A gist of gastrointestinal stromal tumors: A review

Gastrointestinal stromal tumors (GISTs) have been recognized as a biologically distinctive tumor type, different from smooth muscle and neural tumors of the gastrointestinal tract (GIT). They constitute the majority of gastrointestinal mesenchymal tumors of the GIT and are known to be refractory to conventional chemotherapy or radiation. They are defined and diagnosed by the expression of a proto-oncogene protein detected by immunohistochemistry which serves as a crucial diagnostic and therapeutic target. The identification of these mutations has resulted in a better understanding of their oncogenic mechanisms. The remarkable antitumor effects of the molecular inhibitor imatinib have necessitated accurate diagnosis of GIST and their distinction from other gastrointestinal mes-enchymal tumors. Both traditional and minimally invasive surgery are used to remove these tumors with minimal morbidity and excellent perioperative outcomes. The revolutionary use of specific, molecularlytargeted therapies, such as imatinib mesylate, reduces the frequency of disease recurrence when used as an adjuvant following complete resection. Neoadjuvant treatment with these agents appears to stabilize disease in the majority of patients and may reduce the extent of surgical resection required for subsequent complete tumor removal. The important interplay between the molecular genetics of GIST and responses to targeted therapeutics serves as a model for the study of targeted therapies in other solid tumors. This review summarizes our current knowledge and recent advances regarding the histogenesis, pathology, molecular biology, the basis for the novel targeted cancer therapy and current evidence based management of these unique tumors.     

Markers of bile duct tumors

Biliary tract carcinomas are relatively rare,representing less than 1%of cancers.However,their incidence has increased in Japan and in industrialized countries like the USA.Biliary tract tumors have a poor prognosis and a high mortality rate because they are usually detected late in the course of the disease;therapeutic treatment options are often limited and of minimal utility.Recent studies have shown the importance of serum and molecularmarkers in the diagnosis and follow up of biliary tract tumors.This review aims to introduce the main features of the most important serum and molecular markers of biliary tree tumors.Some considerable tumor markers are cancer antigen 125,carbohydrate antigen 19-9,carcinoembryonic antigen,chromogranin A,mucin 1,mucin 5,alpha-fetoprotein,claudins and cytokeratins.     

Epigenetics of cutaneous T-cell lymphoma:biomarkers and therapeutic potentials

Cutaneous T-cell lymphomas(CTCLs)are a heterogeneous group of skin-homing non-Hodgkin lymphomas.There are limited options for effective treatment of patients with advanced-stage CTCL,leading to a poor survival rate.Epigenetics plays a pivotal role in regulating gene expression without altering the DNA sequence.Epigenetic alterations are involved in virtually all key cancerassociated pathways and are fundamental to the genesis of cancer.In recent years,the epigenetic hallmarks of CTCL have been gradually elucidated and their potential values in the diagnosis,prognosis,and therapeutic intervention have been clarified.In this review,we summarize the current knowledge of the best-studied epigenetic modifications in CTCL,including DNA methylation,histone modifications,micro RNAs,and chromatin remodelers.These epigenetic regulators are essential in the development of CTCL and provide new insights into the clinical treatments of this refractory disease.     

miR-218与宫颈癌关系的研究进展(英文)

MicroRNAs (miRNAs) are small endogenous non-coding RNAs which can specifically silence gene expression, and thereby alter cell and organism phenotype. Deregulation of miRNA expression has been discovered in a variety of tumors and it is now clear that they contribute to cancer development and progression. Previous studies have indicated that miRNAs are involved in developmental timing, cell proliferation, apoptosis, morphogenesis [1] , antiviral defense [2] , and tumorigenesis [3] . In cancer pathways, altered expression of tumor suppressive or oncogenic miRNAs can disrupt regulatory mechanisms normal. Altered miRNAs expression patterns have been observed in a variety of diseased tissues. Cervical cancer is the most common malignant tumor in female reproductive tract. Recently more and more study showed a large number of miRNAs were down-regulated or up-regulated in cervical cancer. Recent data revealed that miRNA-218 (miR-218) played important roles in tumor initiation and development. This review focuses on analysis of miR-218 and will provide some insight into the progress of cervical cancer.     

APOPTOSIS INDUCTION BY THE RECOMBINANT FUSION APOPTOSIS INDUCING FACTOR ON HELA CELLS

Objective: To obtain the recombinant fusion AIF genes inserted into the eukaryotic expression vector pIRES2-EGFP, to observe the expression and location of the fusion AIF genes (3NE: PE(280-358)-AIF△1-120, and 4NE:PE(280-364)-AIF△1-120), and to detect and compare their apoptosis inducing effects on the transfected HeLa cells.Methods: Full-length human AIF gene was cloned by RT-PCR, and its N-terminal mitochondrial localization sequence (MLS) was replaced by part sequence of Psuedomonas exotoxin A (PE) translocation domain(PEII(280-358/364)), then the recombinant fusion genes were inserted into the pIRES2-EGFP eukaryotic expression vector. After these genes were transiently transfected into HeLa cells with LipofectAmine, the expression of the recombinant fusion AIF genes and their effects on HeLa cells were detected by fluorescent microscopy, laser confocal microscopy and electron microscopy. Results: The eukaryotic expression vectors containing the recombinant fusion AIF genes (pIRES2-EGFP-PEII(280-358/364)-AIF△1-120) were constructed successfully. It was demonstrated that the fusion AIF protein genes were expressed effectively in the transfected cells, with the GFP co-expressed in cells by indirect immunofluorescence staining analysis. After transfection, expression of the genes could induce HeLa cells to exhibit the typical apoptosis features: such as plasma membrane blebbing and peripheral chromatin condensation. As compared with control groups, the untreated cells and the void vector transfected cells, the living cell number of the AIF gene transfected cells reduced distinctly. Conclusion: Our data prove that the expression of the recombinant human AIF fusion genes could induce apoptosis in transfected HeLa cells, which provides new strategy for cancer killing.     

Expression of the CXCL12/CXCR4 and CXCL16/CXCR6 axes in cervical intraepithelial neoplasia and cervical cancer

The chemokine CXCL12 is highly expressed in gynecologic tumors and is widely known to play a biologically relevant role in tumor growth and spread. Recent evidence suggests that CXCL16, a novel chemokine, is overexpressed in inflammation-associated tumors and mediates pro-tumorigenic effects of inflammation in prostate cancer. We therefore analyzed the expression of CXCL12 and CXCL16 and their respective receptors CXCR4 and CXCR6 in cervical intraepithelial neoplasia (CIN) and cervical cancer and further assessed their association with clinicopathologic features and outcomes. Tissue chip technology and immunohistochemistry were used to analyze the expression of CXCL12, CXCR4, CXCL16, and CXCR6 in healthy cervical tissue (21 cases), CIN (65 cases), and cervical carcinoma (60 cases). The association of protein expression with clinicopathologic features and overall survival was analyzed. These four proteins were clearly detected in membrane and cytoplasm of neoplastic epithelial cells, and their distribution and intensity of expression increased as neoplastic lesions progressed through CIN1, CIN2, and CIN3 to invasive cancer. Furthermore, the expression of CXCR4 was associated significantly with the histologic grade of cervical carcinoma, whereas the expression of CXCR6 was associated significantly with lymph node metastasis. In Kaplan-Meier analysis, patients with high CXCR6 expression had significantly shorter overall survival than did those with low CXCR6 expression. The elevated co-expression levels of CXCL12/CXCR4 and CXCL16/CXCR6 in CIN and cervical carcinoma suggest a durative process in cervical carcinoma development. Moreover, CXCR6 may be useful as a biomarker and a valuable prognostic factor for cervical cancer.     

Molecular markers as therapeutic targets in lung cancer

Lung cancer is responsible for 29% of cancer deaths in the United States and has very low 5-year survival rates of approximately 11% in men and 15% in women.Although the early diagnosis of lung cancer may increase the survival rate with adequate treatment,advanced lung cancers are often metastasized and receive limited benefit from therapeutic regimens.As conventional treatments for lung cancer reach their limitations,researchers have attempted to discover novel drug therapies aimed at specific targets contributing to the progression of tumorigenesis.Recent advances in systems biology have enabled the molecular biology of lung carcinogenesis to be elucidated.Our understanding of the physiologic processes of tumor development provide a means to design more effective and specific drugs with less toxicity,thereby accelerating the delivery of new drug therapies to the patient’s bedside.     

Identification of TM9SF2 as a candidate of the cell surface marker common to breast carcinoma cells

OBJECTIVE We aimed identification of cell surface molecules, which might serve as diagnostic biomarkers or useful targets for therapies, in breast cancer. METHODS We developed unique DNA microarray coupled with spherical self-organizing map （sSOM） analysis to characterize cells and tissues by the cell surface markers. In the microarray 1,797 probes for human genes coding membrane bound proteins were spotted. With this microarray the gene expression profiles of eight breast carcinoma cell lines were compared to identify the genes that were commonly expressed in breast carcinomas but not in normal cells. RESULTS The gene expression profiles of sSOM from the eight breast carcinoma cell lines were successfully distinguished from that of normal breast tissue derived cells suggesting the presence of genes of interest, sSOMon the data extensively filtered revealed several candidate genes, of which expression was significant in carcinoma cells but low in normal cells. Finally, TM9SF2 was nominated through validations of PCR procedures together with CD24 and ErbB3, which are known breast carcinoma markers. TMgSF2 expression was further confirmed by immunological staining. Interestingly, TMgSF2 was found to be expressed in all the cell lines evaluated while CD24 and ErbB3 were not in all of the carcinoma cells, supporting their relationship in sSOM. Although physiological significance of TMgSF2 is unknown yet, siRNA treatment significantly inhibited the growth of MDA- MB-231 cells. CONCLUSION We propose TM9SF2 as a novel and useful diagnostic marker as well as a potential molecular target specific to breast carcinoma cells covering wide range of breast cancer.     

大肠癌中Livin和IGF-Ⅱ表达的相关性研究

Objective: The aim of the study was to test the expressions of Livin and insulin-like growth factor Ⅱ(IGF-Ⅱ)in colorectal cancers and discuss their significance of carcinogenesis and progression in colorectal cancers,to provide a new target and theory basement for cancer therapy.Methods: The expressions of Livin and IGF-Ⅱ were detected by immunohistochemistry SABC in 60 cases of colorectal cancer and their associated colorectal tissues,and the associations between the expression levels of Livin and IGF-histochemistry and clinical pathological characteristics were analyzed.Results: The positive rates of Livin and IGF-Ⅱ in colorectal carcinomas were 68.33% and 63.33% respectively,higher than those of para-carcinomatous normal tissues and colorectal adenomas.There were no significant correlations between the expressions of Livin,IGF-Ⅱ in colorectal carcinomas and the patient's age,sex,tumor size and location,while distant metastasis,Dukes stage,histological type,lymph node metastasis,and whether the tumors have received radiotherapy and chemotherapy were significantly correlated with the expressions of Livin,IGF-cal in colorectal carcinomas.Conclusion: Livin and IGF-cal play important roles in carcinogenesis and progression of colorectal cancer.This study showed obvious correlation between the expressions of Livin and IGF-Ⅱ in colorectal cancers.It could be used as the reference for further researches.Livin is hopeful to be a new molecular target in cancer therapy.     

Lung Cancer: MicroRNA and Target Database

MicroRNAs(miRNAs) are a class of non-coding RNAs that hybridize to mRNAs and induce either translation repression or mRNA cleavage.Recently,it has been reported that miRNAs could possibly play a critical role in cellular processes like regulation of cell growth,differentiation,and apoptosis,emphasizing their role in tumorigenesis.Likewise,several miRNA’s are involved in lung cancer tumorigenesis.The present review puts forth a database of human miRNA’s involved in lung cancer along with their target genes.It also provides sequences of miRNA’s and their chromosomal locations retrieved from different databases like microCosm(218 microRNAs),PhenomiR(293 microRNAs),and mir2Disease(90 microRNAs) and target gene information such as the pathways like cell cycle regulation,angiogenesis,apoptosis etc.Though miRNA’s are still to be explored,they hold a promise as therapeutic targets and diagnostic markers of cancer.     

Multiple cells of origin in cholangiocarcinoma underlie biological, epidemiological and clinical heterogeneity

Recent histological and molecular characterization of cholangiocarcinoma(CCA) highlights the heterogeneity of this cancer that may emerge at different sites of the biliary tree and with different macroscopic or morphological features.Furthermore,different stem cell niches have been recently described in the liver and biliarytree,suggesting this as the basis of the heterogeneity of intrahepatic(IH)-and extrahepatic(EH)-CCAs,which are two largely different tumors from both biological and epidemiological points of view.The complexity of the organization of the liver stem cell compartments could underlie the CCA clinical-pathological heterogeneity and the criticisms in classifying primitive liver tumors.These recent advances highlight a possible new classification of CCAs based on cells of origin and this responds to the need of generating homogenous diagnostic,prognostic and,hopefully,therapeutic categories of IH-and EH-CCAs.     

Targeted treatment of cancer with radiofrequency electromagnetic fields amplitude-modulated at tumor-specific frequencies

In the past century, there have been many attempts to treat cancer with low levels of electric and magnetic fields. We have developed noninvasive biofeedback examination devices and techniques and discovered that patients with the same tumor type exhibit biofeedback responses to the same, precise frequencies. Intrabuccal administration of 27.12 MHz radiofrequency （RF） electromagnetic fields （EMF）, which are amplitude-modulated at tumor-specific frequencies, results in long-term objective responses in patients with cancer and is not associated with any significant adverse effects. Intrabuccal administration allows for therapeutic delivery of very low and safe levels of EMF throughout the body as exemplified by responses observed in the femur, liver, adrenal glands, and lungs. In vitro studies have demonstrated that tumor-specific frequencies identified in patients with various forms of cancer are capable of blocking the growth of tumor cells in a tissue- and tumor-specific fashion. Current experimental evidence suggests that tumor-specific modulation frequencies regulate the expression of genes involved in migration and invasion and disrupt the mitotic spindle. This novel targeted treatment approach is emerging as an appealing therapeutic option for patients with advanced cancer given its excellent tolerability. Dissection of the molecular mechanisms accounting for the anti-cancer effects of tumor-specific modulation frequencies is likely to lead to the discovery of novel pathways in cancer.     

Carcinoid of the Esophagus Concomitant with Adenocarcinoma of the Esophagus: One Case Report and Literature Review

Introduction Neuroendocrine tumor covers a wide range of neoplasms that originate in the neuroendocrine cells which spread throughout the body.Carcinoid tumor, and neuroendocrine tumor are low-grade malignant tumors, their growth is slow, and mainly in the gastrointestinal epithelium. Esophageal adenocarcinoma tumor is a big problem in esophageal cancer. Combined esophageal adenocarcinoma and carcinoid tumor both as primary tumors is very rare[1]. Neuroendocrine tumors of the esophagus are derived from the diffuse neuroendocrine system in the gastrointestinal tract. Neuroendocrine tumors in the esophagus can be distinguished from other mesenchymal tumors by immunostaining for synaptophysin and chromogranin-A. Both carcinoid of the esophagus and adenocarcinoma of the esophagus are malignant tumors and considered to have a specifi c molecular pathogenesis. This paper presents a rare case diagnosed as carcinoid of the esophagus concomitant with an adenocarcinoma of the esophagus, a review of the literature is also presented here.     

In vitro effect of iASPP on cell growth of oral tongue squamous cell carcinoma

iASPP is an inhibitory member of the apoptosis-stimulating proteins of P53 （ASPP） family. iASPP is over expressed in several malignant tumors and potentially affects cancer progression. However, the expression and potential role of iASPP in oral tongue squamous cell carcinoma （OTSCC） have not been addressed. In our study, we detected iASPP expression in OTSCC by immunohistochemistry, iASPP expression is up-regulated in OTSCC tissues. Moreover, in clinical pathology specimens, we found that increased iASPP expression correlates with poor differentiation and lymph node metastasis. Using multicellular tumor spheroids （MTS） and flow cytometry, we demonstrated that iASPP down-regulation arrests OTSCC cells at the G0/G1 phase, induces OTSCC cell apoptosis and inhibits OTSCC cell proliferation. These results indicate that iASPP plays a significant role in the progression of OTSCC and may serve as a biomarker or therapeutic target for OTSCC patients.     

Single-nucleotide polymorphisms of matrix metalloproteinases and their inhibitors in gastrointestinal cancer

Matrix metalloproteinases(MMPs) are implicated in cancer development and progression and are associated with prognosis.Single-nucleotide polymorphisms(SNPs) of MMPs,most frequently located in the promoter region of the genes,have been shown to influence cancer susceptibility and/or progression.SNPs of MMP-1,-2,-3,-7,-8,-9,-12,-13 and-21 and of the tissue inhibitor of metalloproteinases(TIMPs) TIMP-1 and TIMP-2 have been studied in digestive tract tumors.The contribution of these polymorphisms to the cancer risk and prognosis of gastrointestinal tumors are reviewed in this paper.     

EXPERIMENTAL RESEARCH OF EFFECTIVENESS OF siRNA- Her-2/neu ON DRUG SENSITIVITY OF Her-2/neu-OVEREXPRESSING LUNG ADENOCARCINOMA CELL LINE

Lung cancer is a potentially systemic disease. Despite improvements in the detection and treatment of lung cancer in the past two decades, the overall 5-year survival remains <15%. Constitutive overexpression for Her-2/neu gene is a frequent event in a variety of human tumors, including non-small cell lung cancer (NSCLC), but not small cell lungcancer[1-5]. In recent years, many studies have explored the effects on chemosensitivity resulting from altered expression and activation of the Her…     

HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity

Cancer stem cells are rare tumor cells characterized by their ability to self-renew and to induce tumorigenesis. They are present in gliomas and may be responsible for the lethality of these incurable brain tumors. In the most aggressive and invasive type, glloblastoma multiforme （GBM）, an average of about one year spans the period between detection and death [1]. The resistence of gliomas to current therapies may be related to the existence of cancer stem cells [2-6]. We find that human gliomas display a stemness signature and demonstrate that HEDGEHOG （HH）-GLI signaling regulates the expression of sternness genes in and the self-renewal of CD133 （＋） glioma cancer stem cells. HH-GLI signaling is also required for sustained glioma growth and survival. It displays additive and synergistic effects with temozolomide （TMZ）, the current hemotherapeutic agent of choice. TMZ, however, does not block glioma stem cell self-renewal. Finally, interference of HH-GLI signaling with cyclopamine or through lentiviral-mediated silencing demonstrates that the tumorigenicity of human gliomas in mice requires an active pathway. Our results reveal the essential role of HH-GLI signaling in controlling the behavior of human glioma cancer stem cells and offer new therapeutic possibilities.