Adenoviral gene therapy in gastric cancer： A review

Gastric cancer is one of the most common malignancies worldwide. With current therapeutic approaches the prognosis of gastric cancer is very poor, as gastric cancer accounts for the second most common cause of death in cancer related deaths. Gastric cancer like almost all other cancers has a molecular genetic basis which relies on disruption in normal cellular regulatory mechanisms regarding cell growth, apoptosis and cell division. Thus novel therapeutic approaches such as gene therapy promise to become the alternative choice of treatment in gastric cancer. In gene therapy, suicide genes, tumor suppressor genes and anti-angiogenesis genes among many others are introduced to cancer cells via vectors. Some of the vectors widely used in gene therapy are Adenoviral vectors. This review provides an update of the new developments in adenoviral cancer gene therapy including strategies for inducing apoptosis, inhibiting metastasis and targeting the cancer cells.     

Gene therapy in pancreatic cancer

Pancreatic cancer(PC) is a highly lethal disease and notoriously difficult to treat. Only a small proportion of PC patients are eligible for surgical resection, whilst conventional chemoradiotherapy only has a modest effect with substantial toxicity. Gene therapy has become a new widely investigated therapeutic approach for PC.This article reviews the basic rationale, gene delivery methods, therapeutic targets and developments of laboratory research and clinical trials in gene therapy of PC by searching the literature published in English using the PubMed database and analyzing clinical trials registered on the Gene Therapy Clinical Trials Worldwide website(http://www. wiley.co.uk/genmed/ clinical). Viral vectors are main gene delivery tools in gene therapy of cancer, and especially, oncolytic virus shows brighter prospect due to its tumor-targeting property.Efficient therapeutic targets for gene therapy include tumor suppressor gene p53, mutant oncogene K-ras,anti-angiogenesis gene VEGFR, suicide gene HSK-TK,cytosine deaminase and cytochrome p450, multiple cytokine genes and so on. Combining different targets or combination strategies with traditional chemoradiother-apy may be a more effective approach to improve the efficacy of cancer gene therapy. Cancer gene therapy is not yet applied in clinical practice, but basic and clinical studies have demonstrated its safety and clinical benefits. Gene therapy will be a new and promising field for the treatment of PC.     

Endoscopic mucosal resection in the upper gastrointestinal tract

Endoscopic mucosal resection （EMR） is a technique used to locally excise lesions confined to the mucosa. Its main role is the treatment of advanced dysplasia and early gastrointestinal cancers. EMR was originally described as a therapy for early gastric cancer. Recently its use has expanded as a therapeutic option for ampullary masses, colorectal cancer, and large colorectal polyps. In the Western world, the predominant indication for EMR in the upper gastrointestinal tract is the staging and treatment of advance dysplasia and early neoplasia in Barrett＇s esophagus. This review will describe the basis, indications, techniques, and complications of EMR, and its role in the management of Barrett＇s esophagus.     

Current role of minimally invasive approaches in the treatment of early gastric cancer

Despite declining incidence,gastric cancer remains one of the most common cancers worldwide.Early detection in population-based screening programs has increased the number of cases of early gastric cancer,representing approximately 50%of newly detected gastric cancer cases in Asian countries.Endoscopic mucosal resection and endoscopic submucosal dissection have become the preferred therapeutic techniques in Japan and Korea for the treatment of early gastric cancer patients with a very low risk of lymph node metastasis.Laparoscopic and robotic resections for early gastric cancer,including function-preserving resections,have propagated through advances in technology and surgeon experience.The aim of this paper is to discuss the recent advances in minimally invasive approaches in the treatment of early gastric cancer.     

Gastric cancer stem cells in gastric carcinogenesis,progression,prevention and treatment

In recent decades,the study of the mechanism of tumorigenesis has brought much progress to cancer treatment.However,cancer stem cell(CSC)theory has changed previous views of tumors,and has provided a new method for treatment of cancer.The discovery of CSCs and their characteristics have contributed to understanding the molecular mechanism of tumor genesis and development,resulting in a new effective strategy for cancer treatment.Gastric CSCs(GCSCs)are the basis for the onset of gastric cancer.They may be derived from gastric stem cells in gastric tissues,or bone marrow mesenchymal stem cells.As with other stem cells,GCSCs highly express drug-resistance genes such as aldehyde dehydrogenase and multidrug resistance,which are resistant to chemotherapy and thus form the basis of drug resistance.Many specific molecular markers such as CD44 and CD133 have been used for identification and isolation of GCSCs,diagnosis and grading of gastric cancer,and research on GCSC-targeted therapy for gastric cancer.Therefore,discussion of the recent development and advancements in GCSCs will be helpful for providing novel insight into gastric cancer treatment.     

Glucose metabolism in gastric cancer: The cutting-edge

Glucose metabolism in gastric cancer cells differs from that of normal epithelial cells. Upregulated aerobic glycolysis(Warburg effect) in gastric cancer meeting the demands of cell proliferation is associated with genetic mutations, epigenetic modification and proteomic alteration. Understanding the mechanisms of aerobic glycolysis may contribute to our knowledge of gastric carcinogenesis. Metabolomic studies offer novel, convenient and practical tools in the search for new biomarkers for early detection, diagnosis, prognosis, and chemosensitivity prediction of gastric cancer. Interfering with the process of glycolysis in cancer cells may provide a new and promising therapeutic strategy for gastric cancer. In this article, we present a brief review of recent studies of glucose metabolism in gastric cancer, with primary focus on the clinical applications of new biomarkers and their potential therapeutic role in gastric cancer.     

Novel targeting approaches and signaling pathways of colorectal cancer: An insight

Colorectal cancer(CRC) is the third most common cancer of mortality in the world. Chemotherapy based treatment leads to innumerable side effects as it delivers the anticancer drug to both normal cells besides cancer cells. Sonic Hedgehog(SHH), Wnt wingless-type mouse mammary tumor virus/β-catenin, transforming growth factor-β/SMAD, epidermal growth factor receptor and Notch are the main signaling pathways involved in the progression of CRC. Targeted therapies necessitate information regarding the particular aberrant pathways. Advancements in gene therapies have resulted in the recognition of novel therapeutic targets related with these signal-transduction cascades. CRC is a stepwise process where mutations occur over the time and activation of oncogenes and deactivation of tissue suppressor genes takes place. Genetic changes which are responsible for the induction of carcinogenesis include loss of heterozygosity in tumor suppressor genes such as adenomatous polyposis coli, mutation or deletion of genes like p53 and K-ras. Therefore, many gene-therapy approaches like gene correction, virusdirected enzyme-prodrug therapy, immunogenetic manipulation and virotherapy are currently being explored. Development of novel strategies for the safe and effective delivery of drugs to the cancerous site is the need of the hour. This editorial accentuates different novel strategies with emphasis on gene therapy and immunotherapy for the management of CRC.     

Gene expression profile differences in gastric cancer, pencancerous epithelium and normal gastric mucosa by gene chip

AIM: To study the difference of gene expression in gastric cancer (T), pericancerous epithelium (P) and normal tissue of gastric mucosa (C), and to screen an associated novel gene in early gastric carcinogenesis by oligonudeotide microarray. METHODS: U133A (Affymetrix, Santa Clara, CA) gene chip was used to detect the gene expression profile difference in T, P and C, respectively. Bioinformatics was used to analyze the detected results. RESULTS: When gastric cancer was compared with normal gastric mucosa, 766 genes were found, with a difference of more than four times in expression levels. Of the 766 genes, 530 were up-regulated (Signal Log Ratio [SLR]>2), and 236 were down-regulated (SLR<-2). When pericancerous epithelium was compared with normal gastric mucosa, 64 genes were found, with a difference of more than four times in expression levels. Of the 64 genes, 50 were up-regulated (SLR>2), and 14 were down-regulated (SLR<-2). Compared with normal gastric mucosa, a total of 143 genes with a difference in expression levels (more than four times, either in cancer or in pericancerous epithelium) were found in gastric cancer (T) and pericancerous epithelium (P). Of the 143 genes, 108 were up-regulated (SLR>2), and 35 were down-regulated (SLR<-2). CONCLUSION: To apply a gene chip could find 143 genes associated with the genes of gastric cancer in pericancerous epithelium, although there were no pathological changes in the tissue slices. More interesting, six genes of pericancerous epithelium were up-regulated in comparison with genes of gastric cancer and three genes were down-regulated in comparison with genes of gastric cancer. It is suggested that these genes may be related to the carcinogenesis and development of early gastric cancer.     

Survivin： Potential role in diagnosis, prognosis and targeted therapy of gastric cancer

Survivin is a protein that is highly expressed in a vast number of malignancies,but is minimally expressed in normal tissues. It plays a role as an inhibitor of cell death in cancer cells,thus facilitating the growth of these cells. In the case of gastric cancer,survivin is over-expressed in tumor cells and plays a role in the carcinogenesis process. Several studies on gastric cancer have indicated that there is a relationship between survivin expression and the ultimate behavior of the carcinoma. Since the expression pattern of survivin is selective to cancer cells,it has been described as an "ideal target" for cancer therapy. Currently,several pre-clinical and clinical trials are on-going to investigate the effects of interfering with survivin function in cancer cells as a biologic therapy. Survivin is a potentially significant protein in the diagnosis,prognosis and treatment of gastric tumors.     

Gene therapy： Regulations, ethics and its practicalities in liver disease

Gene therapy is a new and promising approach which opens a new door to the treatment of human diseases. By direct transfer of genetic materials to the target cells, it could exert functions on the level of genes and molecules. It is hoped to be widely used in the treatment of liver disease, especially hepatic tumors by using different vectors encoding the aim gene for anti-tumor activity by activating primary and adaptive immunity, inhibiting oncogene and angiogenesis. Despite the huge curative potential shown in animal models and some pilot clinical trials, gene therapy has been under fierce discussion since its birth in academia and the public domain because of its unexpected side effects and ethical problems. There are other challenges arising from the technique itself like vector design, administration route test and standard protocol exploration. How well we respond will decide the fate of gene therapy clinical medical practice.     

Multidisciplinary management of gastric and gastroesophageal cancers

Carcinomas of the stomach and gastroesophageal junction are among the five top leading cancer types worldwide. In spite of radical surgical R0 resections being the basis of cure of gastric cancer, surgery alone provides long-term survival in only 30% of patients with advanced International Union Against Cancer （UICC） stages in Western countries because of the high risk of recurrence and metachronous metastases. However, recent large phase-Ⅲ studies improved the diagnostic and therapeutic options in gastric cancers, indicating a more multidisciplinary management of the disease. Multimodal strategies combining different neoadjuvant and/or adjuvant protocols have clearly improved the gastric cancer prognosis when combined with surgery with curative intention. In particular, the perioperative （neoadjuvant, adjuvant） chemotherapy is now a well-established new standard of care for advanced tumors. Adjuvant therapy alone should be carefully discussed after surgical resection, mainly in individual patients with large lymph node positive tumors when neoadjuvant therapy could not be done. The palliative treatment options have also been remarkably improved with new chemotherapeutic agents and will further be enhanced with targeted therapies such as different monoclonal antibodies. This article reviews the most relevant literature on the multidisciplinary management of gastric and gastroesophageal cancer, and discusses future strategies toimprove Iocoregional failures.     

Immunological treatment of liver tumors

Although multiple options for the treatment of liver tumors have often been described in the past, including liver resection, radiofrequency ablation with or without hepatic pump insertion, laparoscopic liver resection and the use of chemotherapy, the potential of immunotherapy and gene manipulation is still largely unexplored. Immunological therapy by gene manipulation is based on the interaction between virus-based gene delivery systems and dendritic cells. Using viruses as vectors, it is possible to transduce dendritic cells with genes encoding tumor-associated antigens, thus inducing strong humoral and cellular immunity against the antigens themselves. Both chemotherapy and radiation therapy have the disadvantage of destroying healthy cells, thus causing severe side-effects. We need more precisely targeted therapies capable of killing cancer cells while sparing healthy cells. Our goal is to establish a new treatment for solid liver tumors based on the concept of cytoreduction, and propose an innovative algorithm.     

DNA methylation in gastric cancer,related to Helicobacter pylori and Epstein-Barr virus

Gastric cancer is a leading cause of cancer death worldwide,and significant effort has been focused on clarifying the pathology of gastric cancer.In particular,the development of genome-wide analysis tools has enabled the detection of genetic and epigenetic alterations in gastric cancer;for example,aberrant DNA methylation in gene promoter regions is thought to play a crucial role in gastric carcinogenesis.The etiological viewpoint is also essential for the study of gastric cancers,and two distinct pathogens,Helicobacter pylori(H.pylori)and Epstein-Barr virus(EBV),are known to participate in gastric carcinogenesis.Chronic inflammation of the gastric epithelium due to H.pylori infection induces aberrant polyclonal methylation that may lead to an increased risk of gastric cancer.In addition,EBV infection is known to cause extensive methylation,and EBV-positive gastric cancers display a high methylation epigenotype,in which aberrant methylation extends to not only Polycomb repressive complex(PRC)-target genes in embryonic stem cells but also non-PRC-target genes.Here,we review aberrant DNA methylation in gastric cancer and the association between methylation and infection with H.pylori and EBV.     

Endoscopic therapy for early gastric cancer: Standard techniques and recent advances in ESD

The technique of endoscopic submucosal dissection(ESD)is now a well-known endoscopic therapy for early gastric cancer.ESD was introduced to resect large specimens of early gastric cancer in a single piece.ESD can provide precision of histologic diagnosis and can also reduce the recurrence rate.However,the drawback of ESD is its technical difficulty,and,consequently,it is associated with a high rate of complications,the need for advanced endoscopic techniques,and a lengthy procedure time.Various advances in the devices and techniques used for ESD have contributed to overcoming these drawbacks.     

Role of human epidermal growth factor receptor 2 in gastric cancer:Biological and pharmacological aspects

Amplification of the human epidermal growth factor receptor 2(HER2)gene and overexpression of the HER2protein is found in 15%-20%of patients with gastric and gastroesophageal junction cancer.The degree of HER2 overexpression and amplification varies with the location of the carcinoma,with higher expression in the gastroesophageal and proximal parts compared to the distal parts of the stomach.Further,HER2 overexpression and amplification also seems to be related to the Lauren histological classification,with higher levels found in the intestinal phenotype compared to the diffuse and mixed types.The prognostic properties of HER2 overexpression and amplification are still under debate,but a large number of studies seem to indicate that HER2 is a negative prognostic factor.The usefulness of HER2 targeted therapy in gastric cancer was demonstrated in the ToGA trial,where HER2-positive patients with advanced gastric and gastroesophageal junction adenocarcinoma were randomized to receive5-FU/capecitabine and cisplatin,either alone or in combination with trastuzumab.A statically significant gain in overall survival was seen in patients who received the combined treatment of trastuzumab and chemotherapy.Patients with a strong overexpression of the HER2 protein(IHC3+)specifically benefited from the treatment,with a median overall survival of 17.9 mo.As a consequence of the positive results of the ToGA trial,patients with advanced gastric or gastroesophageal junction adenocarcinoma are now routinely tested for HER2.The ToGA trial must be characterized as a landmark in the treatment of gastric cancer and it has paved the way for a number of new HER2 targeted compounds such as pertuzumab,ado-trastuzumab emtansine,lapatinib,afatinib,and dacomitinib,which are currently undergoing phaseⅡandⅢclinical testing.Overall,this review will discuss the current status of HER2 in gastric and gastroesophageal junction cancer and the future direction in relation to HER2 target therapy.     

Gastrointestinal radiation injury:Prevention and treatment

With the recent advances in detection and treatment of cancer,there is an increasing emphasis on the efficacy and safety aspects of cancer therapy.Radiation therapy is a common treatment for a wide variety of cancers,either alone or in combination with other treatments.Ionising radiation injury to the gastrointestinal tract is a frequent side effect of radiation therapy and a considerable proportion of patients suffer acute or chronic gastrointestinal symptoms as a result.These side effects often cause morbidity and may in some cases lower the efficacy of radiotherapy treatment.Radiation injury to the gastrointestinal tract can be minimised by either of two strategies:technical strategies which aim to physically shift radiation dose away from the normal intestinal tissues,and biological strategies which aim to modulate the normal tissue response to ionising radiation or to increase its resistance to it.Although considerable improvement in the safety of radiotherapy treatment has been achieved through the use of modern optimised planning and delivery techniques,biological techniques may offer additional further promise.Different agents have been used to prevent or minimize the severity of gastrointestinal injury induced by ionising radiation exposure,including biological,chemical and pharmacological agents.In this review we aim to discuss various technical strategies to prevent gastrointestinal injury during cancer radiotherapy,examine the different therapeutic options for acute and chronic gastrointestinal radiation injury and outline some examples of research directions and considerations for prevention at a pre-clinical level.     

Role of receptor tyrosine kinases in gastric cancer： New targets for a selective therapy

Receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor family participate in several steps of tumor formation including proliferation and metastatic spread. Several known RTKs are upregulated in gastric cancer being prime targets of a tailored therapy. Only preliminary data exist, however, on the use of the currently clinically available drugs such as trastuzumab, cetuximab, bevacizumab, gefitinib, erlotinib, and imatinib in the setting of gastric cancer. Preclinical data suggest a potential benefit of their use, especially in combination with "conventional" cytostatic therapy. This review summarizes the current knowledge about their use in cancer therapy as well as new approaches and drugs to optimize treatment success.