Receptor tyrosine kinase-like orphan receptor 1:A novel antitumor target in gastrointestinal cancers

Receptor tyrosine kinase-like orphan receptor 1(ROR1)is a member of the type I receptor tyrosine kinase family.ROR1 is pivotal in embryonic development and cancer,and serves as a biomarker and therapeutic target.It has soluble and membrane-bound subtypes,with the latter highly expressed in tumors.ROR1 is conserved throughout evolution and may play a role in the development of gastrointestinal cancer through multiple signaling pathways and molecular mechanisms.Studies suggest that overexpression of ROR1 may increase tumor invasiveness and metastasis.Additionally,ROR1 may regulate the cell cycle,stem cell characteristics,and interact with other signaling pathways to affect cancer progression.This review explores the structure,expression and role of ROR1 in the development of gastrointestinal cancers.It discusses current antitumor strategies,outlining challenges and prospects for treatment.

Role of molecular imaging in prognosis,diagnosis,and treatment of gastrointestinal cancers:An update on new therapeutic methods

One of the leading causes of cancer-related death is gastrointestinal cancer,which has a significant morbidity and mortality rate.Although preoperative risk assessment is essential for directing patient care,its biological behavior cannot be accurately predicted by conventional imaging investigations.Potential pathophysiological information in anatomical imaging that cannot be visually identified can now be converted into high-dimensional quantitative image features thanks to the developing discipline of molecular imaging.In order to enable molecular tissue profile in vivo,molecular imaging has most recently been utilized to phenotype the expression of single receptors and targets of biological therapy.It is expected that molecular imaging will become increasingly important in the near future,driven by the expanding range of biological therapies for cancer.With this live molecular fingerprinting,molecular imaging can be utilized to drive expression-tailored customized therapy.The technical aspects of molecular imaging are first briefly discussed in this review,followed by an examination of the most recent research on the diagnosis,prognosis,and potential future clinical methods of molecular imaging for GI tract malignancies.

Inflammatory response in gastrointestinal cancers:Overview of six transmembrane epithelial antigens of the prostate in pathophysiology and clinical implications

Chronic inflammation is known to increase the risk of gastrointestinal cancers(GICs),the common solid tumors worldwide.Precancerous lesions,such as chronic atrophic inflammation and ulcers,are related to inflammatory responses in vivo and likely to occur in hyperplasia and tumorigenesis.Unfortunately,due to the lack of effective therapeutic targets,the prognosis of patients with GICs is still unsatisfactory.Interestingly,it is found that six transmembrane epithelial antigens of the prostate(STEAPs),a group of metal reductases,are significantly associated with the progression of malignancies,playing a crucial role in systemic metabolic homeostasis and inflammatory responses.The structure and functions of STEAPs suggest that they are closely related to intracellular oxidative stress,responding to inflammatory reactions.Under the imbalance status of abnormal oxidative stress,STEAP members are involved in cell transformation and the development of GICs by inhibiting or activating inflammatory process.This review focuses on STEAPs in GICs along with exploring their potential molecular regulatory mechanisms,with an aim to provide a theoretical basis for diagnosis and treatment strategies for patients suffering from these types of cancers.

Burden of gastrointestinal cancers among working-age population over past thirty years in China

BACKGROUND Although gastrointestinal(GI)cancers have been becoming a great public health concern in China,there is currently a lack of comprehensive literature on the overall burden and changing trends of GI cancers in the working-age population.AIM To assess the burden of GI cancers and to examine the overall,age-and genderspecific trends among the working-age population in China from 1990 to 2019.METHODS Data were extracted from the Global Burden of Disease Study 2019.The burden of GI cancers was indicated by incidence,mortality,disability-adjusted life-years(DALYs),age-standardized incidence rate(ASIR),age-standardized mortality rate,and age-standardized DALYs rate.Trends in the burden of GI cancers from 1990 to 2019 were examined using annual percent change and average annual percent change with Joinpoint regression models.RESULTS For overall GI cancers,a declining trend was observed in the ASIR,age-standardized mortality rate,and agestandardized DALYs rate,with reductions of 0.74%,2.23%,and 2.22%,respectively,from 1999 to 2019 in the Chinese working-age population.However,an increasing trend was observed in the ASIR for overall GI cancers from 2016-2019.The number of either incident cases,mortality cases,and DALYs was higher for colon/rectum cancer and liver cancer in younger participants but lower for esophageal,gallbladder,biliary tract,pancreatic,and stomach cancer among older subjects.Moreover,sex disparity in the GI cancers burden was also examined over 30 years.CONCLUSION The total burden of GI cancers remained heavy among the working-age population in China,although declining trends were observed from 1999 to 2019.Disparities in the GI cancers burden existed between sexes,age groups,and cancer types.Population-based precision prevention strategies are needed to tackle GI cancers among working-age individuals,considering the age,sex,and cancer type disparities in China.

Six transmembrane epithelial antigens of the prostate to illustrate inflammatory response in gastrointestinal cancers

Gastrointestinal cancer(GIC)is a common and widespread form of tumor,with colonoscopy and upper gastrointestinal endoscopy available to detect relevant precancerous polyps and lesions.However,many patients are already in the late stages when first diagnosed with such cancer,resulting in a poor prognosis.Thus,it is necessary to explore new methods and research directions in order to improve the treatment of GIC.Given the specific nature of the gastrointestinal tract,research should focus on the mechanisms of various inflammations and the interactions between food entering and exiting from the gastrointestinal tract and cancer cells.Interestingly,six transmembrane epithelial antigens of the prostates(STEAPs)have been found to be significantly linked to the progression of malignant tumors,associated with intracellular oxidative stress and playing a major role in inflammation with their structure and function.This paper explores the mechanism of STEAPs in the inflammatory response of GIC,providing a theoretical basis for the prevention and early intervention of GIC.The basic properties of the STEAP family as metal reductase are also explained.When it comes to intervention for GIC prevention,STEAPs can affect the activity of Fe^(3+),Cu^(2+) reductase and regulate metal ion uptake in vivo,participating in inflammation-related iron and copper homeostasis.Thus,the mechanism of STEAPs on inflammation is of important value in the prevention of GIC.

Emerging therapies in gastrointestinal cancers

Members of the receptor tyrosine kinase family, that include EGFR, ErbB-2/HER-2, ErbB-3/HER-3 and ErbB-4/ HER-4, are frequently implicated in experimental models of epithelial cell neoplasia as well as in human cancers. Therefore, interference with the activation of these growth factor receptors represents a promising strategy for de- velopment of novel and selective anticancer therapies. Indeed, a number of inhibitors that target either EGFR or HER-2, with the exception of a few that target both; have been developed for treatment of epithelial cancers. Since most solid tumors express different ErbB receptors and/or their ligands, identification of inhibitor(s), targeting multiple EGFR family members may provide a therapeutic benefit to a broader patient population. Here we describe the significance of an ErbB family of receptors in epithelial cancers, and summarize different available therapeutics targeting these receptors. It also emphasizes the need to develop pan-ErbB inhibitors and discusses EGF-Receptor Related Protein, a recently isolated negative regulator of EGFR as a potential pan-ErbB therapeutic for a wide vari- ety of epithelial cancers.

Systems biology and OMIC data integration to understand gastrointestinal cancers

Gastrointestinal(GI)cancers are a set of diverse diseases affecting many parts/organs.The five most frequent GI cancer types are esophageal,gastric cancer(GC),liver cancer,pancreatic cancer,and colorectal cancer(CRC);together,they give rise to 5 million new cases and cause the death of 3.5 million people annually.We provide information about molecular changes crucial to tumorigenesis and the behavior and prognosis.During the formation of cancer cells,the genomic changes are microsatellite instability with multiple chromosomal arrangements in GC and CRC.The genomically stable subtype is observed in GC and pancreatic cancer.Besides these genomic subtypes,CRC has epigenetic modification(hypermethylation)associated with a poor prognosis.The pathway information highlights the functions shared by GI cancers such as apoptosis;focal adhesion;and the p21-activated kinase,phosphoinositide 3-kinase/Akt,transforming growth factor beta,and Toll-like receptor signaling pathways.These pathways show survival,cell proliferation,and cell motility.In addition,the immune response and inflammation are also essential elements in the shared functions.We also retrieved information on protein-protein interaction from the STRING database,and found that proteins Akt1,catenin beta 1(CTNNB1),E1A binding protein P300,tumor protein p53(TP53),and TP53 binding protein 1(TP53BP1)are central nodes in the network.The protein expression of these genes is associated with overall survival in some GI cancers.The low TP53BP1 expression in CRC,high EP300 expression in esophageal cancer,and increased expression of Akt1/TP53 or low CTNNB1 expression in GC are associated with a poor prognosis.The Kaplan Meier plotter database also confirmed the association between expression of the five central genes and GC survival rates.In conclusion,GI cancers are very diverse at the molecular level.However,the shared mutations and protein pathways might be used to understand better and reveal diagnostic/prognostic or drug targets.

Recent advances in gastrointestinal cancers

Gastrointestinal cancers occur in a total of eight different locations,each of them with a different standard of care.This article is not an exhaustive review of what has been published in 2020.We have concentrated on the thirteen phase III randomized studies that are practice-changing.All these studies are oral presentations which have been given in one of the four major oncology congresses,namely American Society of Clinical Oncology(ASCO),ASCO gastrointestinal(GI),European Society of Medical Oncology(ESMO)and ESMO-GI.We provide a concise view of these major trials and their main outcomes,and put these results into context.

Photodynamic Therapy for Upper Gastrointestinal Cancers during Past 25 Years in China

Objective： To evaluate the status of photodynamic therapy （PDT） for upper gastrointestinal cancers, and then discuss how to solve the problems that hinder the development of PDT. Methods： A total of 30 pertinent literatures about PDT for upper gastrointestinal cancers during past 25 years were collected through the retrieval of several related medical databases （Chinese Medical Current Contents, China Bio-Medical Bibliographic Database, China Journal Fulltext Database）. The data, including the gender, age of patients, tumor position, pathologic findings, treatment efficacy, adverse effects and the applied laser and photosensitizer, were statistically analyzed. Results： For all the 1687 cases with upper gastrointestinal cancers, the excellent-effective rate （complete remission or prominent remission） and effective rate （complete remission or prominent remission or minor remission） were 53.2% and 87%, respectively. The therapeutic effect of combined treatment （PDT with other methods） was superior to that of PDT （u=4.456, P〈0.01）. All the involved pathological types were sensitive to PDT. Different photosensitizers and lasers were used by different authors, but all of them were effective without any serious side effect. Conclusion： PDT shows a radical effect on the tumors of early stage and a favorable palliative effect on the tumors of advanced stage, so it is one of the optional strategies for the treatment of upper gastrointestinal cancers.

Roles of cancer stem cells in gastrointestinal cancers

Cancer stem cells(CSCs)are the main cause of tumor growth,invasion,metastasis and recurrence.Recently,CSCs have been extensively studied to identify CSCspecific surface markers as well as signaling pathways that play key roles in CSCs self-renewal.The involvement of CSCs in the pathogenesis of gastrointestinal(GI)cancers also highlights these cells as a priority target for therapy.The diagnosis,prognosis and treatment of GI cancer have always been a focus of attention.Therefore,the potential application of CSCs in GI cancers is receiving increasing attention.This review summarizes the role of CSCs in GI cancers,focusing on esophageal cancer,gastric cancer,liver cancer,colorectal cancer,and pancreatic cancer.In addition,we propose CSCs as potential targets and therapeutic strategies for the effective treatment of GI cancers,which may provide better guidance for clinical treatment of GI cancers.

Myeloid-derived suppressor cells in gastrointestinal cancers:A systemic review

Gastrointestinal(GI)cancers are one of the most common malignancies worldwide,with high rates of morbidity and mortality.Myeloid-derived suppressor cells(MDSCs)are major components of the tumor microenvironment(TME).MDSCs facilitate the transformation of premalignant cells and play roles in tumor growth and metastasis.Moreover,in patients with GI malignancies,MDSCs can lead to the suppression of T cells and natural killer cells.Accordingly,a better understanding of the role and mechanism of action of MDSCs in the TME will aid in the development of novel immune-targeted therapies.

Correlations between P2RX1 Expression and Gastrointestinal Cancers Prognosis and Immune Infiltration Based on Bioinformatics Analysis

This study was conducted to explore the correlations between the expression,methylation,and various clinicopathological factors of purinergic P2X1 receptor(P2RX1)and the prognosis of patients with gastrointestinal tumors.The Cancer Genome Atlas(TCGA)and the Genotype-Tissue Expression(GTEx)databases were used to analyze the expression of P2RX1 in different types of gastrointestinal cancers.Kaplan-Meier analysis and univariate Cox regression analysis were used to analyze the correlations between P2RX1 expression and the prognosis of various gastrointestinal tumors.Correlations between P2RX1 expression and N6 methyladenine(m6A)-related genes as well as immune checkpoint genes were analyzed by R packages(R version:4.0.3)based on TCGA database.The association between P2RX1 methylation level and the prognosis of patients with gastrointestinal cancers was analyzed using the MethSurv database.In order to explore the biological functions of P2RX1 in hepatocellular carcinoma,the Kyoto Encyclopedia of Genes and Genomes(KEGG)and Gene Ontology(GO)enrichment analysis were carried out using R software.In order to evaluate the correlations between P2RX1 and tumor immune infiltration,Spearman correlation test was performed.The correlations between P2RX1 expression and immune score as well as immune checkpoint genes were analyzed based on TCGA and Tumor Immune Estimation Resource(TIMER)databases.The expression of P2RX1 was found to be significantly downregulated in gastrointestinal tumors except in cholangiocarcinoma(P<0.05).High expression of P2RX1 tended to present better prognosis in hepatocellular carcinoma(P<0.05).It was noted that cg06475633 of P2RX1 presented a higher methylation level compared with other CpG sites in hepatocellular carcinoma.Overall,six CpGs of P2RX1 were associated with significant prognosis in patients with hepatocellular carcinoma(P<0.05).Among all the 20 m6A-related genes,Wilms'tumor 1-associating protein(WTAP)was the most strongly correlated with P2RX1 in hepatocellular carcinoma.Gene enrichment analysis showed that P2RX1 is widely involved in the proliferation,activation,organization,and differentiation of various immune cells.After investigating the TIMER database,P2RX1 was found to be tightly correlated with immune infiltrating cells in gastrointestinal tumors,especially with dendritic cells.Moreover,P2RX1 was found to be strongly positively associated with programmed cell death 1(PD1),programmed death-ligand 1(PD-L1),and cytotoxic T-lymphocyte-associated protein 4(CTLA4)in hepatocellular carcinoma(P<0.05).In conclusion,the dual role of P2RX1 in cancers and its involvement in the recruitment as well as regulation of tumor infiltrating cells in gastrointestinal cancers may be appreciated through this study.

Role of Ubiquitin-Conjugating Enzyme UBE2C in Gastrointestinal Cancers

Ubiquitin-conjugating enzyme UBE2C is one of the important members of ubiquitin-proteasome pathway(UPP).Amplification and/or overexpression of UBE2C have been reported in many malignancies,and a high expression of UBE2C is associated with poor clinical outcomes.In this review,the pathological role of dysregulated UBE2C in gastrointestinal cancers and its potential role as a diagnostic and/or a prognostic marker as well as a therapeutic target in these cancers are discussed.

Endoscopic submucosal dissection for premalignant lesions and noninvasive early gastrointestinal cancers

AIM: To investigate the indication, feasibility, safety, and clinical utility of endoscopic submucosal dissection (ESD) in the management of various gastrointestinal pathologies. METHODS: The medical records of 60 consecutive patients (34 female, 26 male) who underwent ESD at the gastroenterology department of Kocaeli University from 2006-2010 were examined. Patients selected for ESDhad premalignant lesions or non-invasive early cancers of the gastrointestinal tract and had endoscopic and histological diagnoses. Early cancers were considered to be confined to the submucosa, with no lymph node involvement by means of computed tomography and endosonography. RESULTS: Sixty ESD procedures were performed. The indications were epithelial lesions (n = 39) (33/39 adenoma with high grade dysplasia, 6/39 adenoma with low grade dysplasia), neuroendocrine tumor (n = 7), cancer (n = 7) (5/7 early colorectal cancer, 2/7 early gastric cancer), granular cell tumor (n = 3), gastrointestinal stromal tumor (n = 2), and leiomyoma (n = 2). En bloc and piecemeal resection rates were 91.6% (55/60) and 8.3% (5/60), respectively. Complete and incomplete resection rates were 96.6% (58/60) and 3.3% (2/60), respectively. Complications were major bleeding [n = 3 (5%)] and perforations [n = 5 (8.3%)] (4 colon, 1 stomach). Two patients with colonic perforations and two patients with submucosal lymphatic and microvasculature invasion (1 gastric carcinoid tumor, 1 colonic adenocarcinoma) were referred to surgery. During a mean follow-up of 12 mo, 1 patient with adenoma with high grade dysplasia underwent a second ESD procedure to resect a local recurrence. CONCLUSION: ESD is a feasible and safe method for treatment of premalignant lesions and early malignant gastrointestinal epithelial and subepithelial lesions. Successful en bloc and complete resection of lesions yield high cure rates with low recurrence.

Fish consumption and risk of gastrointestinal cancers:A meta-analysis of cohort studies

AIM: To assess quantitatively the relationship between fish intake and the incidence of gastrointestinal cancers in a meta-analysis of cohort studies.

Emerging role of cystic fibrosis transmembrane conductance regulator- an epithelial chloride channel in gastrointestinal cancers

Cystic fibrosis transmembrane conductance regulator(CFTR), a glycoprotein with 1480 amino acids, has been well established as a chloride channel mainly expressed in the epithelial cells of various tissues and organs such as lungs, sweat glands, gastrointestinal system, and reproductive organs. Although defective CFTR leads to cystic fibrosis, a common genetic disorder in the Caucasian population, there is accumulating evidence that suggests a novel role of CFTR in various cancers, especially in gastroenterological cancers, such as pancreatic cancer and colon cancer. In this review, we summarize the emerging findings that link CFTR with various cancers, with focus on the association between CFTR defects and gastrointestinal cancers as well as the underlying mechanisms. Further study of CFTR in cancer biology may help pave a new way for the diagnosis and treatment of gastrointestinal cancers.

Regulatory role of the transforming growth factor-β signaling pathway in the drug resistance of gastrointestinal cancers

Gastrointestinal(GI)cancer,including esophageal,gastric,and colorectal cancer,is one of the most prevalent types of malignant carcinoma and the leading cause of cancer-related deaths.Despite significant advances in therapeutic strategies for GI cancers in recent decades,drug resistance with various mechanisms remains the prevailing cause of therapy failure in GI cancers.Accumulating evidence has demonstrated that the transforming growth factor(TGF)-βsignaling pathway has crucial,complex roles in many cellular functions related to drug resistance.This review summarizes current knowledge regarding the role of the TGF-βsignaling pathway in the resistance of GI cancers to conventional chemotherapy,targeted therapy,immunotherapy,and traditional medicine.Various processes,including epithelial-mesenchymal transition,cancer stem cell development,tumor microenvironment alteration,and microRNA biogenesis,are proposed as the main mechanisms of TGF-β-mediated drug resistance in GI cancers.Several studies have already indicated the benefit of combining antitumor drugs with agents that suppress the TGF-βsignaling pathway,but this approach needs to be verified in additional clinical studies.Moreover,the identification of potential biological markers that can be used to predict the response to TGF-βsignaling pathway inhibitors during anticancer treatments will have important clinical implications in the future.

Biomarkers for response to immune checkpoint inhibitors in gastrointestinal cancers

Gastrointestinal(GI)cancers account for a large proportion of cancer deaths worldwide and pose a major public health challenge.Immunotherapy is considered to be one of the prominent and successful approaches in cancer treatment in recent years.Among them,immune checkpoint inhibitor(ICI)therapy,has received widespread attention,and many clinical findings support the feasibility of ICIs,with sustained responses and significantly prolonged lifespan observed in a wide range of tumors.However,patients treated with ICIs have not fully benefited,and therefore,the identification and development of biomarkers for predicting ICI treatment response have received further attention and exploration.From tumor genome to molecular interactions in the tumor microenvironment,and further expanding to circulating biomarkers and patient characteristics,the exploration of biomarkers is evolving with high-throughput sequencing as well as bioinformatics.More large-scale prospective and specific studies are needed to explore biomarkers in GI cancers.In this review,we summarize the known biomarkers used in ICI therapy for GI tumors.In addition,some ICI biomarkers applied to other tumors are included to provide insights and further validation for GI tumors.Moreover,we present single-cell analysis and machine learning approaches that have emerged in recent years.Although there are no clear applications yet,it can be expected that these techniques will play an important role in the application of biomarker prediction.

Alternative splicing of DNA damage response genes and gastrointestinal cancers

Alternative splicing,which is a common phenomenon in mammalian genomes,is a fundamental process of gene regulation and contributes to great protein diversity.Alternative splicing events not only occur in the normal gene regulation process but are also closely related to certain diseases including cancer.In this review,we briefly demonstrate the concept of alternative splicing and DNA damage and describe the association of alternative splicing and cancer pathogenesis,focusing on the potential relationship of alternative splicing,DNA damage,and gastrointestinal cancers.We will also discuss whether alternative splicing leads to genetic instability,which is considered to be a driving force for tumorigenesis.Better understanding of the role and mechanism of alternative splicing in tumorigenesis may provide new directions for future cancer studies.

Radiofrequency Ablation Combined with Transarterial Chemoembolization for Liver Metastases from Gastrointestinal Cancers

Transarterial chemoembolization（TACE） combined with radiofrequency ablation（RFA） has been reported to be effective for local control of different-sized hepatocellular carcinomas. However, it is unclear if these benefits could also be applicable to different-sized liver metastases from gastrointestinal cancers. The aim of this study was to evaluate the outcomes of TACE combined with RFA for liver metastases from gastrointestinal cancers. In this study, we retrospectively analyzed clinical data of 19 consecutive patients who had a total of 26 liver metastatic lesions from gastrointestinal cancers and underwent RFA followed by first-time TACE treatment. The tumor recurrence, overall survival rate and procedure-related complications were evaluated. Moreover, patients＇ demographics and tumor characteristics were analyzed to determine their impact on the outcomes. The technical success of TACE plus RFA was achieved with 2 major procedure-related complications found. The mean follow-up was 21.3 months. The total 1-, 2-, and 3-year survival rate was 89.4%, 52.6%, and 35.1%, respectively. It was found that the tumor size and the ratio of enhancement area were significant factors that influenced the overall survival. In conclusion, patients with gastrointestinal cancer-derived liver metastatic lesions of smaller size and larger enhancement area are considered appropriate candidates for TACE plus RFA.