がんの科学と治療

Objective: Malignant Mesothelioma is an aggressive tumor occurring in the context of chronic inflammation and characterized by hypoxic areas. This study explores how hypoxia impacts on the pro-inflammatory phenotype of MSTO-211H and MPP89 mesothelioma cells and investigates the role of HIF-1 alpha and NF-kB in this process. The prognostic values of two molecules upregulated by oxygen deprivation, HIF-3 alpha and CXCR4, is also analyzed.

Methods: Hypoxic condition was obtained in a sealed modular incubator chamber flushed with 1% O2. mRNA and protein levels were evaluated by real-time PCR and western blot. Silencing of HIF-1alpha was achieved by specific shRNA and NF-kB inhibition by parthenolide treatment. HIF-3 alpha and CXCR4 expression in tumor tissues from mesothelioma patients was detected by immunohistochemistry.

Results: The hypoxic stimulation of mesothelioma cells induced an early activation of HIF-1 alpha and NF-kB and a later increase of HIF-3 alpha expression. In addition, the upregulation of a set of inflammation-related genes was observed. Silencing of HIF-1 alpha and treatment with parthenolide highlighted that the observed increase in gene expression depends on both HIF-1 alpha and NF-kB transcriptional activity. A correlation between high expression of CXCR4 in human mesothelioma samples and poor survival was also observed and HIF3 alpha was suggested as a potential new prognostic marker.

Conclusions: This study evidences a cross-talk between hypoxia adaptation and pro-inflammatory phenotype in mesothelioma accomplished through the combined transactivation activity of HIFs and NFkB. Immunohistochemistry analysis of tissue samples confirms CXCR4 and suggests HIF-3 alpha as potential prognostic markers for mesothelioma.

Background: Traditional management of women with advanced ovarian cancer with surgery and chemotherapy provides limited duration of survival. Targeting specific pathways in angiogenesis or DNA repair may provide therapeutic benefit.

Results: In this manuscript, we review the use of various compounds including antibodies that target specific growth factors receptors or ligands for receptors as well as small molecule compounds that inhibit tyrosine kinase activities or regulate the DNA repair mechanism in the management of women with ovarian, fallopian tube and primary peritoneal cancers. Randomized clinical trials have shown a PFS benefit in the use of bevacizumab in the adjuvant setting and at disease recurrence. Randomized clinical trials are currently ongoing with several PARP inhibitors in the maintenance setting post-chemotherapy and in the recurrent disease setting.

Conclusion: In particular, bevacizumab an antibody to VEGF-A and the PARP inhibitors show promise in extending overall survival from this disease. Use of these agents especially in a maintenance strategy is promising

Glioma is a brain tumor that arises from glial cells or glial progenitor cells, and represents 80% of malignant brain tumor incidence in the United States. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor malignancy with fewer than 8% of patients with GBM surviving for more than 3 years. Over the past 10 years, despite improvement in diagnosis and therapies for cancer, the survival rate for high-grade glioma patients remains dismal. The main focus of our research is to identify potent novel antiglioma small molecules. We previously showed that EDL-360, a tetrahydroisoquinoline (THIQ) analog, as being highly cytotoxic to human glioma cell cultures. Here we show that EDL-360 significantly induced apoptosis in human glioma cell lines (U87 and LN18). However, in normal astrocytic cells, EDL-360 induced a modest G0/G1 cell cycle arrest but did not induce apoptosis. In an attempt to enhance EDL-360 induced cell death, we tested simultaneous treatment with EDL‑360 and embelin (an inhibitor of the anti-apoptotic protein, XIAP). We found that, glioma cells had significant lower viability when EDL‑360 and embelin were used in combination when compared to EDL-360 alone. We also used combination treatment of EDL-360 with decylubiquinone (dUb), a caspase-9 inhibitor, and found that the combination treatment induced a significant cell death when compared to treatment with EDL-360 alone. This is the first report that suggests that dUb has anticancer activity, and perhaps acts as a XIAP inhibitor. Finally, our in vivo data showed that EDL-360 treatment induced a partial regression in glioma tumorigenesis and induced cell death in the treated tumors as shown by H&E staining. Taken together these data suggests that EDL-360 has a potential therapeutic application for treating glioma, especially when combined with XIAP inhibitors.

A case of ossifying fibromyxoid tumour of the soft part, a rare neoplasm arising about the knee of a young man is reported. The tumour has the characteristic morphology, having a thin bony shell, vascular myxohyaline stroma with oval or slightly spindly epitheloid cells arranged in cord pattern. The important histomorphological features have been highlighted and illustrated. The histogenesis, biological behavioral variations and differential diagnosis has been briefly discussed.

Ascorbic acid (AA), long known to treat scurvy, has had debatable use as an anti-neoplastic drug in the past. However recent in vitro and in vivo studies have revealed previously unexplored mechanisms through which AA selectively damages cancer cells without causing damage to normal cells. In view of newly emerging evidence, many clinical trials have been designed to study these effects in patients with different types of cancers. Promising results from these initial trials are giving renewed hope to the use of AA as an adjuvant to the conventional chemotherapeutic drugs to treat cancer, to alleviate toxicity from the treatment and to reduce patient morbidity.

The use of p53 as a biological marker to predict chemotherapeutic outcome has been challenging, with clinical research showing positive as well as negative correlations with p53 mutations. Recent research reveals the complexity that underlies the use of p53 as a single predictive marker as well as the challenges associated with classifying p53 mutations. It is becoming clear that various p53 mutations are associated with differential treatment response and outcomes. In addition, different drug regimens could also play a role in modifying the effects of p53 mutations on therapeutic outcome. Finally, we discuss improvements in the diagnostic detection of p53 mutations and gene signatures that may better reflect p53 functionality in tumors, which may serve as a more reliable tool in correlating p53 mutations to clinical response.

Histone epigenetic modifications are one of the frequently observed epigenetic alterations in leukemic cells. To efficiently identify histone acetylation status of a number of gene promoters in chronic lymphocytic leukemia (CLL) specimens, we performed a combination of chromatin immunoprecipitation (ChIP) and PCR array. ChIP by an antipan acetylated H4 histone antibody was followed by a PCR amplification of gene promoters (n=84) to determine their histone acetylation status. A subset of genes with differential histone acetylation status was identified in CLL specimens, and their RNA expression level was correlated with real time quantitative RT-PCR analysis (qRT-PCR). Globally CLL specimens have more hypo-acetylated or epigenetically silenced gene promoters as compared to normal peripheral-blood mononuclear cells. Promoters of E-cadherin, Fos, CDKN2B, c-Jun, BAX genes were found to be histone hypo-acetylated while the promoters of cyclin D1, CDK4, Myc, and TGF beta were hyper-acetylated. The histone acetylation status correlated well with qRT-PCR analysis of a number of CLL specimens. Based on the ChIP-PCR array epigenetically silenced genes and transcriptionaly active genes can be identified. Histone deacetylase inhibitors (HDACi) induce apoptosis in CLL specimens and to determine changes in gene transcription induced by HDACi the ChIP-PCR array was performed with HDACi treatment. Interestingly the HDACi exposure resulted in histone hyper-acetylation of a subset of genes with increased expression of CDKN2B, c-Jun and BAX RNA while promoters of pro-growth and survival genes such as BCL-2, NFKB1, beta-catenin and CDK4 underwent promoter histone hypo-acetylation and downregulation of their RNA expression. The ChIP-PCR array assay can be utilized to detect histone modifications in the genome of leukemic cells and reflects the transcriptional status of the genes.

Acquired genetic alterations which include balanced and unbalanced chromosome aberrations and submicroscopic gene mutations and changes in gene expression strongly influenced by pretreatment clinical features and prognosis of adults patients with acute myeloid leukemia (AML). Cytogenetic profiling separate AML patients into three broad prognostic groups: favorable, intermediate and adverse. The cytogenetic risk classifications vary to some extent for younger adult patients and for those aged 60 years or older. In many cases, patients with specific cytogenetic rearrangement such as those with a normal karyotype or those with either RUNX1-RUNX1T1 or CBFB-MYH11 feature of core-binding factor (CBF) can be further subdivided into prognostic categories depend on the presence or absence of specific gene mutations or changes in gene expression. Advancement in the understanding of cancer genetic and discovery of recurrent mutations in AML provide opportunity to develop targeted therapies and improve the clinical outcome. The identified gene mutations, mainly targetable lesions are gain of function mutations of JAK2 and cKIT and FLT3 in APL have been associated with clinical features and/ or outcome of patients with these AML subtypes. These data emphasize the significance of genetic testing for common translocations for diagnosis, prognosis and increasingly targeted therapy in acute leukemia. Notably, these several molecular genetic alterations constitute a variety of diverse new targets for salvage therapies. These approaches intend to develop targeted treatment concepts that depend on interference with molecular genetics or epigenetic mechanisms. This report provides an overview on characteristic gene mutations, discuss their biological functions and Prognostic significance, which serve as basis for selected therapy approaches now or might represent options for such approaches in the future and expected to have a role in treating AML subtypes with characteristic molecular alterations

Ezrin is involves in multiple cancer cell functions. In this study, differentially expressed genes (DEGs) identified from mRNA expression profiling following Ezrin knockdown in esophageal squamous cell carcinoma (ESCC), were analyzed by multiple bioinformatics methods for a comprehensive understanding. Gene Ontology enrichment found significant terms related to immunity, stimulus response, extracellular matrix-binding and signal transduction. Functional Annotation Chart showed except GO categories, these DEGs were annotated by 72 functional category terms. Subpathway analyses revealed the DEGs were involved in 36 subpathways, overwhelming the traditional pathway enrichment. Promoter analyses showed specific sequence patterns and transcription factors correspond to the co-downregulation and co-upregulation of DEGs. MNB1A, DOF2, PBF, YY1, PRRX2, UBX and ARNTAHR co-regulate the downregulated genes, whereas GATA2, ZNF42, deltaEF1, MYCN and ARNT co-regulate the upregulated genes. This paper provides a workflow for a better understanding the roles of Ezrin knockdown in ESCC by the bioinformatics analyses of its DEGs.