Role of ion channels in gastrointestinal cancer

In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer cell.The functions of ion channels in the gastrointestinal(GI) tract influence a variety of cellular processes,many of which overlap with these hallmarks of cancer.In this review we focus on the roles of the calcium(Ca~(2+)),sodium(Na~+),potassium(K~+),chloride(Cl~-) and zinc(Zn~(2+)) transporters in GI cancer,with a special emphasis on the roles of the KCNQ1 K~+ channel and CFTR Cl channel in colorectal cancer(CRC).Ca~(2+)is a ubiquitous second messenger,serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle,apoptosis,and migration.Various members of the TRP superfamily,including TRPM8,TRPM7,TRPM6 and TRPM2,have been implicated in GI cancers,especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon cancer.Voltage-gated sodium channels(VGSCs) are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle cells.The VGSC Na_v1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC samples.Studies have demonstrated that conductance through Na_v1.5 contributes significantly to CRC cell invasiveness and cancer progression.Zn~(2+)transporters of the ZIP/SLC39 A and ZnT/SLC30 A families are dysregulated in all major GI organ cancers,in particular,ZIP4 up-regulation in pancreatic cancer(PC).More than 70 K~+ channel genes,clustered in four families,are found expressed in the GI tract,where they regulate a range of cellular processes,including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal tract.Several distinct types of K~+ channels are found dysregulated in the GI tract.Notable are hERG1 upregulation in PC,gastric cancer(GC) and CRC,leading to enhanced cancer angiogenesis and invasion,and KCNQ1 down-regulation in CRC,where KCNQ1 expression is associated with enhanced disease-free survival in stage Ⅱ,Ⅲ,and Ⅳ disease.Cl~-channels are critical for a range of cellular and tissue processes in the GI tract,especially fluid balance in the colon.Most notable is CFTR,whose deficiency leads to mucus blockage,microbial dysbiosis and inflammation in the intestinal tract.CFTR is a tumor suppressor in several GI cancers.Cystic fibrosis patients are at a significant risk for CRC and low levels of CFTR expression are associated with poor overall disease-free survival in sporadic CRC.Two other classes of chloride channels that are dysregulated in GI cancers are the chloride intracellular channels(CLIC1,3 4) and the chloride channel accessory proteins(CLCA1,2,4).CLIC1 4 are upregulated in PC,GC,gallbladder cancer,and CRC,while the CLCA proteins have been reported to be down-regulated in CRC.In summary,it is dear,from the diverse influences of ion channels,that their aberrant expression and/or activity can contribute to malignant transformation and tumor progression.Further,because ion channels are often localized to the plasma membrane and subject to multiple layers of regulation,they represent promising clinical targets for therapeutic intervention including the repurposing of current drugs.     

Role of radiomics in the diagnosis and treatment of gastrointestinal cancer

Gastrointestinal cancer (GIC) has high morbidity and mortality as one of the main causes of cancer death. Preoperative risk stratification is critical to guide patient management, but traditional imaging studies have difficulty predicting its biological behavior. The emerging field of radiomics allows the conversion of potential pathophysiological information in existing medical images that cannot be visually recognized into high-dimensional quantitative image features. Tumor lesion characterization, therapeutic response evaluation, and survival prediction can be achieved by analyzing the relationships between these features and clinical and genetic data. In recent years, the clinical application of radiomics to GIC has increased dramatically. In this editorial, we describe the latest progress in the application of radiomics to GIC and discuss the value of its potential clinical applications, as well as its limitations and future directions.     

Application of Big Data analysis in gastrointestinal research

Big Data,which are characterized by certain unique traits like volume,velocity and value,have revolutionized the research of multiple fields including medicine.Big Data in health care are defined as large datasets that are collected routinely or automatically,and stored electronically.With the rapidly expanding volume of health data collection,it is envisioned that the Big Data approach can improve not only individual health,but also the performance of health care systems.The application of Big Data analysis in the field of gastroenterology and hepatology research has also opened new research approaches.While it retains most of the advantages and avoids some of the disadvantages of traditional observational studies(case-control and prospective cohort studies),it allows for phenomapping of disease heterogeneity,enhancement of drug safety,as well as development of precision medicine,prediction models and personalized treatment.Unlike randomized controlled trials,it reflects the real-world situation and studies patients who are often under-represented in randomized controlled trials.However,residual and/or unmeasured confounding remains a major concern,which requires meticulous study design and various statistical adjustment methods.Other potential drawbacks include data validity,missing data,incomplete data capture due to the unavailability of diagnosis codes for certain clinical situations,and individual privacy.With continuous technological advances,some of the current limitations with Big Data may be further minimized.This review will illustrate the use of Big Data research on gastrointestinal and liver diseases using recently published examples.     

Bisphosphonate use and gastrointestinal tract cancer risk: Meta-analysis of observational studies

AIM: To perform a meta-analysis of observational studies to further elucidate the relationship between oral bisphosphonate use and gastrointestinal cancer risk.METHODS: Systematic literature search was conducted in MEDLINE, EMBASE, and the Cochrane Library to identify studies through January 2011. Search terms were “bisphosphonates” or trade names of the drugs, and “observational studies” or “cohort studies” or “case-control studies”. Two evaluators reviewed and selected articles on the basis of predetermined selection criteria as followed: (1) observational studies (case-control or cohort studies) on bisphosphonate use; (2) with at least 2 years of follow-up; and (3) reported data on the incidence of cancer diagnosis. The DerSimonian and Laird random effects model were used to calculate the pooled relative risk (RR) with 95% confidence interval (CI). Two-by-two contingency table was used to calculate the outcomes not suitable for meta-analysis. Subgroup meta-analyses were conducted for the type of cancer (esophageal, gastric and colorectal cancers). Sensitivity analyses were performed to examine the effect sizes when only studies with long-term follow-up (mean 5 years; subgroup 3 years) were included.RESULTS: Of 740 screened articles, 3 cohort studies and 3 case-control studies were included in the analyses. At first, 4 cohort studies and 3 case-control studies were selected for the analyses but one cohort study was excluded because the cancer outcomes were not categorized by type of gastrointestinal cancer. More than 124 686 subjects participated in the 3 cohort studies. The mean follow-up time in all of the cohort studies combined was approximately 3.88 years. The 3 case-control studies reported 3070 esophageal cancer cases and 15 417 controls, 2018 gastric cancer cases and 10 007 controls, and 11 574 colorectal cancer cases and 53 955 controls. The percentage of study participants who used bisphosphonate was 2.8% among the cases and 2.9% among the controls. The meta-analysis of all the studies found no significant association between bisphosphonate use and gastrointestinal cancer. Also no statistically significant association was found in a meta-analysis of long-term follow-up studies. There was no negative association between bisphosphonate use and the incidence of esophageal cancer in the overall analysis (RR 0.96, 95% CI: 0.65-1.42, I² = 52.8%, P = 0.076) and no statistically significant association with long-term follow-up (RR 1.74, 95% CI: 0.97-3.10, I² = 58.8%, P = 0.119). No negative association was found in the studies reporting the risk of gastric cancer (RR 0.89, 95% CI: 0.71-1.13, I² = 0.0%, P = 0.472). In case of colorectal cancer, there was no association between colorectal cancer and bisphosphonate use (RR 0.62, 95% CI: 0.30-1.29, I² = 88.0%, P = 0.004) and also in the analysis with long-term follow-up (RR 0.61, 95% CI: 0.28-1.35, I² = 84.6%, P = 0.011).CONCLUSION: Oral bisphosphonate use had no significant effect on gastrointestinal cancer risk. However, this finding should be validated in randomized controlled trials with long-term follow-up.     

Surveillance of patients with hereditary gastrointestinal cancer syndromes

Gastrointestinal cancers are among the most frequent tumors. Although most cases are sporadic, up to 5–6% develops in the context of gastrointestinal hereditary syndromes. These entities have specific characteristics and often a germline mutation identified, thus allowing performing genetic counseling. This review summarizes the most common gastrointestinal hereditary syndromes, focusing on the surveillance recommendations.     

Risk of gastrointestinal cancer in a symptomatic cohort after a complete colonoscopy:Role of faecal immunochemical test

BACKGROUND Faecal immunochemical test(FIT) has been recommended to assess symptomatic patients for colorectal cancer(CRC) detection. Nevertheless, some conditions could theoretically favour blood originating in proximal areas of the gastrointestinal tract passing through the colon unmetabolized. A positive FIT result could be related to other gastrointestinal cancers(GIC).AIM To assess the risk of GIC detection and related death in FIT-positive symptomatic patients(threshold 10 μg Hb/g faeces) without CRC.METHODS Post hoc cohort analysis performed within two prospective diagnostic test studies evaluating the diagnostic accuracy of different FIT analytical systems for CRC and significant colonic lesion detection. Ambulatory patients with gastrointestinal symptoms referred consecutively for colonoscopy from primary and secondary healthcare, underwent a quantitative FIT before undergoing a complete colonoscopy. Patients without CRC were divided into two groups(positive and negative FIT) using the threshold of 10 μg Hb/g of faeces and data from follow-up were retrieved from electronic medical records of the public hospitals involved in the research. We determined the cumulative risk of GIC,CRC and upper GIC. Hazard rate(HR) was calculated adjusted by age, sex and presence of significant colonic lesion.RESULTS We included 2709 patients without CRC and a complete baseline colonoscopy,730(26.9%) with FIT ≥ 10 μgr Hb/gr. During a mean time of 45.5 ± 20.0 mo, a GIC was detected in 57(2.1%) patients: An upper GIC in 35(1.3%) and a CRC in 14(0.5%). Thirty-six patients(1.3%) died due to GIC: 22(0.8%) due to an upper GIC and 9(0.3%) due to CRC. FIT-positive subjects showed a higher CRC risk(HR 3.8,95%CI: 1.2-11.9) with no differences in GIC(HR 1.5, 95%CI: 0.8-2.7) or upper GIC risk(HR 1.0, 95%CI: 0.5-2.2). Patients with a positive FIT had only an increased risk of CRC-related death(HR 10.8, 95%CI: 2.1-57.1) and GIC-related death(HR2.2, 95%CI: 1.1-4.3), with no differences in upper GIC-related death(HR 1.4,95%CI: 0.6-3.3). An upper GIC was detected in 22(0.8%) patients during the first year. Two variables were independently associated: anaemia(OR 5.6, 95%CI: 2.2-13.9) and age ≥ 70 years(OR 2.7, 95%CI: 1.1-7.0).CONCLUSION Symptomatic patients without CRC have a moderate risk increase in upper GIC,regardless of the FIT result. Patients with a positive FIT have an increased risk of post-colonoscopy CRC.     

Metabolomics profile in gastrointestinal cancers: Update and future perspectives

Despite recent progress in diagnosis and therapy, gastrointestinal(GI) cancers remain one of the most important causes of death with a poor prognosis due to late diagnosis. Serum tumor markers and detection of occult blood in the stool are the current tests used in the clinic of GI cancers; however, these tests are not useful as diagnostic screening since they have low specificity and low sensitivity.Considering that one of the hallmarks of cancer is dysregulated metabolism and metabolomics is an optimal approach to illustrate the metabolic mechanisms that belong to living systems, is now clear that this-omics could open a new way to study cancer. In the last years, nuclear magnetic resonance(NMR) metabolomics has demonstrated to be an optimal approach for diseases' diagnosis nevertheless a few studies focus on the NMR capability to find new biomarkers for early diagnosis of GI cancers. For these reasons in this review, we will give an update on the status of NMR metabolomic studies for the diagnosis and development of GI cancers using biological fluids.     

Neutrophil extracellular traps in gastrointestinal cancer

Gastrointestinal (GI) cancer is a high-risk malignancy and is characterized by high mortality and morbidity worldwide. Neutrophil extracellular traps (NETs), a weblike structure consisting of chromatin DNA with interspersed cytoplasmic and granule proteins, are extruded by activated neutrophils to entrap and kill bacteria and fungi. However, accumulating evidence shows that NETs are related to the progression and metastasis of cancer. In clinical studies, NETs infiltrate primary GI cancer tissues and are even more abundant in metastatic lesions. The quantity of NETs in peripheral blood is revealed to be associated with ascending clinical tumour stages, indicating the role of NETs as a prognostic markers in GI cancer. Moreover, several inhibitors of NETs or NET-related proteins have been discovered and used to exert anti-tumour effects in vitro or in vivo, suggesting that NETs can be regarded as targets in the treatment of GI cancer. In this review, we will focus on the role of NETs in gastric cancer and colorectal cancer, generalizing their effects on tumour-related thrombosis, invasion and metastasis. Recent reports are also listed to show the latest evidences of how NETs affect GI cancer. Additionally, notwithstanding the scarcity of systematic studies elucidating the underlying mechanisms of the interaction between NETs and cancer cells, we highlight the potential importance of NETs as biomarkers and anti-tumour therapeutic targets.     

人胃癌,肝癌的c—myc癌基因甲基化的研究

目的：了解人胃癌和肝癌相关癌基因的甲基化情况。材料与方法：将22例进展期胃癌的癌区、癌旁和外周正常区组织和33例原发性肝癌的癌区、癌旁区及10例正常肝组织的DNA，以限制性内切酶Hpall／Mspl消化、Southernblot分析其c－myc癌基因片段的甲基化情况。结果：发现47％（10／22）的胃癌区、59％（13／22）的胃癌旁和30％（10／33）的肝癌区、13％（4／33）的肝癌旁组织的c－myc癌基因呈低甲基化状态。结论：在消化系常见的恶性肿瘤的发生中，某些癌基因甲基化水平降低。     

Endoscopic submucosal dissection and surgical treatment for gastrointestinal cancer

Endoscopic submucosal dissection (ESD) is widely usedin Japan as a minimally invasive treatment for earlygastric cancer. The application of ESD has expanded tothe esophagus and colorectum. The indication criteriafor endoscopic resection (ER) are established for eachorgan in Japan. Additional treatment, including surgery with lymph node dissection, is recommended when pathological examinations of resected specimens donot meet the criteria. Repeat ER for locally recurrent gastrointestinal tumors may be difficult because of submucosal fibrosis, and surgical resection is required inthese cases. However, ESD enables complete resectionin 82%-100% of locally recurrent tumors. Transanal endoscopic microsurgery (TEM) is a well-developed sur-gical procedure for the local excision of rectal tumors.ESD may be superior to TEM alone for superficial rectaltumors. Perforation is a major complication of ESD,and it is traditionally treated using salvage laparotomy.However, immediate endoscopic closure followed byadequate intensive treatment may avoid the need forsurgical treatment for perforations that occur during ESD. A second primary tumor in the remnant stomach after gastrectomy or a tumor in the reconstructedorgan after esophageal resection has traditionally required surgical treatment because of the technical difficulty of ER. However, ESD enables complete resectionin 74%-92% of these lesions. Trials of a combination ofESD and laparoscopic surgery for the resection of gastric submucosal tumors or the performance of sentinellymph node biopsy after ESD have been reported, butthe latter procedure requires a careful evaluation of itsclinical feasibility.     

Hepatocellular carcinoma and synchronous liver metastases from colorectal cancer in cirrhosis: A case report

A 68-year-old Caucasian man with hepatitis C virus-related cirrhosis was admitted to our Unit in February 2010 for a diagnostic evaluation of three centimetric hypoechoic focal liver lesions detected by regular surveillance ultrasound. The subsequent computer tomography (CT) led to a diagnosis of unifocal hepatocellular carcinoma (HCC) in VI hepatic segment, defined the other two nodules in the VI and VII segment as suspected metastases, and showed a luminal narrowing with marked segmental circumferential thickening of the hepatic flexure of the colon. Colonoscopy detected an ulcerated, bleeding and stricturing lesion at the hepatic flexure, which was subsequently defined as adenocarcinoma with a moderate degree of differentiation at histological examination. Finally, ultrasound-guided liver biopsy of the three focal liver lesions confirmed the diagnosis of HCC for the nodule in the VI segment, and characterized the other two lesions as metastases from colorectal cancer. The patient underwent laparotomic right hemicolectomy with removal of thirty-nine regional lymph nodes (three of them tested positive for metastasis at histological examination), and simultaneous laparotomic radio-frequency ablation of both nodule of HCC and metastases. The option of adjuvant chemotherapy was excluded because of the post-surgical onset of ascites. Abdomen CT and positron emission tomography/CT scans performed after 1, 6 and 12 mo highlighted a complete response to treatments without any radiotracer accumulation. After 18 mo, the patient died due to progressive liver failure. Our experience emphasizes the potential coexistence of two different neoplasms in a cirrhotic liver and the complexity in the proper diagnosis and management of the two tumours.     

ABO blood type, diabetes and risk of gastrointestinal cancer in northern China

AIM: To explore the potential risk factors related to gastrointestinal cancer in northern China.METHODS: A total of 3314 cases of gastrointestinal cancer (esophageal, gastric, pancreatic and biliary) and 2223 controls (including healthy individuals, glioma and thyroid cancer) were analyzed by case-control study. Multivariable logistic regression analysis was applied to evaluate the association between different cancers and hepatitis B surface antigen, sex, age, blood type, diabetes, or family history of cancer.RESULTS: Type 2 diabetes was significantly associated with gastric, biliary and pancreatic cancer with an OR of 2.0-3.0. Blood type B was significantly associated with esophageal cancer [odd ratio (OR) = 1.53, 95% confidence interval (CI) = 1.10-2.14] and biliary cancer (OR = 1.49, 95% CI = 1.09-2.05). The prevalence of type 2 diabetes was significantly higher in gastric, biliary and pancreatic cancers compared with other groups, with ORs ranging between 2.0 and 3.0. Family history of cancer was strongly associated with gastrointestinal compared with other cancers.CONCLUSION: Blood type B individuals are susceptible to esophageal and biliary cancer. Type 2 diabetes is significantly associated with gastric, biliary and especially pancreatic cancer.     

Immunotherapy in colorectal cancer: Available clinical evidence,challenges and novel approaches

In contrast to other tumor types, immunotherapy has not yet become a relevant part of the treatment landscape of unselected colorectal cancer. Beside the small subgroup of deficient mismatch repair or microsatellite instable tumors (about 5%) as a surrogate for high mutational burden and subsequently high neoantigen load and immunogenicity, inhibitors of programmed death 1 (PD-1), programmed death ligand 1 (PD-L1) and/or cytotoxic T lymphocyte-associated antigen-4 were not or only modestly effective in metastatic colorectal cancer. Thus, a variety of combination approaches with chemotherapy, targeted therapy, toll-like receptor agonists, local ablation or oncolytic viruses is currently being evaluated in different disease settings. Despite several encouraging single arm data already presented or published, available randomized data are unimpressive. Adding PD-1/PD-L1 inhibitors to fluoropyrimidines and bevacizumab maintenance showed no beneficial impact on delaying progression. In refractory disease, the combination of PD-1/PD-L1 and MEK inhibitor was not different from regorafenib, whereas a PD-1/PD-L1 and cytotoxic T lymphocyteassociated antigen-4 inhibitor combination demonstrated better overall survival compared to supportive care alone. Clinical trials in all disease settings applying different combination approaches are ongoing and may define the role of immunotherapy in colorectal cancer.     

Fucosylation and gastrointestinal cancer

Fucose (6-deoxy-L-galactose) is a monosaccharide that is found on glycoproteins and glycolipids in verte-brates, invertebrates, plants, and bacteria. Fucosylation, which comprises the transfer of a fucose residue to oligosaccharides and proteins, is regulated by many kinds of molecules, including fucosyltransferases, GDP-fucose synthetic enzymes, and GDP-fucose transporter(s). Dramatic changes in the expression of fucosylated oligosaccharides have been observed in cancer and inflammation. Thus, monoclonal antibodies and lectins recognizing cancer-associated fucosylated oligosaccharides have been clinically used as tumor markers for the last few decades. Recent advanced glycomic approaches allow us to identify novel fucosylation-related tumor markers. Moreover, a growing body of evidence supports the functional significance of fucosylation at various pathophysiological steps of carcinogenesis and tumor progression. This review highlights the biological and medical significance of fucosylation in gastrointestinal cancer.     

Narrow line between benefit and harm: Additivity of hyperthermia to cisplatin cytotoxicity in different gastrointestinal cancer cells

AIM To investigate the response to hyperthermia and chemotherapy, analyzing apoptosis, cytotoxicity, and cisplatin concentration in different digestive system cancer cells.METHODS AGS(gastric cancer cell line), Caco-2(colon cancer cell line) and T3M4(pancreatic cancer cell line) were treated by cisplatin and different temperature setting(37 ℃ to 45 ℃) either in isolation, or in combination. Treatment lasted for one hour. 48 h after the treatment viability was evaluated by MTT, cell apoptosis by Annexin V-PE and 7 ADD flow cytometry. Intracellular cisplatin concentration was measured immediately after the treatment, using mass spectrometry. Isobologram analysis was performed to evaluate the mathematical combined effect of temperature and cisplatin.RESULTS AGS cells were the most sensitive to isolated application of hyperthermia. Hyperthermia, in addition to cisplatin treatment, did not provoke a synergistic effect at intervals from 37 ℃ to 41 ℃ in neither cancer cell line. However, a temperature of 43 ℃ enhanced cisplatin cytotoxicity for Caco-2 cells. Moreover, isobologram analysis revealed mathematical antagonistic effects of cisplatin and temperature combined treatment in AGS cells; variations between synergistic, additive, and antagonistic effects in Caco-2 cells; and additive and antagonistic effects in T3 M4 cells. Combined treatment enhanced initiation of cell apoptosis in AGS, Caco-2, and T3 M4 cells by 61%, 20%, and 19% respectively. The increase of intracellular cisplatin concentration was observed at 43 ℃ by 30%, 20%, and 18% in AGS, Caco-2, and T3 M4 cells, respectively.CONCLUSION In addition to cisplatin, hyperthermia up to 43 ℃ does not affect the viability of cancer cells in a synergistic manner.