Journal of Carcinogenesis最新文献

{"title":"Antisense oligonucleotides directed against insulin-like growth factor-II messenger ribonucleic acids delay the progress of rat hepatocarcinogenesis.","authors":"Miltu Kumar Ghosh,&nbsp;Falguni Patra,&nbsp;Shampa Ghosh,&nbsp;Chowdhury Mobaswar Hossain,&nbsp;Biswajit Mukherjee","doi":"10.4103/1477-3163.126761","DOIUrl":"https://doi.org/10.4103/1477-3163.126761","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is a multistep complex process, caused by many of genetic alteration. Insulin-like growth factors and their receptor have been widely implicated to HCC. Insulin-like growth factor-II (IGF-II) is a mitogenic polypeptide, found in various fetal and neonatal tissues of humans and rats and expresses in HCC. Here we investigated anticancer potential of phosphorothioate antisense oligonucleotides (ASOs) against three coding exons (exon-1/exon-2/exon-3) of IGF-II messenger ribonucleic acid in rat hepatocarcinogenesis model.</p><p><strong>Materials and methods: </strong>During diethylnitrosamine and 2-acetylaminofluorene induced hepatocarcinogenesis, rats were treated with ASOs. Various biochemical and histological studies were conducted.</p><p><strong>Results: </strong>About 40% of carcinogen treated rats, which received two oligomers (against exon-1 or-3) did not show any hepatic lesion, hyperplastic nodule or tumor and remaining 60% of those rats showed lesion incidence and had about 59% and 55% reductions in the numbers of hepatic altered foci, respectively. Reductions in the total lesion-area when compared with carcinogen control rats were 64% and 53%, respectively for the animals treated with carcinogen and received the ASOs against exon-1/-3. Fluorescein isothiocyanate-labeled ASO reached in the hepatocytes in 2 h. No predominant IGF-II overexpression was observed in case of rats treated with the two ASOs. Treatment of the antisense IGF-II oligomers in carcinogen treated rats show better hepatocellular integrity along with several preneoplastic/neoplastic marker isoenzyme/enzyme modulations.</p><p><strong>Conclusions: </strong>Two of the three antisense oligomer-types effectively controlled IGF-II overexpression, causing the delay of the development and/or progress of hepatic cancer in rats.</p>","PeriodicalId":52464,"journal":{"name":"Journal of Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4103/1477-3163.126761","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32266755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BRAF and beyond: Tailoring strategies for the individual melanoma patient.","authors":"Anthony Jarkowski,&nbsp;Nikhil I Khushalani","doi":"10.4103/1477-3163.126759","DOIUrl":"https://doi.org/10.4103/1477-3163.126759","url":null,"abstract":"<p><p>Until recently, options for therapy in metastatic melanoma were limited. The understanding of immune check-point blockade and the discovery of molecular pathways involving driver mutations like BRAF has transformed the therapeutic landscape in this disease. Ipilimumab was the first drug shown to improve survival while vemurafenib demonstrated rapid responses never seen before in melanoma. Drugs from these classes and others are now in advanced stages of development and primed to positively impact patient survival in an incremental fashion. In this review, we highlight some of the developments during this renaissance in melanoma therapy and discuss agents of promise. Clinical challenges we face include individualizing therapy for patients, overcoming resistance to molecularly targeted therapy and developing rationale combinations or sequences of drugs. A concerted bench and bedside effort in this direction will undoubtedly keep melanoma in the forefront in an era of personalized medicine. </p>","PeriodicalId":52464,"journal":{"name":"Journal of Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4103/1477-3163.126759","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32266754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted therapies in development for non-small cell lung cancer.","authors":"Thanyanan Reungwetwattana, Grace Kho Dy","doi":"10.4103/1477-3163.123972","DOIUrl":"10.4103/1477-3163.123972","url":null,"abstract":"<p><p>The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by \"druggable\" protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC), the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2]), RAS (rat sarcoma gene), BRAF (v-raf murine sarcoma viral oncogene homolog B1), MAPK (mitogen-activated protein kinase) c-MET (c-mesenchymal-epithelial transition), FGFR (fibroblast growth factor receptor), DDR2 (discoidin domain receptor 2), PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha)), PTEN (phosphatase and tensin homolog), AKT (protein kinase B), ALK (anaplastic lym phoma kinase), RET (rearranged during transfection), ROS1 (reactive oxygen species 1) and EPH (erythropoietin-producing hepatoma) are key targets of various agents currently in clinical development. These oncogenic targets exert their selective growth advantage through various intercommunicating pathways, such as through RAS/RAF/MEK, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and SRC-signal transduction and transcription signaling. The recent clinical studies, EGFR tyrosine kinase inhibitors and crizotinib were considered as strongly effective targeted therapies in metastatic NSCLC. Currently, five molecular targeted agents were approved for treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4)-ALK translocation and bevacizumab. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes are predicted and demonstrated to be synergistic and advantageous in overcoming treatment resistance compared with monotherapy approaches. Understanding the role of the tumor microenvironment in the development and maintenance of the malignant phenotype provided additional therapeutic approaches as well. More recently, improved knowledge on tumor immunology has set the stage for promising immunotherapies in NSCLC. This review will focus on the rationale for the development of targeted therapies in NSCLC and the various strategies employed in preventing or overcoming the inevitable occurrence of treatment resistance. </p>","PeriodicalId":52464,"journal":{"name":"Journal of Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2013-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32157352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"p53 and regulation of tumor metabolism.","authors":"Peng Jiang,&nbsp;Wenjing Du,&nbsp;Xiaolu Yang","doi":"10.4103/1477-3163.122760","DOIUrl":"https://doi.org/10.4103/1477-3163.122760","url":null,"abstract":"<p><p>The tumor suppressor p53 plays a pre-eminent role in protecting against cancer, through its ability to sense various stresses and in turn invoke anti-proliferative and repair responses. Emerging evidence suggest that p53 is both a central sentinel for metabolic stresses and a master regulator of metabolic fluxes. This newly identified function of p53, along with the ability of p53 to induce senescence, appears to be crucial for the prevention of oncogenic transformation. A better understanding of the reciprocal regulation of p53 and metabolism, as well as p53-mediated connection between metabolism and senescence, may lead to the identification of valuable targets for tumor therapy. </p>","PeriodicalId":52464,"journal":{"name":"Journal of Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2013-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31991171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"O-6-methylguanine-deoxyribonucleic acid methyltransferase methylation enhances response to temozolomide treatment in esophageal cancer.","authors":"Rifat Hasina,&nbsp;Mosmi Surati,&nbsp;Ichiro Kawada,&nbsp;Qudsia Arif,&nbsp;George B Carey,&nbsp;Rajani Kanteti,&nbsp;Aliya N Husain,&nbsp;Mark K Ferguson,&nbsp;Everett E Vokes,&nbsp;Victoria M Villaflor,&nbsp;Ravi Salgia","doi":"10.4103/1477-3163.120632","DOIUrl":"https://doi.org/10.4103/1477-3163.120632","url":null,"abstract":"<p><strong>Background: </strong>World-wide, esophageal cancer is a growing epidemic and patients frequently present with advanced disease that is surgically inoperable. Hence, chemotherapy is the predominate treatment. Cytotoxic platinum compounds are mostly used, but their efficacy is only moderate. Newer alkylating agents have shown promise in other tumor types, but little is known about their utility in esophageal cancer.</p><p><strong>Methods: </strong>We utilized archived human esophageal cancer samples and esophageal cancer cell lines to evaluate O-6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) hypermethylation status and determined sensitivity to the alkylating drug temozolomide (TMZ). Immunoblot analysis was performed to determine MGMT protein expression in cell lines. To assess and confirm the effect of TMZ treatment in a methylated esophageal cancer cell line in vivo, a mouse flank xenograft tumor model was utilized.</p><p><strong>Results: </strong>Nearly 71% (12/17) of adenocarcinoma and 38% (3/8) of squamous cell carcinoma (SCC) patient samples were MGMT hypermethylated. Out of four adenocarcinoma and nine SCC cell lines tested, one of each histology was hypermethylated. Immunoblot analyses confirmed that hypermethylated cell lines did not express the MGMT protein. In vitro cell viability assays showed the methylated Kyse-140 and FLO cells to be sensitive to TMZ at an IC50 of 52-420 μM, whereas unmethylated cells Kyse-410 and SKGT-4 did not respond. In an in vivo xenograft tumor model with Kyse-140 cells, which are MGMT hypermethylated, TMZ treatment abrogated tumor growth by more than 60%.</p><p><strong>Conclusion: </strong>MGMT methylation may be an important biomarker in subsets of esophageal cancers and targeting by TMZ may be utilized to successfully treat these patients.</p>","PeriodicalId":52464,"journal":{"name":"Journal of Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2013-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4103/1477-3163.120632","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31939203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obesity, metabolism and the microenvironment: Links to cancer.","authors":"Sneha Sundaram,&nbsp;Amy R Johnson,&nbsp;Liza Makowski","doi":"10.4103/1477-3163.119606","DOIUrl":"https://doi.org/10.4103/1477-3163.119606","url":null,"abstract":"<p><p>Historically, cancer research has focused on identifying mutations or amplification of genes within the tumor, which informed the development of targeted therapies against affected pathways. This work often considers tumor cells in isolation; however, it is becoming increasingly apparent that the microenvironment surrounding tumor cells strongly influences tumor onset and progression. This is the so-called \"seed and soil\" hypothesis wherein the seed (cancer cell) is fed and molded by the metabolites, growth factors, modifications of the extracellular matrix or angiogenic factors provided by the soil (or stroma). Currently, 65% of the US population is obese or overweight; similarly staggering figures are reported in US children and globally. Obesity mediates and can exacerbate, both normal and tumor microenvironment dysfunction. Many obesity-associated endocrine, metabolic and inflammatory mediators are suspected to play a role in oncogenesis by modifying systemic nutrient metabolism and the nutrient substrates available locally in the stroma. It is vitally important to understand the biological processes linking obesity and cancer to develop better intervention strategies aimed at curbing the carcinogenic events associated with obesity. In this review, obesity-driven changes in both the normal and tumor microenvironment, alterations in metabolism, and release of signaling molecules such as endocrine, growth, and inflammatory mediators will be highlighted. In addition, we will discuss the effects of the timing of obesity onset or particular \"windows of susceptibility,\" with a focus on breast cancer etiology. </p>","PeriodicalId":52464,"journal":{"name":"Journal of Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2013-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4103/1477-3163.119606","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31862329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intersection of Smoking, Human immunodeficiency virus/acquired immunodeficiency syndrome and Cancer: Proceedings of the 8(th) Annual Texas Conference on Health Disparities.","authors":"Smrithi Rajendiran,&nbsp;Meghana V Kashyap,&nbsp;Jamboor K Vishwanatha","doi":"10.4103/1477-3163.119388","DOIUrl":"https://doi.org/10.4103/1477-3163.119388","url":null,"abstract":"<p><p>The Texas Center for Health Disparities, a National Institute on Minority Health and Health Disparities Center of Excellence, presents an annual conference to discuss prevention, awareness education and ongoing research about health disparities both in Texas and among the national population. The 2013 Texas Conference on Health Disparities brought together experts, in research, patient care and community outreach, on the \"Intersection of Smoking, Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and Cancer\". Smoking, HIV/AIDS and cancer are three individual areas of public health concern, each with its own set of disparities and risk factors based on race, ethnicity, gender, geography and socio-economic status. Disparities among patient populations, in which these issues are found to be comorbid, provide valuable information on goals for patient care. The conference consisted of three sessions addressing \"Comorbidities and Treatment\", \"Public Health Perspectives\", and \"Best Practices\". This article summarizes the basic science, clinical correlates and public health data presented by the speakers. </p>","PeriodicalId":52464,"journal":{"name":"Journal of Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2013-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4103/1477-3163.119388","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31862327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dealing with hunger: Metabolic stress responses in tumors.","authors":"Michael A Reid,&nbsp;Mei Kong","doi":"10.4103/1477-3163.119111","DOIUrl":"https://doi.org/10.4103/1477-3163.119111","url":null,"abstract":"<p><p>Increased nutrient uptake and usage is a hallmark of many human malignancies. During the course of tumorigenesis, cancer cells often outstrip their local nutrient supply leading to periods of nutrient deprivation. Interestingly, cancer cells often develop strategies to adapt and survive these challenging conditions. Accordingly, understanding these processes is critical for developing therapies that target cancer metabolism. Exciting new progress has been made in elucidating the mechanisms used by cancer cells under nutrient restricted conditions. In this review, we highlight recent studies that have brought insight into how cancer cells deal with low nutrient environments. </p>","PeriodicalId":52464,"journal":{"name":"Journal of Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2013-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4103/1477-3163.119111","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31862326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unravelling the connection between metabolism and tumorigenesis through studies of the liver kinase B1 tumour suppressor.","authors":"David B Shackelford","doi":"10.4103/1477-3163.116323","DOIUrl":"https://doi.org/10.4103/1477-3163.116323","url":null,"abstract":"<p><p>The liver kinase B1 (LKB1) tumour suppressor functions as a master regulator of growth, metabolism and survival in cells, which is frequently mutated in sporadic human non-small cell lung and cervical cancers. LKB1 functions as a key upstream activator of the AMP-activated protein kinase (AMPK), a central metabolic switch found in all eukaryotes that govern glucose and lipid metabolism and autophagy in response to alterations in nutrients and intracellular energy levels. The LKB1/AMPK signalling pathway suppresses mammalian target of rapamycin complex 1 (mTORC1), an essential regulator of cell growth in all eukaryotes that is deregulated in a majority of human cancers. LKB1 inactivation in cancer leads to both tumorigenesis and metabolic deregulation through the AMPK and mTORC1-signalling axis and there remain critical challenges to elucidate the direct role LKB1 inactivation plays in driving aberrant metabolism and tumour growth. This review addresses past and current efforts to delineate the molecular mechanisms fueling metabolic deregulation and tumorigenesis following LKB1 inactivation as well as translational promise of therapeutic strategies aimed at targeting LKB1-deficient tumors. </p>","PeriodicalId":52464,"journal":{"name":"Journal of Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2013-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4103/1477-3163.116323","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31772837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restoration of the methylation status of hypermethylated gene promoters by microRNA-29b in human breast cancer: A novel epigenetic therapeutic approach.","authors":"Athena Starlard-Davenport,&nbsp;Kristi Kutanzi,&nbsp;Volodymyr Tryndyak,&nbsp;Beverly Word,&nbsp;Beverly Lyn-Cook","doi":"10.4103/1477-3163.115720","DOIUrl":"https://doi.org/10.4103/1477-3163.115720","url":null,"abstract":"<p><p>It is well established that transcriptional silencing of critical tumor-suppressor genes by DNA methylation is a fundamental component in the initiation of breast cancer. However, the involvement of microRNAs (miRNAs) in restoring abnormal DNA methylation patterns in breast cancer is not well understood. Therefore, we investigated whether miRNA-29b, due to its complimentarity to the 3'- untranslated region of DNA methyltransferase 3A (DNMT3A) and DNMT3B, could restore normal DNA methylation patterns in human breast cancers and breast cancer cell lines. We demonstrated that transfection of pre-miRNA-29b into less aggressive MCF-7 cells, but not MDA-MB-231 mesenchymal cells, inhibited cell proliferation, decreased DNMT3A and DNMT3B messenger RNA (mRNA), and decreased promoter methylation status of ADAM23 , CCNA1, CCND2, CDH1, CDKN1C, CDKN2A, HIC1, RASSF1, SLIT2, TNFRSF10D, and TP73 tumor-suppressor genes. Using methylation polymerase chain reaction (PCR) arrays and real-time PCR, we also demonstrated that the methylation status of several critical tumor-suppressor genes increased as stage of breast disease increased, while miRNA-29b mRNA levels were significantly decreased in breast cancers versus normal breast. This increase in methylation status was accompanied by an increase in DNMT1 and DNMT3B mRNA in advanced stage of human breast cancers and in MCF-7, MDA-MB-361, HCC70, Hs-578T, and MDA-MB-231 breast cancer cells as compared to normal breast specimens and MCF-10-2A, a non-tumorigenic breast cell line, respectively. Our findings highlight the potential for a new epigenetic approach in improving breast cancer therapy by targeting DNMT3A and DNMT3B through miRNA-29b in non-invasive epithelial breast cancer cells. </p>","PeriodicalId":52464,"journal":{"name":"Journal of Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2013-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4103/1477-3163.115720","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31670876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}