Extracellular vesicles associated microRNAs: Their biology and clinical significance as biomarkers in gastrointestinal cancers.

Gastrointestinal (GI) cancers, including colorectal, gastric, esophageal, pancreatic, and liver, are associated with high mortality and morbidity rates worldwide. One of the underlying reasons for the poor survival outcomes in patients with these malignancies is late disease detection, typically when the tumor has already advanced and potentially spread to distant organs. Increasing evidence indicates that earlier detection of these cancers is associated with improved survival outcomes and, in some cases, allows curative treatments. Consequently, there is a growing interest in the development of molecular biomarkers that offer promise for screening, diagnosis, treatment selection, response assessment, and predicting the prognosis of these cancers. Extracellular vesicles (EVs) are membranous vesicles released from cells containing a repertoire of biological molecules, including nucleic acids, proteins, lipids, and carbohydrates. MicroRNAs (miRNAs) are the most extensively studied non-coding RNAs, and the deregulation of miRNA levels is a feature of cancer cells. EVs miRNAs can serve as messengers for facilitating interactions between tumor cells and the cellular milieu, including immune cells, endothelial cells, and other tumor cells. Furthermore, recent years have witnessed considerable technological advances that have permitted in-depth sequence profiling of these small non-coding RNAs within EVs for their development as promising cancer biomarkers -particularly non-invasive, liquid biopsy markers in various cancers, including GI cancers. Herein, we summarize and discuss the roles of EV-associated miRNAs as they play a seminal role in GI cancer progression, as well as their promising translational and clinical potential as cancer biomarkers as we usher into the area of precision oncology.

Emerging Trends in Gastrointestinal Cancer Targeted Therapies: Harnessing Tumor Microenvironment, Immune Factors, and Metabolomics Insights.

Gastrointestinal (GI) cancers are the leading cause of new cancer cases and cancer-related deaths worldwide. The treatment strategies for patients with GI tumors have focused on oncogenic molecular profiles associated with tumor cells. Recent evidence has demonstrated that the tumor cell functions are modulated by its microenvironment, compromising fibroblasts, extracellular matrices, microbiome, immune cells, and the enteric nervous system. Along with the tumor microenvironment components, alterations in key metabolic pathways have emerged as a hallmark of tumor cells. From these perspectives, this review will highlight the functions of different cellular components of the GI tumor microenvironment and their implications for treatment. Furthermore, we discuss the major metabolic reprogramming in GI tumor cells and how understanding metabolic rewiring could lead to new therapeutic strategies. Finally, we briefly summarize the targeted agents currently being studied in GI cancers. Understanding the complex interplay between tumor cell-intrinsic and -extrinsic factors during tumor progression is critical for developing new therapeutic strategies.

A phase 1 study of biweekly nab-paclitaxel/oxaliplatin/S-1/LV for advanced upper gastrointestinal cancers: TCOG T1216 study.

BACKGROUND: Oxaliplatin- and fluoropyrimidine-based triplet regimens have demonstrated feasibility and efficacy in the treatment of upper gastrointestinal (UGI) cancers. Herein, we evaluate the feasibility and preliminary efficacy of biweekly nab-paclitaxel plus oxaliplatin and S-1/leucovorin (SOLAR) in chemonaïve UGI cancers. METHODS: A 3 + 3 phase 1 study was conducted to determine the maximal tolerated dose (MTD) of oxaliplatin in SOLAR (nab-paclitaxel [150 mg/m2 in D1], oxaliplatin [60, 75, or 85 mg/m2 in D1], and oral S-1/leucovorin [35 mg/m2 and 30 mg bid from D1 to D7]). The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Thirteen and 6 accruals were in the dose-escalation and MTD expansion cohorts, respectively. One of 6 patients at level III experienced dose-limiting toxicity (grade 3 diarrhea), which revealed that the MTD of oxaliplatin was 85 mg/m2. After a mean of 15.9 cycles of treatment, the most common treatment-related grade 3/4 toxicities were neutropenia (57.9%) and diarrhea (21.1%). The ORR was 63.2%. The median PFS and OS were 12.5 and 24.7 months, respectively. CONCLUSION: The current study revealed the MTD of oxaliplatin and demonstrated the preliminary efficacy of SOLAR in UGI cancers, which deserves further investigation. CLINICALTRIALS.GOV IDENTIFIER: NCT03162510.

Racial disparities in colorectal cancer clinicopathological and molecular tumor characteristics: a systematic review.

PURPOSE: African Americans have the highest colorectal cancer (CRC) mortality of all racial groups in the USA, which may relate to differences in healthcare access or advanced stage at diagnosis. Recent evidence indicates that differences in tumor characteristics may also underlie disparities in mortality. To highlight recent findings and areas for investigation, we completed the first systematic review of racial disparities in CRC tumor prognostic markers, including clinicopathological markers, microsatellite instability (MSI), oncogene mutations, and novel markers, including cancer stem cells and immune markers. METHODS: Relevant studies were identified via PubMed, limited to original research published within the last 10 years. Ninety-six articles were identified that compared the prevalence of mortality-related CRC tumor characteristics in African Americans (or other African ancestry populations) to White cases. RESULTS: Tumors from African ancestry cases are approximately 10% more likely to contain mutations in KRAS, which confer elevated mortality and resistance to epidermal growth factor receptor inhibition. Conversely, African Americans have approximately 50% lower odds for BRAF-mutant tumors, which occur less frequently but have similar effects on mortality and therapeutic resistance. There is less consistent evidence supporting disparities in mutations for other oncogenes, including PIK3CA, TP53, APC, NRAS, HER2, and PTEN, although higher rates of PIK3CA mutations and lower prevalence of MSI status for African ancestry cases are supported by recent evidence. Although emerging evidence suggests that immune markers reflecting anti-tumor immunity in the tumor microenvironment may be lower for African American cases, there is insufficient evidence to evaluate disparities in other novel markers, cancer stem cells, microRNAs, and the consensus molecular subtypes. CONCLUSION: Higher rates of KRAS-mutant tumors in in African Americans may contribute to disparities in CRC mortality. Additional work is required to understand whether emerging markers, including immune cells, underlie the elevated CRC mortality observed for African Americans.

Chronic atrophic gastritis and risk of incident upper gastrointestinal cancers: a systematic review and meta-analysis.

BACKGROUND: Previous literature has explored the relationship between chronic atrophic gastritis (CAG) and isolated cancers within the upper gastrointestinal cancers; However, an integrative synthesis across the totality of upper gastrointestinal cancers was conspicuously absent. The research objective was to assess the relationship between CAG and the risk of incident upper gastrointestinal cancers, specifically including gastric cancer, oesophageal cancer, and oesophagogastric junction cancer. METHODS: Rigorous systematic searches were conducted across three major databases, namely PubMed, Embase and Web of Science, encompassing the timeline from database inception until August 10, 2023. We extracted the necessary odds ratio (OR) and their corresponding 95% confidence interval (CI) for subsequent meta-analysis. Statistical analyses were conducted using Stata 17.0 software. RESULTS: This meta-analysis included a total of 23 articles encompassing 5858 patients diagnosed with upper gastrointestinal cancers. CAG resulted in a statistically significant 4.12-fold elevated risk of incident gastric cancer (OR = 4.12, 95% CI 3.20-5.30). Likewise, CAG was linked to a 2.08-fold increased risk of incident oesophageal cancer (OR = 2.08, 95%CI 1.60-2.72). Intriguingly, a specific correlation was found between CAG and the risk of incident oesophageal squamous cell carcinoma (OR = 2.29, 95%CI 1.77-2.95), while no significant association was detected for oesophageal adenocarcinoma (OR = 0.62, 95%CI 0.17-2.26). Moreover, CAG was correlated with a 2.77-fold heightened risk of oesophagogastric junction cancer (OR = 2.77, 95%CI 2.21-3.46). Notably, for the same type of upper gastrointestinal cancer, it was observed that diagnosing CAG through histological methods was linked to a 33-77% higher risk of developing cancer compared to diagnosing CAG through serological methods. CONCLUSION: This meta-analysis indicated a two- to fourfold increased risk of gastric cancer, oesophageal cancer, and oesophagogastric junction cancer in patients with CAG. Importantly, for the same upper gastrointestinal cancer, the risk of incident cancer was higher when CAG was diagnosed histologically compared to serological diagnosis. Further rigorous study designs are required to explore the impact of CAG diagnosed through both diagnostic methods on the risk of upper gastrointestinal cancers.

Gastrointestinal cancers in lean individuals with non-alcoholic fatty liver disease: A systematic review and meta-analysis.

BACKGROUND & AIMS: Obesity and non-alcoholic fatty liver disease (NAFLD) are known risk factors for gastrointestinal (GI) cancers. However, GI carcinogenesis in lean NAFLD patients remains unclear. This systematic review and meta-analysis aims to investigate the association between lean NAFLD and GI cancer risk. METHODS: PubMed, Embase and Cochrane Library databases were systematically searched (from inception date to April 2023) for cohort studies assessing GI cancers in lean (body mass index [BMI] < 25 kg/m2 or < 23 kg/m2 in Asians) and non-lean (BMI ≥25 kg/m2 or ≥ 23 kg/m2 in Asians) NAFLD individuals. Data from eligible studies were extracted, and meta-analysis was carried out using a random effects model to obtain risk ratios (RRs) with 95% confidence intervals (CIs). Subgroup analyses, meta-regressions and sensitivity analyses were also performed. This study was registered in PROSPERO (CRD42023420902). RESULTS: Eight studies with 56,745 NAFLD individuals (11% were lean) and 704 cases of incident GI cancers were included. Lean NAFLD was associated with higher risk of hepatic (RR 1.77, 95% CI 1.15-2.73), pancreatic (RR 1.97, 95% CI 1.01-3.86) and colorectal cancers (RR 1.53, 95% CI 1.12-2.09), compared to non-lean NAFLD. No significant differences were observed for oesophagus, gastric, biliary and small intestine cancers. CONCLUSIONS: This study shows that lean NAFLD patients have an increased risk of liver, pancreatic and colorectal cancers compared to non-lean NAFLD patients, emphasizing the need to explore tailored cancer prevention strategies for this specific patient group. Further research is required to explore the mechanisms underlying the association between lean NAFLD and specific GI cancers.

Advancing gastrointestinal cancer diagnostics: a systematic review and meta-analysis of circulating microRNA-1246 as a non-invasive biomarker.

BACKGROUND: Despite numerous reports on the alterations of microRNA-1246 (miR-1246) expression level in digestive system cancers, its role in gastrointestinal cancers (GICs) remains unclear. This meta-analysis aimed to assess the diagnostic potential of circulating miR-1246 in GICs. METHODS: Meta-disc version 1.4 and Comprehensive Meta-Analysis (CMA) version 3.7 software were used to calculate pooled sensitivity, specificity, likelihood ratios, diagnostic odds ratio (DOR), area under the curve (AUC), Q*index and summary receiver-operating characteristic (SROC). Subgroup analyses were conducted for cancer type, sample type and geographical region. Publication bias was assessed using Begg's and Egger's tests. RESULTS: A total of 14 articles involving 18 studies and 1526 participants (972 cases and 554 controls) were included. The diagnostic accuracy of miRNA-1246 in GICs was as follows: pooled sensitivity: 0.81 (95% CI: 0.79 - 0.83), specificity: 0.74 (95% CI: 0.71 - 0.77), PLR: 3.315 (95% CI: 2.33 - 4.72), NLR: 0.221 (95% CI: 0.153 - 0.319), DOR: 16.87 (95% CI: 9.45 - 30.09), AUC: 0.891, and Q*-index: 0.807. No publication bias was found based on Begg's (p = 0.172) and Egger's (p = 0.113) tests. CONCLUSION: Circulating miR-1246 shows promise as a non-invasive biomarker for early detection of GICs.

Investigating the mortality trend of gastrointestinal cancers in Babol, North Iran (2013-2021).

BACKGROUND AND AIM: This study aims to examine the mortality rate and trend of gastrointestinal cancers, particularly gastric cancer, as the leading cause of death among cancers in northern Iran over a 9-year period. In light of the changing incidence and mortality rates of cancer in Iran and around the world, the importance of these diseases in people's lives, and the necessity of updating and monitoring the trend of cancer mortality, we have decided to report on the mortality trend of gastrointestinal cancers, based on crude and age-standardized rates. METHOD: This study is a cross-sectional examination of deaths caused by gastrointestinal cancers in Babol city, Iran, between 2013 and 2021. Data was collected from the cause of death registration and classification system of Babol University of Medical Sciences. Population estimation was obtained from the latest census reports. The crude and age-standardized mortality rates and trends of the cancers were calculated. RESULTS: Overall, there were 1345 deaths from gastrointestinal cancers with an average age of 69.11 ± 14.25 years. The crude and age-standardized rates of these cancers rose from 24.1 to 20.1 per hundred thousand people in 2012 to 29.5 and 25.5 per hundred thousand people, respectively. This trend became more prevalent significantly with the increase of each decade of age for both men (P-value Trend = 0.002) and women (P-value Trend = 0.012). An analysis of gastrointestinal cancers revealed a decreasing trend for cancers of the small intestine, an increasing trend for cancers of the colon, pancreas, and gallbladder, and a stable trend for the remaining cancers over the study period. CONCLUSION: The age-standardized rate and the number of gastrointestinal cancers is rising, highlighting the importance of preventative measures such as screening, increasing public awareness, and appropriate diagnostic methods.

Metabolic syndrome, its components, and gastrointestinal cancer risk: a meta-analysis of 31 prospective cohorts and Mendelian randomization study.

BACKGROUND AND AIM: Cohort studies have linked metabolic syndrome (MetS) to gastrointestinal (GI) cancer risk. We aimed to evaluate the associations between MetS, its components, and combinations of MetS components with eight GI cancers risk. METHODS: We conducted a systematic search of prospective cohort studies and performed a meta-analysis. Subgroup analyses regarding diagnostic criteria, sex, cancer sites, histological subtypes, ethnic groups, and studies adjusted for alcohol consumption were carried out. Mendelian randomization (MR) was employed to evaluate the causality between 17 MetS-related traits and eight GI cancers among Europeans and Asians separately. RESULTS: Meta-analyses of 31 prospective studies indicated that MetS was significantly associated with an increased risk of colorectal cancer (CRC) (RR [95% CI] = 1.13 [1.12-1.15]), esophageal cancer (EC) (RR [95% CI] = 1.17 [1.03-1.32]), gallbladder cancer (GBC) (RR [95% CI] = 1.37[1.10-1.71]), liver cancer (LC) (RR [95% CI] = 1.46 [1.29-1.64]), and pancreatic cancer (PaC) (RR [95% CI] = 1.25 [1.20-1.30]), but not gastric cancer (GC) (RR [95% CI] = 1.11 [0.96-1.28]). Regarding the associations between MetS components and GI cancers risk, the following associations showed statistical significance: obesity-CRC/LC/EC/, hypertriglyceridemia-LC/PaC, reduced high-density lipoprotein (HDL)-CRC/LC/GC/PaC, hyperglycemia-CRC/LC/PaC, and hypertension-CRC/LC/EC/PaC. Sex-specific associations were observed between individual MetS components on GI cancers risk. Among the top three common combinations in both sexes, obesity + HTN + hyperglycemia had the strongest association with CRC risk (RR [95% CI] = 1.54 [1.49-1.61] for males and 1.27 [1.21-1.33] for females). MR analyses revealed causality in 16 exposure-outcome pairs: waist-to-hip ratio/BMI/HbA1c-CRC; BMI/childhood obesity/waist circumference/T2DM/glucose-EC; BMI/waist circumference/cholesterol-LC; cholesterol/childhood obesity/waist circumference/HbA1c-PaC; and HbA1c-GBC. These results were robust against sensitivity analyses. CONCLUSIONS: Since MetS is reversible, lifestyle changes or medical interventions targeting MetS patients might be potential prevention strategies for GI cancers.

Working title: Molecular involvement of p53-MDM2 interactome in gastrointestinal cancers.

The interaction between murine double minute 2 (MDM2) and p53, marked by transcriptional induction and feedback inhibition, orchestrates a functional loop dictating cellular fate. The functional loop comprising p53-MDM2 axis is made up of an interactome consisting of approximately 81 proteins, which are spatio-temporally regulated and involved in DNA repair mechanisms. Biochemical and genetic alterations of the interactome result in dysregulation of the p53-mdm2 axis that leads to gastrointestinal (GI) cancers. A large subset of interactome is well known and it consists of proteins that either stabilize p53 or MDM2 and proteins that target the p53-MDM2 complex for ubiquitin-mediated destruction. Upstream signaling events brought about by growth factors and chemical messengers invoke a wide variety of posttranslational modifications in p53-MDM2 axis. Biochemical changes in the transactivation domain of p53 impact the energy landscape, induce conformational switching, alter interaction potential and could change solubility of p53 to redefine its co-localization, translocation and activity. A diverse set of chemical compounds mimic physiological effectors and simulate biochemical modifications of the p53-MDM2 interactome. p53-MDM2 interactome plays a crucial role in DNA damage and repair process. Genetic aberrations in the interactome, have resulted in cancers of GI tract (pancreas, liver, colorectal, gastric, biliary, and esophageal). We present in this article a review of the overall changes in the p53-MDM2 interactors and the effectors that form an epicenter for the development of next-generation molecules for understanding and targeting GI cancers.

Targeted ferritinophagy in gastrointestinal cancer: from molecular mechanisms to implications.

Gastrointestinal cancer is a significant global health burden, necessitating the development of novel therapeutic strategies. Emerging evidence has highlighted the potential of targeting ferritinophagy as a promising approach for the treatment of gastrointestinal cancer. Ferritinophagy is a form of selective autophagy that is mediated by the nuclear receptor coactivator 4 (NCOA4). This process plays a crucial role in regulating cellular iron homeostasis and has been implicated in various pathological conditions, including cancer. This review discusses the molecular mechanisms underlying ferritinophagy and its relevance to gastrointestinal cancer. Furthermore, we highlight the potential therapeutic implications of targeting ferritinophagy in gastrointestinal cancer. Several approaches have been proposed to modulate ferritinophagy, including small molecule inhibitors and immunotherapeutic strategies. We discuss the advantages and challenges associated with these therapeutic interventions and provide insights into their potential clinical applications.

Occupational exposure to silica and risk of gastrointestinal cancers: a systematic review and meta-analysis of cohort studies.

BACKGROUND: Although silica is a proven lung carcinogen, there is no convincing evidence linking crystalline silica to gastrointestinal malignancies. METHODS: We detailedly searched studies on the link between gastrointestinal malignancies and occupational silica exposure. Studies published between 1987 and 2023 were found by searching PubMed, Scopus, Cochrane Library, and Web of Science databases. Further studies were included from reference searching. We conducted a meta-analysis of the incidence and mortality of gastrointestinal malignancies and occupational silica exposure. We computed pooled-risk estimates using random effects models. Egger's regression asymmetry test and a funnel plot were used to identify publication bias. Moreover, sensitivity analysis and subgroup analysis were out. RESULTS: We identified 40 research with individuals from 13 different countries. The results indicate that occupational silica exposure raises the risk of gastric and esophageal cancer incidence, with pooled standardized incidence ratio of 1.35 (95% CI 1.21-1.51, p < 0.001), 1.31 (95% CI 1.04-1.65, p = 0.023), respectively, but there was a lack of statistically significant relationship between standardized mortality ratio. In addition, we found that silica exposure did not increase the risk of colorectal and pancreatic cancers. Occupational silica exposure was found to increase the risk of liver cancer, with pooled SIR and SMR of 1.19 (95% CI 1.04-1.35, p = 0.009), 1.24 (95% CI 1.03-1.49, p = 0.026), respectively. CONCLUSIONS: We discovered a link between occupational silica exposure and gastrointestinal malignancies, with cancers of the liver, stomach, and esophagus being the most prevalent. Colorectal and pancreatic cancer were not linked to occupational silica exposure.

Two-sample Mendelian randomization analysis of the relationship between periodontitis and risk of upper gastrointestinal cancers.

PURPOSE: The aim of the present study is to explore the possible association between periodontitis and upper gastrointestinal (UGI) cancers, including esophageal and gastric cancers, utilizing the Mendelian randomization method. METHODS: In this research, we utilized the Mendelian randomization method to examine the causal association between periodontitis and UGI cancers. Genome-wide association studies data for periodontitis were obtained from the Gene-Lifestyle Interactions in Dental Endpoints consortium, while UGI cancers' data were accessed from FinnGen's Biobank. After rigorously screening instrumental variables for periodontitis, we analyzed them with UGI cancers primarily using the inverse variance weighted. Finally, to identify outliers, the results were subjected to a leave-one-out sensitivity analysis. RESULTS: Inverse variance weighted (fixed effect) results revealed that periodontitis is a risk factor for gastric cancer (OR = 1.7735, 95% CI: 1.1576 to 2.7170, P = 0.0085). As for esophageal cancer, no statistically significant correlation was observed. Furthermore, no outliers were detected in any of the results. CONCLUSION: Our two-sample Mendelian randomization study obviously demonstrates a significant positive association between periodontitis and gastric cancer, while no statistically significant correlation was found for esophageal cancer.

Burden of gastrointestinal cancers among people younger than 50 years in China, 1990 to 2019.

OBJECTIVES: This study aimed to assess the burden of early-onset gastrointestinal (GI) cancers in China over three decades. STUDY DESIGN: A comprehensive analysis was performed using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. METHODS: Data on early-onset GI cancers in 2020 and from 1990 to 2019 were extracted from GLOBOCAN 2020 database and GBD 2019, respectively. The average annual percent change (AAPC) was calculated to analyze the temporal trends using the Joinpoint Regression Program. The Bayesian age-period-cohort (BAPC) model was used to predict future trends up to 2030. RESULTS: In China, there were 185,980 incident cases and 119,116 deaths of early-onset GI cancer in 2020, with the highest incidence and mortality observed in liver cancer (new cases: 71,662; deaths: 62,412). The spectrum of early-onset GI cancers in China has transitioned over the last 30 years. The age-standardized rates of incidence, mortality, and disability-adjusted life years for colorectal and pancreatic cancers exhibited rapid increases (AAPC >0, P ≤ 0.001). The fastest-growing incidence rate was found in colorectal cancer (AAPC: 3.06, P < 0.001). Despite the decreases in liver, gastric, and esophageal cancers, these trends have been reversed or flattened in recent years. High body mass index was found to be the fastest-growing risk factor for early-onset GI cancers (estimated annual percentage change: 2.75-4.19, P < 0.05). Projection analyses showed an increasing trend in age-standardized incidence rates for almost all early-onset GI cancers during 2020-2030. CONCLUSIONS: The transitioning pattern of early-onset GI cancers in China emphasizes the urgency of addressing this public health challenge.

Gastrointestinal Cancer Therapeutics via Triggering Unfolded Protein Response and Endoplasmic Reticulum Stress by 2-Arylbenzofuran.

Gastrointestinal cancers are a major global health challenge, with high mortality rates. This study investigated the anti-cancer activities of 30 monomers extracted from Morus alba L. (mulberry) against gastrointestinal cancers. Toxicological assessments revealed that most of the compounds, particularly immunotoxicity, exhibit some level of toxicity, but it is generally not life-threatening under normal conditions. Among these components, Sanggenol L, Sanggenon C, Kuwanon H, 3'-Geranyl-3-prenyl-5,7,2',4'-tetrahydroxyflavone, Morusinol, Mulberrin, Moracin P, Kuwanon E, and Kuwanon A demonstrate significant anti-cancer properties against various gastrointestinal cancers, including colon, pancreatic, and gastric cancers. The anti-cancer mechanism of these chemical components was explored in gastric cancer cells, revealing that they inhibit cell cycle and DNA replication-related gene expression, leading to the effective suppression of tumor cell growth. Additionally, they induced unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, potentially resulting in DNA damage, autophagy, and cell death. Moracin P, an active monomer characterized as a 2-arylbenzofuran, was found to induce ER stress and promote apoptosis in gastric cancer cells, confirming its potential to inhibit tumor cell growth in vitro and in vivo. These findings highlight the therapeutic potential of Morus alba L. monomers in gastrointestinal cancers, especially focusing on Moracin P as a potent inducer of ER stress and apoptosis.

Gut microbes in gastrointestinal cancers.

Gut microbes (GMs), dominated by bacteria, play important roles in many physiological processes. The structures and functions of GMs are closely related to human health, the occurrence and development of diseases and the rapid recovery of the body. Gastrointestinal cancers are the major diseases affecting human health worldwide. With the development of metagenomic technology and the wide application of new generation sequencing technology, a large number of studies suggest that complex GMs are related to the occurrence and development of gastrointestinal cancers. Fecal microbiota transplantation (FMT) and probiotics can treat and prevent the occurrence of gastrointestinal cancers. This article reviews the latest research progress of microbes in gastrointestinal cancers from the perspectives of the correlation, the influence mechanism and the application, so as to provide new directions for the prevention, early diagnosis and treatment of gastrointestinal cancers.

Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers.

Mesenchymal gastrointestinal cancers are represented by the gastrointestinal stromal tumors (GISTs) which occur throughout the whole gastrointestinal tract, and affect human health and economy globally. Curative surgical resections and tyrosine kinase inhibitors (TKIs) are the main managements for localized GISTs and recurrent/metastatic GISTs, respectively. Despite multi-lines of TKIs treatments prolonged the survival time of recurrent/metastatic GISTs by delaying the relapse and metastasis of the tumor, drug resistance developed quickly and inevitably, and became the huge obstacle for stopping disease progression. Immunotherapy, which is typically represented by immune checkpoint inhibitors (ICIs), has achieved great success in several solid tumors by reactivating the host immune system, and been proposed as an alternative choice for GIST treatment. Substantial efforts have been devoted to the research of immunology and immunotherapy for GIST, and great achievements have been made. Generally, the intratumoral immune cell level and the immune-related gene expressions are influenced by metastasis status, anatomical locations, driver gene mutations of the tumor, and modulated by imatinib therapy. Systemic inflammatory biomarkers are regarded as prognostic indicators of GIST and closely associated with its clinicopathological features. The efficacy of immunotherapy strategies for GIST has been widely explored in pre-clinical cell and mouse models and clinical experiments in human, and some patients did benefit from ICIs. This review comprehensively summarizes the up-to-date advancements of immunology, immunotherapy and research models for GIST, and provides new insights and perspectives for future studies.

Role of Some microRNA/ADAM Proteins Axes in Gastrointestinal Cancers as a Novel Biomarkers and Potential Therapeutic Targets-A Review.

Gastrointestinal (GI) cancers are some of the most common cancers in the world and their number is increasing. Their etiology and pathogenesis are still unclear. ADAM proteins are a family of transmembrane and secreted metalloproteinases that play a role in cancerogenesis, metastasis and neoangiogenesis. MicroRNAs are small single-stranded non-coding RNAs that take part in the post-transcriptional regulation of gene expression. Some ADAM proteins can be targets for microRNAs. In this review, we analyze the impact of microRNA/ADAM protein axes in GI cancers.

Associations of mitochondrial DNA copy number with incident risks of gastrointestinal cancers: A prospective case-cohort study.

Epidemiological investigations implied that mitochondrial DNA copy number (mtDNAcn) variations could trigger predisposition to multiple cancers, but evidence regarding gastrointestinal cancers (GICs) was still uncertain. We conducted a case-cohort study within the prospective Dongfeng-Tongji cohort, including incident cases of colorectal cancer (CRC, n = 278), gastric cancer (GC, n = 138), and esophageal cancer (EC, n = 72) as well as a random subcohort (n = 1173), who were followed up from baseline to the end of 2018. We determined baseline blood mtDNAcn and associations of mtDNAcn with the GICs risks were estimated by using weighted Cox proportional hazards models. Significant U-shaped associations were observed between mtDNAcn and GICs risks. Compared to subjects within the second quartile (Q2) mtDNAcn subgroup, those within the 1st (Q1), 3rd (Q3), and 4th (Q4) quartile subgroups showed increased risks of CRC (hazard ratio [HR] [95% confidence interval, CI] = 2.27 [1.47-3.52], 1.65 [1.04-2.62], and 2.81 [1.85-4.28], respectively) and total GICs (HR [95%CI] = 1.84 [1.30-2.60], 1.47 [1.03-2.10], and 2.51 [1.82-3.47], respectively], and those within Q4 subgroup presented elevated GC and EC risks (HR [95% CI] = 2.16 [1.31-3.54] and 2.38 [1.13-5.02], respectively). Similar associations of mtDNAcn with CRC and total GICs risks remained in stratified analyzes by age, gender, smoking, and drinking status. This prospective case-cohort study showed U-shaped associations between mtDNAcn and GICs risks, but further research works are needed to uncover underlying biological mechanisms.

Association between oxidative stress, mitochondrial function of peripheral blood mononuclear cells and gastrointestinal cancers.

BACKGROUND: The incidence and mortality rate of gastrointestinal cancers are high worldwide. Increasing studies have illustrated that the occurrence, progression, metastasis and prognosis of cancers are intimately linked to the immune system. Mitochondria, as the main source of cellular energy, play an important role in maintaining the physiological function of immune cells. However, the relationship between mitochondrial function of immune cells and tumorigenesis has not yet been systematically investigated. METHODS: A total of 150 cases, including 60 healthy donors and 90 primary gastrointestinal cancer patients without anti-tumor treatments (30 with gastric cancer, 30 with liver cancer and 30 with colorectal cancer) were involved in our study. The oxidant/antioxidant and cytokine levels in plasma, the ROS level, mitochondrial function and apoptosis ratio of peripheral blood mononuclear cells (PBMCs) were evaluated. RESULTS: The imbalance between oxidant and antioxidant in plasma was discovered in the primary gastrointestinal cancer patients. The levels of cell reactive oxygen species (ROS) and mitochondrial ROS in PBMCs of primary gastrointestinal cancers were significantly increased compared with that in healthy donors. Meanwhile, the ATP content, the mtDNA copy number and the mitochondrial membrane potential (MMP) in PBMCs of patients with primary gastrointestinal cancers were lower than those in control group. The decreased MMP also occurred in immune cells of gastrointestinal cancers, including T cell, B cell, NK cell and monocyte. Furthermore, the PBMCs apoptosis ratio of primary gastrointestinal cancer patients was significantly higher than that of control group. Importantly, an increase of IL-2 and IL-6 and a decrease of IgG in plasma were found in the patients with primary gastrointestinal cancers. These changes of mitochondrial function in immune cells were consistent among primary gastrointestinal cancers without anti-tumor treatments, such as liver cancer, gastric cancer and colorectal cancer. CONCLUSION: Our study demonstrated that the imbalance of oxidation/antioxidation in primary gastrointestinal cancer patients without anti-tumor treatments results in excessive ROS. The oxidative stress was associated to the mitochondrial dysfunction, the apoptosis of immune cells and eventually the abnormal immune function in primary gastrointestinal cancers. The application of immune cell mitochondrial dysfunction into clinical evaluation is anticipated.