams. These data provided interesting elements for developing a tool to help coordination among professionals. Conclusions This preliminary study, with its participatory design, brings interesting elements of reflection on the care pathway for patients with colorectal cancer. It will continue through the creation of a larger participatory project. Patient or Public Contribution Patient partners were included in all steps of this study. This transdisciplinary project was coordinated by a group composed of three patient partners, two healthcare professionals and two humanities and social sciences researchers. Their knowledge of the patient's perspective on the care pathway enriched discussions from the study design to results analysis.

Abstract Background Colorectal cancer is the third most common cancer in the Western Hemisphere. It is the third most common cancer in men after prostate and lung cancers and the second most common cancer in women after breast cancer. According to some studies, the incidence and prevalence of colorectal cancer is increasing rapidly. Main Body In the present study, a systematic review of the articles related to the economic burden of colorectal cancer was carried out. The articles were taken from the following databases: SID, Medline/Pubmed, Embase, Scopus, Web of Science, NHS Economic Evaluation Database (EED), Econlit, and Google Scholar. Furthermore, the PICOTS model was used to select the inclusion criteria. The quality of the articles' methodologies was evaluated using Drummond's checklist. Then, some data were extracted from relevant articles, in terms of year, place of research, sample size, costing approach, type of measured costs, average direct medical costs, average direct nonmedical costs, and average indirect costs. The data from 37 studies dealing with the costs of patients with colorectal cancer were extracted. Most of the studies were conducted in the United States, and the social perspective was the most common perspective to measure the costs. According to the majority of the studies, direct medical costs were considered the greatest driver in causing the economic burden of colorectal cancer. The costs of hospitalization, medicine, surgery, chemotherapy, and radiotherapy accounted for the largest share of direct medical costs, and the costs of transportation, accommodation, and home care were the greatest share of direct nonmedical costs. Furthermore, the costs associated with disability, absenteeism, and premature death were identified as the main drivers of indirect costs. Conclusion The findings of this study showed that colorectal cancer imposes great direct and indirect costs on families, the health system, and society. The best way to deal with this disease and, hence, to reduce its economic burden is to take comprehensive preventive measures and modify the lifestyle. In addition, health policymakers can limit the costs of this disease by expanding the screening program.

Abstract Visual observation and therapeutic intervention against tumors hold significant appeal for tumor treatment, particularly in meeting the demands of intraoperative navigation. From a clinical perspective, the naked‐eye visualization of tumors provides a direct and convenient approach to identifying tumors and navigating during surgery. Nevertheless, there is an ongoing need to develop effective solutions in this frontier. Genetically engineered microorganisms are promising as living therapeutics for combatting malignant tumors, leveraging precise tumor targeting and versatile programmed functionalities. Here, genetically modified Escherichia coli (E. coli) MG1655 bacterial cells are introduced, called MelaBac cells, designed to express tyrosinase continuously. This bioengineered melanogenesis produces melanin capable of pigmenting both subcutaneous CT26 xenografts and chemically induced colorectal cancer (CRC). Additionally, MelaBac cells demonstrate the initiation of photonic hyperthermia therapy and immunotherapy against tumors, offering promising selective therapeutic interventions with high biocompatibility.

Abstract Colorectal cancer (CRC) is one of the most common malignancies worldwide. In the clinical realm, platinum‐based drugs hold an important role in the chemotherapy of CRC. Nonetheless, a multitude of patients, due to tumor protein 53 (TP53) gene mutations, experience the emergence of drug resistance. This phenomenon gravely impairs the effectiveness of therapy and long‐term prognosis. Gallium, a metallic element akin to iron, has been reported that has the potential to be used to develop new metal anticancer drugs. In this study, we screened and established the gallium complex K6 as a potent antitumor agent in both in vitro and in vivo. K6 exhibited superior efficacy in impeding the growth, proliferation, and viability of CRC cells carrying TP53 mutations compared to oxaliplatin. Mechanistically, K6 escalated reactive oxygen species levels and led deoxyribonucleic acid (DNA) damage. Furthermore, K6 effectively suppressed the phosphoinositide 3‐kinase (PI3K)/protein kinase B (PKB)/glycogen synthase kinase 3 beta (GSK3β) pathway, leading to the degradation of its downstream effectors myelocytomatosis (c‐Myc) and Krueppel‐like factor 5 (KLF5). Conversely, K6 diminished the protein expression of WW domain‐containing protein 1 (WWP1) while activating phosphatase and tensin homolog (PTEN) through c‐Myc degradation. This dual action further demonstrated the potential of K6 as a promising therapeutic compound for TP53‐mutated CRC.

Abstract The incidence of brain metastasis (BM) from colorectal cancer (CRC) is increasing. This study aims to identify the clinical prognosticators and evaluate the prognostic validity of common comorbidity indices in patients with BM from CRC. This retrospective single‐center study analyzed 93 patients with BM from CRC who received surgical excision and/or radiotherapy. The clinical characteristics and prognostic indices including the 5‐item modified frailty index (mFI‐5) and prognostic nutritional index (PNI) were calculated from the collected patient data and analyzed. In this study, 66 (71.0%), 10 (10.8%), and 17 (18.3%) patients received whole‐brain radiotherapy (WBRT) alone, surgery alone, and surgery plus WBRT, respectively. The median survival of all patients was 3.98 months (IQR: 1.74–7.99). The 2‐ and 3‐year survival rates were 7.4% and 3.7%, respectively. Controlled primary tumor (p = 0.048), solitary BM (p = 0.001), surgery + radiation (p

The peptide mimetic, NC114, is a promising anticancer compound that specifically kills colorectal cancer cells without affecting normal colon epithelial cells. In our previous study, we observed that NC114 inhibited the Wnt/β‐catenin pathway, with significant downregulation of both Ser 675‐phosphorylated β‐catenin and its target genes, cyclin D1 and survivin. However, the molecular mechanism responsible for its cytotoxic effect has not yet been fully characterized. In the present study, we demonstrated that NC114 prevented cell cycle progression from S to G2/M phase by downregulating cell cycle‐related gene expression, and also induced growth arrest in SW480 and HCT‐116 colorectal cancer cells. A novel covariation network analysis combined with transcriptome analysis revealed a series of signaling cascades affected by NC114 treatment, and identified protein kinase C‐δ (PKCδ) and forkhead box protein M1 (FOXM1) as important regulatory factors for NC114‐induced growth arrest. NC114 treatment inhibits the activation of PKCδ and its kinase activity, which suppresses MEK/ERK signaling. Attenuated MEK/ERK signaling then results in a reduction in FOXM1 phosphorylation and subsequent nuclear translocation of FOXM1 and β‐catenin. Consequently, formation of a T‐cell factor‐4 (TCF4)/β‐catenin transcription complex in the nucleus is inhibited and transcription of its target genes, such as cell cycle‐related genes, is downregulated. The efficacy of NC114 on tumor growth was confirmed in a xenograft model. Collectively, elucidation of the mechanism by which NC114 induces growth arrest in colorectal cancer cells should provide a novel therapeutic strategy for colorectal cancer treatment.

Abstract Colorectal cancer (CRC) is a heterogeneous disease and one of the most prevalent malignancies worldwide. Previous research has indicated that phosphatase and tensin homolog (PTEN)‐related genes found in CRC may serve as potential biomarkers for individualized treatment options. The present study aimed to examine the association between PTEN‐related genes and the prognosis of CRC patients by evaluating the significance of PTEN‐related hub genes and determining potential mechanisms and genes associated with them. Gene expression profiles and clinical information were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. At present, PTEN mutations have been identified in 7% of CRC patients, according to the most recent TCGA data. Differential expression analysis revealed 54 genes as differentially expressed genes (DEGs) between PTEN‐related genes and GEO databases (GSE39582 and GSE6263). Further gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted on PTEN‐related DEGs. The prognostic efficacy of the PTEN‐related DEG signature was assessed using Kaplan–Meier survival and receiver operating characteristic curve analyses. Bioinformatics methods were utilized to analyze the correlation between PTEN‐related DEGs and CRC prognosis, survival, and drug efficacy. Through these analyses, eight prognostic‐related PTEN‐related hub genes (PPARGC1A, NTRK2, ANK2, PLCB4, STC2, PLAU, CDKN1A, and HPGDS) were identified and a risk prognosis model was constructed. Notably, NTRK2 and HPGDS were found to affect drug treatment response in CRC. Targeting these prognostic‐related PTEN‐related hub genes can regulate cell death signaling, which may benefit the prognosis of CRC patients and improve drug sensitivity.

Abstract Aim The aim of this study was to clarify the significance of resection of ovarian metastases from colorectal cancer and to identify the clinicopathologic characteristics. Methods In this multicenter retrospective study, we evaluated data on ovarian metastases from colorectal cancer obtained from patients at 20 centers in Japan between 2000 and 2014. We examined the impact of resection on the prognosis of patients with ovarian metastases and examined prognostic factors. Results The study included 296 patients with ovarian metastasis. The 3‐y overall survival rate was 68.6% for solitary ovarian metastases. In all cases of this cohort, the 3‐y overall survival rates after curative resection, noncurative resection, and nonresection were 65.9%, 31.8%, and 6.1%, respectively (curative resection vs noncurative resection [P

Microtubule‐targeting agents represent one of the most successful classes of anticancer agents. However, the development of drug resistance and the appearance of adverse effects hamper their clinical implementation. Novel microtubule‐targeting agents without such limitations are urgently needed. By employing a gene expression‐based drug repositioning strategy, this study identifies VU‐0365114, originally synthesized as a positive allosteric modulator of human muscarinic acetylcholine receptor M5 (M5 mAChR), as a novel type of tubulin inhibitor by destabilizing microtubules. VU‐0365114 exhibits a broad‐spectrum in vitro anticancer activity, especially in colorectal cancer cells. A tumor xenograft study in nude mice shows that VU‐0365114 slowed the in vivo colorectal tumor growth. The anticancer activity of VU‐0365114 is not related to its original target, M5 mAChR. In addition, VU‐0365114 does not serve as a substrate of multidrug resistance (MDR) proteins, and thus, it can overcome MDR. Furthermore, a kinome analysis shows that VU‐0365114 did not exhibit other significant off‐target effects. Taken together, our study suggests that VU‐0365114 primarily targets microtubules, offering potential for repurposing in cancer treatment, although more studies are needed before further drug development.

Abstract Background Parameters obtained from two‐dimensional (2D) cross‐sectional images have been used to determine body composition. However, data from three‐dimensional (3D) volumetric body images reflect real body composition more accurately and may be better predictors of patient outcomes in cancer. This study aimed to assess the 3D parameters and determine the best predictive factors for patient prognosis. Methods Patients who underwent surgery for colorectal cancer (CRC) between 2010 and 2016 were included in this study. Preoperative computed tomography images were analysed using an automatic segmentation program. Body composition parameters for muscle, muscle adiposity, subcutaneous fat (SF) and abdominal visceral fat (AVF) were assessed using 2D images at the third lumbar (L3) level and 3D images of the abdominal waist (L1–L5). The cut‐off points for each parameter were determined using X‐tile software. A Cox proportional hazards regression model was used to identify the association between the parameters and the treatment outcomes, and the relative influence of each parameter was compared using a gradient boosting model. Results Overall, 499 patients were included in the study. At a median follow‐up of 59 months, higher 3D parameters of the abdominal muscles and SF from the abdominal waist were found to be associated with longer overall survival (OS) and disease‐free survival (all P

Abstract Background Toll‐like receptors (TLRs) are a family of fundamental pattern recognition receptors in the innate immune system, constituting the first line of defense against endogenous and exogenous antigens. The gut microbiota, a collection of commensal microorganisms in the intestine, is a major source of exogenous antigens. The components and metabolites of the gut microbiota interact with specific TLRs to contribute to whole‐body immune and metabolic homeostasis. Objective This review aims to summarize the interaction between the gut microbiota and TLR signaling pathways and to enumerate the role of microbiota dysbiosis‐induced TLR signaling pathways in obesity, inflammatory bowel disease (IBD), and colorectal cancer (CRC). Results Through the recognition of TLRs, the microbiota facilitates the development of both the innate and adaptive immune systems, while the immune system monitors dynamic changes in the commensal bacteria to maintain the balance of the host‐microorganism symbiosis. Dysbiosis of the gut microbiota can induce a cascade of inflammatory and metabolic responses mediated by TLR signaling pathways, potentially resulting in various metabolic and inflammatory diseases. Conclusion Understanding the crosstalk between TLRs and the gut microbiota contributes to potential therapeutic applications in related diseases, offering new avenues for treatment strategies in conditions like obesity, IBD, and CRC.

Abstract Introduction Abnormal results in common blood tests may occur several months before lung cancer (LC) and colorectal cancer (CRC) diagnosis. Identifying early blood markers of cancer and distinct blood test signatures could support earlier diagnosis in general practice. Methods Using linked Australian primary care and hospital cancer registry data, we conducted a cohort study of 855 LC and 399 CRC patients diagnosed between 2001 and 2021. Requests and results from general practice blood tests (six acute phase reactants [APR] and six red blood cell indices [RBCI]) were examined in the 2 years before cancer diagnosis. Poisson regression models were used to estimate monthly incidence rates and examine pre‐diagnostic trends in blood test use and abnormal results prior to cancer diagnosis, comparing patterns in LC and CRC patients. Results General practice blood test requests increase from 7 months before CRC and 6 months before LC diagnosis. Abnormalities in many APR and RBCI tests increase several months before cancer diagnosis, often occur prior to or in the absence of anaemia (in 51% of CRC and 81% of LC patients with abnormalities), and are different in LC and CRC patients. Conclusions This study demonstrates an increase in diagnostic activity in Australian general practice several months before LC and CRC diagnosis, indicating potential opportunities for earlier diagnosis. It identifies blood test abnormalities and distinct signatures that are early markers of LC and CRC. If combined with other pre‐diagnostic information, these blood tests have potential to support GPs in prioritising patients for cancer investigation of different sites to expedite diagnosis.

Abstract Background Colorectal cancer (CRC) is among the most hackneyed malignancies. Even patients with identical clinical symptoms and the same TNM stage still exhibit radically different clinical outcomes after receiving equivalent treatment regimens, indicating extensive heterogeneity of CRC. Myriad molecular subtypes of CRC have been exploited for decades, including the most compelling consensus molecular subtype (CMS) classification that has been broadly applied for patient stratification and biomarker‐drug combination formulation. Encountering barriers to clinical translation, however, CMS classification fails to fully reflect inter‐ or intra‐tumor heterogeneity of CRC. As a consequence, addressing heterogeneity and precisely managing CRC patients with unique characteristics remain arduous tasks for clinicians. Review In this review, we systematically summarize molecular subtypes of CRC and further elaborate on their clinical applications, limitations, and future orientations. Conclusion In recent years, exploration of subtypes through cell lines, animal models, patient‐derived xenografts (PDXs), organoids, and clinical trials contributes to refining biological insights and unraveling subtype‐specific therapies in CRC. Therapeutic interventions including nanotechnology, clustered regulatory interspaced short palindromic repeat/CRISPR‐associated nuclease 9 (CRISPR/Cas9), gut microbiome, and liquid biopsy are powerful tools with the possibility to shift the immunologic landscape and outlook for CRC precise medicine.

Abstract Background and Aim Colorectal cancer (CRC) is one of the most prevalent cancers around the world. The link between nutrients and the likelihood of developing CRC remains uncertain. The primary objective of the present study was to investigate the potential connection between dietary intake/dietary supplements and the occurrence of CRC through a literature review. Methods A comprehensive online search was conducted in PubMed, Scopus, Web of Science, and the Cochrane Library from January 1990 to March 2023 using appropriate keywords. A systematic search was conducted for clinical trials and cohort studies in order to determine the relationship between dietary components/supplements and CRC. Results The intake of long‐chain n‐3 polyunsaturated fatty acids (n‐3 LCPUFAs), consisting of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has the potential to decrease the likelihood of developing CRC (eight studies found positive effects and four studies found no association). Some other dietary components such as probiotics, prebiotics, and synbiotics may contribute to suppressing CRC development (three studies found positive effects, whereas three studies did not find any association). There is inconclusive evidence that supplementation with certain micronutrients including vitamin D (one trial found positive effects and another trial reported no association), folate, zinc, and selenium may reduce the risk of CRC. Conclusion Some dietary supplements such as n‐3 LCPUFAs and probiotics have the potential to reduce the risk of developing CRC. Further studies are necessary to validate these results and understand the underlying mechanisms.

Abstract As one of the most prevalent digestive system tumours, colorectal cancer (CRC) poses a significant threat to global human health. With the emergence of immunotherapy and target therapy, the prognosis for the majority of CRC patients has notably improved. However, the subset of patients with BRAF exon 15 p.V600E mutation (BRAFV600E) has not experienced remarkable benefits from these therapeutic advancements. Hence, researchers have undertaken foundational investigations into the molecular pathology of this specific subtype and clinical effectiveness of diverse therapeutic drug combinations. This review comprehensively summarised the distinctive molecular features and recent clinical research advancements in BRAF‐mutant CRC. To explore potential therapeutic targets, this article conducted a systematic review of ongoing clinical trials involving patients with BRAFV600E‐mutant CRC.