Colorectal cancer: Genetic alterations, novel biomarkers, current therapeutic strategies and clinical trials.

Colorectal cancer (CRC) is the third most commonly detected cancer with a serious global health issue. The rates for incidence and mortality for CRC are alarming, especially since the prognosis is abysmal when the CRC is diagnosed at an advanced or metastatic stage. Both type of (modifiable/ non-modifiable) types of risk factors are established for CRC. Despite the advances in recent technology and sophisticated research, the survival rate is still meager due to delays in diagnosis. Therefore, there is urgently required to identify critical biomarkers aiming at early diagnosis and improving effective therapeutic strategies. Additionally, a complete understanding of the dysregulated pathways like PI3K/Akt, Notch, and Wnt associated with CRC progression and metastasis is very beneficial in designing a therapeutic regimen. This review article focused on the dysregulated signaling pathways, genetics and epigenetics alterations, and crucial biomarkers of CRC. This review also provided the list of clinical trials targeting signaling cascades and therapies involving small molecules. This review discusses up-to-date information on novel diagnostic and therapeutic strategies alongside specific clinical trials.

Expression of CD44 is regulated by ELF3 in 5-FU treated colorectal cancer cells.

The development of chemoresistance in colorectal cancer (CRC) cells was usually thought to be inevitable as a result of continuing exposure to chemotherapeutic drugs. The existence of cancer stem cells (CSCs) within CRC tissues was recently suggested to play importance roles for this process. In this study, in order to mimic a dose schedule used in clinic (continuous infusion), low dose of fluorouracil (IC10 of 5-FU) was used to treat CRC cells. Our results showed that the expression of CD44, including some other CSCs markers were all increased after 5-FU treatment. The stemness properties of survived CRC cells were also observed to be enhanced. RNA-seq analysis revealed that ELF3, one of the members of ETS (E26 transformation-specific) transcription activator family, was increased along with CD44 after 5-FU treatment of CRC cells. Results from dual-luciferase reporter assay revealed that the transcription of CD44 could be activated by ELF3 in CRC cells. The induced CD44 expression in 5-FU treated CRC cells could also be decreased after the expression of ELF3 was inhibited. Moreover, it could be observed that the expression of ELF3 is significantly higher in CD44+ CRC cells. Taken together, our results suggested that CD44 expression might be regulated by ELF3 and could be induced after 5-FU treatment of CRC cells. Inhibition of ELF3 might be a promising treatment method when it was used in combination with chemotherapeutics to overcome chemoresistance formation during CRC treatment in clinic.

Unveiling the metal mutation nexus: Exploring the genomic impacts of heavy metal exposure in lung adenocarcinoma and colorectal cancer.

Mutations that activate oncogenes and deactivate tumor suppressor genes are widely recognized as significant contributors to cancer development. We investigated relationships between heavy metal exposure and the frequencies and types of gene mutations in patients with lung adenocarcinoma (LUAD) and colorectal cancer (CRC). Plasma concentrations of arsenic (As), cadmium (Cd), chromium (Cr), mercury (Hg), and lead (Pb) were measured using inductively coupled plasma mass spectrometry (ICPMS), and next-generation sequencing (NGS) of 1123 cancer-related genes was performed using the tumor tissues. Through Bayesian kernel machine regression (BKMR) analysis, we found associations between the integrated concentrations of the heavy metals and the number of gene mutations, especially insertions/deletions (indels), and Pb, As, and Cd were found to be the most significant contributors to the increased mutation rates. We extracted previously established mutational signatures and observed that they exhibit significant correlations with metal exposure. Moreover, we detected substantial shifts in the mutational landscape when comparing groups with high and low metal exposures. Several frequently mutated genes displayed positive correlations with metal exposure, whereas EGFR indels showed a negative association with Cd exposure. These findings suggest that heavy metal exposure can impact genomic stability in cancer-related genes, underscoring the importance of heavy metal exposure in cancer development.

A biospectroscopic approach toward colorectal cancer diagnosis from bodily fluid samples via ATR-MIR spectroscopy combined with multivariate data analysis.

In this study, a biospectroscopic approach was reported for the detection of spectral changes and biomarkers for the diagnosis of colorectal cancer (CC) cases from different bodily fluids (blood plasma, blood serum, saliva and colonoscopy disinfection/wash fluids) by using attenuated total reflection-mid infrared (ATR-MIR) spectroscopy. To recognize the molecular level changes in the spectral characteristics of CC and their healthy/control (CH) groups, different multivariate data analyses (HCA, LDA, PCA and SIMCA) were successfully performed over the data of ATR-MIR spectroscopy. Two hundred specimens were characterized in detail over the data of spectral regions (4000-650 cm-1 and regions V-XXII). The findings revealed that significant changes were clearly observed in the concentrations of lipid, protein, nucleic acid and carbohydrate biomolecules for cancer cases based upon their necessity to overcome energy requirements. Supervised multivariate data methodology SIMCA, presented an excellent classification for the studied groups; similarly 100% of the specimens from different bodily fluids were correctly classified by supervised methodology LDA. As a result, the developed ATR-MIR methodology for the classification of CC and their healthy groups highlighted a rapid cancer diagnosis approach from different bodily fluids; therefore, it could be guide to make well decision before histopathological assessment and to screen CC populations existing in society.

Gab2 promotes the growth of colorectal cancer by regulating the M2 polarization of tumor­associated macrophages.

Tumor­associated macrophages (TAMs) are pivotal components in colorectal cancer (CRC) progression, markedly influencing the tumor microenvironment through their polarization into the pro­inflammatory M1 or pro­tumorigenic M2 phenotypes. Recent studies have highlighted that the Grb2­associated binder 2 (Gab2) is a critical gene involved in the development of various types of tumor, including CRC. However, the precise role of Gab2 in mediating TAM polarization remains incompletely elucidated. In the present study, it was discovered that Gab2 was highly expressed within CRC tissue TAMs, and was associated with a poor prognosis of patients with CRC. Functionally, it was identified that the tumor­conditioned medium (TCM) induced Gab2 expression, facilitating the TAMs towards an M2­like phenotype polarization. Of note, the suppression of Gab2 expression using shRNA markedly inhibited the TCM­induced expression of M2­associated molecules, without affecting M1­type markers. Furthermore, the xenotransplantation model demonstrated that Gab2 deficiency in TAMs inhibited tumor growth in the mouse model of CRC. Mechanistically, Gab2 induced the M2 polarization of TAMs by regulating the AKT and ERK signaling pathways, promoting CRC growth and metastasis. In summary, the present study study elucidates that decreasing Gab2 expression hinders the transition of TAMs towards the M2 phenotype, thereby suppressing the growth of CRC. The exploration of the regulatory mechanisms of Gab2 in TAM polarization may enhance the current understanding of the core molecular pathways of CRC development and may thus provide a foundation for the development of novel immunotherapeutic strategies targeted against TAMs.

Collagen 1A1 (COL1A1) and Collagen11A1(COL11A1) as diagnostic biomarkers in Breast, colorectal and gastric cancers.

PURPOSE: Collagen family genes (CFGs) play a significant role in the pathogenesis of cancers. This study aimed to evaluate changes in the expression levels (Els) of CFGs related to epithelial-mesenchymal transition (EMT) and metastasis in gastric (GC), breast (BC), and colorectal (CRC) cancers to introduce these genes as potential diagnostic biomarkers for these three types of cancer. METHODS: The Cancer Genome Atlas (TCGA) examined ELS changes in CFGs associated with EMT and metastasis to determine their diagnostic value for GC, BC, and CRC. InteractiVenn was used to find genes shared by these three cancers. The biomarker role of CFGs was determined using the receiver operating characteristic (ROC) analysis. GC, BC, and CRC samples were analyzed using the RT-qPCR method to verify the bioinformatics results and evaluate the EL of the selected genes as biomarkers for these cancers. RESULTS: The in-silico results showed a significant increase in the EL of several CFGs involved in EMT and metastasis in GC, BC, and CRC samples compared to healthy samples. Six common genes (COL11A1, COL12A1, COL1A1, COL1A2, COL5A1, and COL5A2) showed significantly increased in these three cancers, therebysupporting their oncogenic role. Furthermore, the biomarker-related analyses indicated that COL11A1 and COL1A1 were common diagnostic biomarkers for the three cancers. The RT-qPCR method confirmed that the ELs of COL11A1 and COL1A1 in the GC, BC, and CRC samples increased significantly compared to the adjacent normal samples. CONCLUSION: CFGs in EMT and metastasis of GC, BC, and CRC are strong common diagnostic biomarkers for these cancers.

DNMT1-mediated NR3C1 DNA methylation enables transcription activation of connexin40 and augments angiogenesis during colorectal cancer progression.

Colorectal cancer (CRC) continues to be a major contributor to cancer-related mortality. Connexin 40 (CX40) is one of the major gap junction proteins with the capacity in regulating cell-to-cell communication and angiogenesis. This study investigates its role in angiogenesis in CRC and explores the regulatory mechanism. Aberrant high CX40 expression was detected in tumor tissues, which was associated with a poor prognosis in CRC patients. Elevated CX40 expression was detected in CRC cell lines as well. Conditioned medium of SW620 and HT29 cell lines was used to induce angiogenesis of human umbilical vein endothelial cells (HUVECs). CX40 knockdown in CRC cells reduced angiogenesis and mobility of HUVECs and blocked CRC cell proliferation, mobility, and survival. Following bioinformatics predictions, we validated by chromatin immunoprecipitation and luciferase assays that nuclear receptor subfamily 3 group C member 1 (NR3C1), which was poorly expressed in CRC samples, suppressed CX40 transcription. The poor NR3C1 expression was attributive to DNA hypermethylation induced by DNA methyltransferase 1 (DNMT1). Restoration of NR3C1 suppressed the pro-angiogenic effect, proliferation and survival, and tumorigenic activity of CRC cells, which were, however, rescued by CX40 upregulation. Collectively, this study demonstrates that transcription activation of CX40 upon DNMT1-mediated NR3C1 DNA methylation potentiates angiogenesis in CRC.

Macelignan prevents colorectal cancer metastasis by inhibiting M2 macrophage polarization.

BACKGROUND: Colorectal cancer (CRC) metastasis is a complicated process that not only involves tumor cells but also the effects of M2 type tumor-associated macrophages, a key component of the tumor microenvironment (TME), act a crucial role in cancer metastasis. Macelignan, an orally active lignan isolated from Myristica fragrans, possesses various beneficial biological activities, including anti-cancer effects, but its effect on macrophage polarization in the TME remains unknown. PURPOSE: To evaluate the inhibitory potency and prospective mechanism of macelignan on M2 polarization of macrophages and CRC metastasis. METHODS: The polarization and specific mechanism of M1 and M2 macrophage regulated by macelignan were determined by western blot, flow cytometry, immunofluorescence and network pharmacology. In vitro and in vivo function assays were performed to investigate the roles of macelignan in CRC metastasis. RESULTS: Macelignan efficiently inhibited IL-4/13-induced polarization of M2 macrophages by suppressing the PI3K/AKT pathway in a reactive oxygen species (ROS)-dependent manner. The proportion of CD206+ M2 macrophages was elevated in patients with CRC liver metastasis. Furthermore, macelignan inhibited M2 macrophage-mediated metastasis of CRC cells in vitro and in vivo. Mechanistically, macelignan reduced secretion of IL-1ß from M2 macrophages, which in turn blocked NF-κB p65 nuclear translocation and inhibited metastasis. CONCLUSION: Macelignan suppressed macrophage M2 polarization via ROS-mediated PI3K/AKT signaling pathway, thus preventing IL-1ß/NF-κB-dependent CRC metastasis. In the present study, we reveal a previously unrecognized mechanism of macelignan in the prevention of CRC metastasis and demonstrate its effectively and safely therapeutic potential in CRC treatment.

Association between serum urea concentrations and the risk of colorectal cancer, particularly in individuals with type 2 diabetes: A cohort study.

Dysregulation of the urea cycle (UC) has been detected in colorectal cancer (CRC). However, the impact of the UC's end product, urea, on CRC development remains unclear. We investigated the association between serum urea and CRC risk based on the data of 348 872 participants cancer-free at recruitment from the UK Biobank. Multivariable Cox proportional hazards models were fitted to conduct risk estimates. Stratification analyses based on sex, diet pattern, metabolic factors (including body mass index [BMI], the estimated glomerular filtration rate [eGFR] and type 2 diabetes [T2D]) and genetic profiles (the polygenic risk score [PRS] of CRC) were conducted to find potential modifiers. During an average of 9.0 years of follow-up, we identified 3408 (1.0%) CRC incident cases. Serum urea showed a nonlinear relationship with CRC risk (P-nonlinear: .035). Lower serum urea levels were associated with a higher CRC risk, with a fully-adjusted hazard ratio (HR) of 1.26 (95% confidence interval [CI]: 1.13-1.41) in the first quartile (Q1) of urea, compared to the Q4. This association was largely consistent across subgroups of sex, protein diet, BMI, eGFR and CRC-PRSs (P-interaction >.05); however, it was stronger in the T2D, with an interaction between urea and T2D on both additive (synergy index: 3.32, [95% CI: 1.24-8.88]) and multiplicative scales (P-interaction: .019). Lower serum urea concentrations were associated with an increased risk of CRC, with a more pronounced effect observed in individuals with T2D. Maintaining stable levels of serum urea has important implications for CRC prevention, particularly in individuals with T2D.

Small-molecule drugs of colorectal cancer: Current status and future directions.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the world's fourth most deadly cancer. CRC, as a genetic susceptible disease, faces significant challenges in optimizing prognosis through optimal drug treatment modalities. In recent decades, the development of innovative small-molecule drugs is expected to provide targeted interventions that accurately address the different molecular characteristics of CRC. Although the clinical application of single-target drugs is limited by the heterogeneity and high metastasis of CRC, novel small-molecule drug treatment strategies such as dual/multiple-target drugs, drug repurposing, and combination therapies can help overcome these challenges and provide new insights for improving CRC treatment. In this review, we focus on the current status of a range of small molecule drugs that are being considered for CRC therapy, including single-target drugs, dual/multiple-target drugs, drug repurposing and combination strategies, which will pave the way for targeting CRC vulnerabilities with small-molecule drugs in future personalized treatment.

Generalizability of COBRA: A Parsimonious Perioperative Venous Thromboembolism Risk Assessment Model.

INTRODUCTION: Standardized use of venous thromboembolism (VTE) risk assessment models (RAMs) in surgical patients has been limited, in part due to the cumbersome workflow addition required to use available models. The COBRA score-capturing cancer diagnosis, (old) age, body mass index, race, and American Society of Anesthesiologists Physical Status score-has been reported as a potentially automatable VTE RAM that circumvents the cumbersome workflow addition that most RAMs represent. We aimed to test the ability of the COBRA model to effectively risk-stratify patients across various populations. METHODS: Patients were included from the 2014-2019 American College of Surgeons National Surgical Quality Improvement Program (NSQIP) Participant Use Data File for two hospitals, representing colorectal, endocrine, breast, transplant, plastic, and general surgery services. COBRA score was calculated for each patient using preoperative characteristics. We calculated negative predictive value (NPV) for VTE outcomes and compared the COBRA score to NSQIP's expected VTE rate for all patients, between the two hospitals, and between subspecialty service lines. RESULTS: Of the 10,711 patients included, those with COBRA <4 (31%) had projected median VTE rate of 0.21% (interquartile range, 0.09-0.68%; mean, 0.54%). Patients with higher scores (69%) had median rate of 0.88% (0.26-2.07%; 1.46%); relative rate 2.7. The median projected VTE rates for patients identified as low risk were 0.21% and 0.16% and as high risk were 0.87% and 0.89% at hospitals one and 2, respectively. The median projected VTE rates for patients identified as low risk were 0.17%, 0.61%, and 0.08% and as high risk were 0.52%, 1.43%, and 0.18% among general, colorectal, and endocrine surgery patients, respectively. COBRA had NPV of 0.995 and sensitivity of 0.871 as compared to NPV 0.997 and sensitivity 0.857 of the NSQIP model. CONCLUSIONS: The COBRA score is concordant with the traditional gold standard NSQIP VTE RAM and demonstrates interhospital and service-specific generalizability, although performance was limited in especially low-risk patients. The model adequately risk-stratifies surgical patients preoperatively, potentially providing clinical decision support for perioperative workflows.

Outcomes of Colectomy in United States Veterans With Cirrhosis: Predicting Outcomes Using Nomogram.

INTRODUCTION: With growing incidence of liver cirrhosis worldwide, there is more need for a risk assessment tool to aid in perioperative management of cirrhotic patients undergoing colorectal procedures. We aim to assess the association of open (OC) versus laparoscopic (LC) approach with colorectal procedures' outcomes and develop an easy-to-use nomogram to predict outcomes. METHODS: We analyzed the Veterans Affairs Surgical Quality Improvement Program to identify all patients with cirrhosis and ascites who underwent colorectal procedures from 2008 to 2015. Model for End-stage Liver Disease score was calculated as well as five-items modified frailty index. The chi-square test was utilized to analyze categorical variables. Two-sided unpaired Student's t-test or Mann-Whitney U-test were used for numerical variables as appropriate. Multivariate logistic regression adjusting for demographics, comorbidities, and other preoperative factors was used to analyze postoperative outcomes. A predictive nomogram was constructed and internally validated. RESULTS: A total of 731 patients were identified. Overall, complications occurred in 48.2% of patients, and 30-d mortality was 24.8%, with 57.5% were performed emergently. Malignant neoplasm was the most common indication (25.4%). LC was performed in 22.4%, with shorter operative time, less blood transfusions, shorter length of stay, and lower morbidity compared to OC. Overall, Model for End-stage Liver Disease score was an independent factor of mortality, while laparoscopic approach had a protective effect on morbidity. An easy-to-use nomogram was generated for morbidity and 30-d mortality with calculated area under cure of 74.5% and 77.9%, respectively, indicating reliability. CONCLUSIONS: Although colectomy is a high-risk operation in cirrhotic veterans, LC may have favorable outcomes than OC in selected patients. An easy-to-use nomogram to predict morbidity and mortality for cirrhotic patients undergoing colectomy is proposed.

Timosaponin AIII induces lipid peroxidation and ferroptosis by enhancing Rab7-mediated lipophagy in colorectal cancer cells.

BACKGROUND: Colorectal cancer (CRC) is a common digestive system malignancy, and despite significant therapeutic advancements, more effective treatments are needed. Timosaponin AIII (TA-III), a major steroidal saponin derived from Anemarrhena asphodeloides Bge, is a potential anticancer agent. Ferroptosis plays an important role in cancer treatment. PURPOSE: To investigate the molecular mechanism of TA-III as a novel ferroptosis inducer in suppressing CRC through lipophagy. Ferroptosis, an autophagy-dependent mode of cell death, has been implicated in CRC. METHODS: CRC cells were treated with TA-III, and lipophagy levels were evaluated via BODIPY493/503 staining and western blotting. Autophagy turnover was tracked using GFP-RFP-LC3B. Lipid peroxidation was quantified using an malondialdehyde kit and C11-BODIPY flow assay. Mitochondrial morphology was observed using transmission electron microscopy. GC-MS/MS was used to detect lipid metabolism changes. The role of ras related protein Rab 7a (Rab7) was assessed by western blotting and glutathione S-transferase pull-down assays. In vivo, the anticancer efficacy of TA-III was tested using a xenograft model. RESULTS: RNA-seq analysis unveiled the potential of TA-III as an anticancer agent through ferroptosis. In vivo experiments revealed how TA-III treatment triggered degradation of lipid droplets in CRC cells, resulting in an accumulation of FFAs, heightened unsaturated free fatty acids, and increased lipid peroxidation. These events ultimately lead to mitochondrial shrinkage and downregulation of ferroptosis markers (FSP1 and GPX4). Intriguingly, the Rab7 protein emerged as a crucial bridge between lipophagy and ferroptosis, underlining its significance in the anticancer mechanism of TA-III. Moreover, TA-III treatment in a xenograft tumour model substantially reduced tumour volume via ferroptosis, underscoring its therapeutic efficacy. CONLUSION: Our study is the first to establish that TA-III triggers lipophagy in CRC cells via the Rab7 gene, subsequently promoting ferroptosis. This suggests its potential use as an antitumour agent.

Liver Transplantation for Colorectal Liver Metastases.

Colorectal cancer is one of the most common malignancies worldwide. Approximately half of the patients diagnosed will develop colorectal liver metastases (CRLM). Liver resection has a 50% 5-year survival; however, only a fourth of cases are resectable. Unresectable CRLM has poor prognosis despite improved systemic and local ablative treatments. Liver transplantation (LT) has demonstrated a survival benefit in initial prospective clinical trials. Current use of LT for CRLM is limited to several randomized trials and high-performing centers. Improving patient selection criteria and perioperative management, LT will likely become an important part of the multidisciplinary approach to managing the metastatic disease.

Jianpi Huayu Decoction suppresses cellular senescence in colorectal cancer via p53-p21-Rb pathway: Network pharmacology and in vivo validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Jianpi Huayu Decoction (JHD) is an herbal prescription in traditional Chinese medicine based on Sijunzi Decoction to treat patients with colorectal cancer (CRC). Its effects on the inhibition of CRC cell proliferation and tumor growth are promising; however, its multicomponent nature makes a complete understanding of its mechanism challenging. AIM OF THE STUDY: To explore the therapeutic targets and underlying molecular pathways of JHD in CRC treatment using network pharmacology techniques and in vivo validation. MATERIALS AND METHODS: The active ingredients and targets of JHD were identified, compound-target interactions were mapped, and enrichment analyses were conducted. We identified the hub targets of JHD-induced cellular senescence in CRC. The binding affinities between compounds and targets were evaluated through molecular docking. Subsequently, we conducted bioinformatic analyses to compare the expression of hub targets between colorectal tissue and normal tissue. Finally, in vivo experiments were carried out utilizing a xenograft model to assess the effects of JHD on cellular senescence biomarkers. RESULTS: Network pharmacology revealed 129 active ingredients in JHD that were associated with 678 targets, leading to the construction of compound-target and target-pathway networks. Enrichment analyses highlighted key pathways including cellular senescence. Based on this, hub targets associated with cellular senescence were determined and validated. Molecular docking indicated favorable interactions between the active components and hub targets. Gene expression and survival analysis in CRC tissue were consistent with the potential roles of hub genes. Animal experiments showed that JHD triggered cellular senescence and suppressed the growth of CRC by regulating the p53-p21-Rb signaling pathway. CONCLUSIONS: This research adopted network pharmacology, bioinformatics, and animal experiments to unveil that JHD induces cellular senescence in CRC by influencing the p53-p21-Rb pathway and senescence-associated secretory phenotypes, highlighting its potential as a CRC treatment.

Tong-Xie-Yao-Fang promotes dendritic cells maturation and retards tumor growth in colorectal cancer mice with chronic restraint stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Depression is one of the important risk factors that accelerate the progression of colorectal cancer (CRC). Tong-Xie-Yao-Fang (TXYF) is a widely used classical formula for treating psychiatric-related intestinal diseases in traditional Chinese medicine, that is composed of four different herbs: Atractylodes macrocephala Koidz. (Baizhu), Paeonia lactiflora Pall. (Baishaoyao), Citrus reticulata Blanco (Chenpi), Saposhnikovia divaricata (Turcz.) Schischk (Fangfeng). TXYF has over a hundred years of history and can significantly improve depression and reduce intestinal symptoms. However, the intervention effect and mechanism of TXYF on colorectal cancer accompanied by psychological stress are not still clear. AIM OF STUDY: This study investigated the therapeutic effect of TXYF on CRC mice with chronic restraint stress (CRS) and to explore its mechanism. MATERIALS AND METHODS: We constructed a mouse model of chronic stress by CRS and subcutaneous injection of CT26-Luc cells, and administered TXYF by gavage. We measured the body weight, tumor size, and tumor weight of each group of mice. The tumor growth was monitored dynamically of by vivo bioluminescence analysis. The depressive state of each group of mice were evaluated by tail suspension test, forced swimming test, and hormone level changes. We used flow cytometry to detect the ratio of CD4+ T cells, CD8+ T cells, Th1 cells, Th2 cells, and dendritic cells (DCs) phenotype (MHC II, CD80, and CD86) and chemotaxis ability (CXCR4 and CCR7) of in peripheral blood and tumor tissue. the levels of IL-12, IL-18, Th1 cytokines, and Th2 cytokines in the serum of each group of mice were determined by ELISA. RESULTS: TXYF can improve the body weight of CRC mice with CRS, inhibit tumor volume and weight, alleviate depressive state, upregulate 5-HT levels, and inhibit HPA axis hormone secretion. The results of flow cytometry showed that TXYF can promote the maturation of DCs phenotype and function, enhance antigen presentation ability, increase the ratio of CD4+ T cells and CD4+/CD8+ T cells, and shift Th1/Th2 balance towards Th1 cells, thus increasing serum levels of IFN-γ, IL-18, IL-2, and IL-12, while decreasing serum levels of IL-4 and IL-10, and effectively triggering T cell-mediated immune response. CONCLUSIONS: This study shows that TXYF inhibits the growth of tumors in CRC mice with CRS by stimulating immune response. The mechanism may be inhibiting the HPA axis and promoting DCs maturation, thus activating T cells and enhancing anti-tumor immune response, ultimately preventing the progression of CRC.

Circulating white blood cell traits and colorectal cancer risk: A Mendelian randomisation study.

Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, 95% CI: 0.78-0.99, P = .04; OR: 0.93, 95% CI: 0.88-0.98, P = .01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, 95% CI: 0.80-0.97, P = .01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76-0.93, P = 6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, 95% CI: 0.93-0.99, P = .02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93-0.99, P = .001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.

Prolyl hydroxylase 2 inhibits glycolytic activity in colorectal cancer via the NF­κB signaling pathway.

A variety of malignancies preferentially meet energy demands through the glycolytic pathway. Hypoxia­induced cancer cell adaptations are essential for tumor development. However, in cancerous glycolysis, the functional importance and underlying molecular mechanism of prolyl hydroxylase domain protein 2 (PHD2) have not been fully elucidated. Gain­ and loss­of­function assays were conducted to evaluate PHD2 functions in colon cancer cells. Glucose uptake, lactate production and intracellular adenosine­5'­triphosphate/adenosine diphosphate ratio were measured to determine glycolytic activities. Protein and gene expression levels were measured by western blot analysis and reverse transcription­quantitative PCR, respectively. The human colon cancer xenograft model was used to confirm the role of PHD2 in tumor progression in vivo. Functionally, the data demonstrated that PHD2 knockdown leads to increased glycolysis, while PHD2 overexpression resulted in suppressed glycolysis in colorectal cancer cells. In addition, the glycolytic activity was enhanced without PHD2 and normalized after PHD2 reconstitution. PHD2 was shown to inhibit colorectal tumor growth, suppress cancer cell proliferation and improve tumor­bearing mice survival in vivo. Mechanically, it was found that PHD2 inhibits the expression of critical glycolytic enzymes (glucose transporter 1, hexokinase 2 and phosphoinositide­dependent protein kinase 1). In addition, PHD2 inhibited Ikkß­mediated NF­κB activation in a hypoxia­inducible factor­1α­independent manner. In conclusion, the data demonstrated that PHD2/Ikkß/NF­κB signaling has critical roles in regulating glycolysis and suggests that PHD2 potentially suppresses colorectal cancer.

Health-economic valuation of lowering nitrate standards in drinking water related to colorectal cancer in Denmark.

Nitrate in drinking water is a contaminant which can affect human health and has been associated with an increased risk of, amongst other diseases, colorectal cancer. Based on epidemiologic data from Denmark on the association between drinking water nitrate and colorectal cancer, the health and economic consequences of lowering the standard of nitrate in drinking water from 50 mg/L to 9.25 mg/L and 3.87 mg/L, respectively are analyzed. The drinking water nitrate attributable number of cases was estimated using the risk in the exposed and unexposed population based on current nationwide exposure distributions. The analysis shows that a lower limit of 9.25 mg/L would decrease the annual number of colorectal cancer cases by 72 (95 % confidence interval: 34-114) and by an additional 55 (95 % CI: 10-100) for a stricter limit of 3.87 mg/L. The resulting avoided health-related costs are $179 million per year for the 9.25 mg/L nitrate limit and another $138 million per year for a further reduction to 3.87 mg/L nitrate. The new requirements would incur costs linked to either i) changes in land use management, ii) well reallocation or iii) use of treatment technologies. The additional costs are estimated to $0.03-1.84 per m3 abstracted water from public water companies, which together with costs for owners of private wells, will result in an average additional cost of $9 and $6 million per year for the two levels. The economic health benefits are higher than the costs for both limits with net gains of $170 million (9.25 mg/L) and additionally $132 million (3.87 mg/L) a year. Even in a worst-case scenario (lowest health-related benefits and highest mitigation costs), there is a likely economic gain for society from lowering the limit to 9.25 mg/L, but this might not be the case for the lower limit of 3.87 mg/L.