Gerwin Heller | Medical University of Vienna (original) (raw)

Papers by Gerwin Heller

Memo - Magazine of European Medical Oncology, 2010

Summary Despite the use of new drugs for the treatment of stage IV non-small cell lung cancer (N... more Summary Despite the use of new drugs for the treatment of stage IV non-small cell lung cancer (NSCLC) patients, only a moderate overall survival benefit could be reached and the prognosis of this disease is still bad. Therefore, the intensive search for additional, especially targeted, drugs is still ongoing. In recent years evidence has been grown that the insulin-like growth factor type I receptor (IGF-IR) and its ligands play an important role in oncogenic transformation, growth and survival of malignant cells. Thus, strategies have been developed to block this receptor. The most promising concepts include anti-IGF-IR antibodies and anti-IGF-IR tyrosine kinase inhibitors. Currently, most data are available for the monoclonal antibody CP-751,871 (figitumumab). A recent phase II study (Karp et al., J Clin Oncol, 27: 2516, 2009) compared the efficacy and side effects of paclitaxel/carboplatin/CP-751,871 versus paclitaxel/carboplatin in untreated locally advanced or metastatic NSCLC...

Journal of Hepatology, 2006

Background/Aims: In human hepatocellular carcinoma (HCC) the ras-proto-oncogene is rarely mutated... more Background/Aims: In human hepatocellular carcinoma (HCC) the ras-proto-oncogene is rarely mutated. We therefore studied the possible inactivation of the putative tumor-suppressors and ras-associating proteins, NORE1A, NORE1B, and RASSF1A in HCCs by mutation or epigenetic gene silencing through promoter-CpG hypermethylation.

Endocrine Abstracts, 2016

Cancer and Metastasis Reviews, Jan 23, 2010

DNA methylation as part of the epigenetic genesilencing complex is a universal occurring change i... more DNA methylation as part of the epigenetic genesilencing complex is a universal occurring change in lung cancer. Numerous studies investigated methylation of specific genes in primary tumors, in serum or plasma samples, and in specimens from the aerodigestive tract epithelium of lung cancer patients. In most studies, single genes or small numbers of genes were analyzed. Moreover, it has been observed that methylation of certain genes can already be detected in samples from the upper aerodigestive tract epithelium of cancer-free heavy smokers. These findings indicated that methylation of certain genes may be a useful biomarker for prognosis, disease recurrence, early detection, and lung cancer risk assessment. So far, several genes were identified which seem to be of worse prognostic relevance when they were found to be methylated. In addition, it has been shown that a panel of markers may be relevant to predict disease recurrence after surgery. In comparison to analysis of single or small numbers of genes, methods for genome-wide detection of methylation were developed recently. These approaches are focused on either pharmacological re-activation of methylated genes followed by expression microarray analysis or on microarray analysis of sodium bisulfite-treated or affinityenriched methylated DNA sequences. With currently available methods for the simultaneous detection of methylation, up to 28,000 CpG islands can be analyzed. Overall, we are just at the beginning of translating these findings into the clinic and there is hope that future patients will benefit from these results.

The Journal of Pathology, 2015

Malignant pleural mesothelioma (MPM) is a devastating malignancy characterized by invasive growth... more Malignant pleural mesothelioma (MPM) is a devastating malignancy characterized by invasive growth and rapid recurrence. The identification and inhibition of molecular components leading to this migratory and invasive phenotype are thus essential. Accordingly, a genome-wide expression array analysis was performed on MPM cell lines and a set of 139 genes was identified as differentially expressed in cells with high versus low migratory activity. Reduced expression of the novel tumour suppressor integrin α7 (ITGA7) was found in highly motile cells. A significant negative correlation was observed between ITGA7 transcript levels and average displacement of cells. Forced overexpression of ITGA7 in MPM cells with low endogenous ITGA7 expression inhibited cell motility, providing direct evidence for the regulatory role of ITGA7 in MPM cell migration. MPM cells showed decreased ITGA7 expressions both at transcription and protein levels when compared to non-malignant mesothelial cells. The majority of MPM cell cultures displayed hypermethylation of the ITGA7 promoter when compared to mesothelial cultures. A statistically significant negative correlation between ITGA7 methylation and ITGA7 expression was also observed in MPM cells. While normal human pleura samples unambiguously expressed ITGA7, a varying level of expression was found in a panel of 200 human MPM samples. In multivariate analysis, ITGA7 expression was found to be an independent prognostic factor. Although there was no correlation between histological subtypes and ITGA7 expression, importantly, patients with high tumour cell ITGA7 expression had an increased median overall survival compared to the low or no-expression groups (463 vs. 278 days). In conclusion, our data suggest that ITGA7 is an epigenetically regulated tumour suppressor gene and a prognostic factor in human MPM.

Molecular cancer research : MCR, 2015

Tumor-initiating subpopulations of cancer cells, also known as cancer stem cells (CSC), were rece... more Tumor-initiating subpopulations of cancer cells, also known as cancer stem cells (CSC), were recently identified and characterized in prostate cancer. A well-characterized murine model of prostate cancer was used to investigate the regulation of hypoxia-inducible factor 1α (HIF1A/HIF1α) in CSCs and a basal stem cell subpopulation (Lin(-)/Sca-1(+)/CD49f(+)) was identified, in primary prostate tumors of mice, with elevated HIF1α expression. To further analyze the consequences of hypoxic upregulation on stem cell proliferation and HIF1α signaling, CSC subpopulations from murine TRAMP-C1 cells (Sca-1(+)/CD49f(+)) as well as from a human prostate cancer cell line (CD44(+)/CD49f(+)) were isolated and characterized. HIF1α levels and HIF target gene expression were elevated in hypoxic CSC-like cells, and upregulation of AKT occurred through a mechanism involving an mTOR/S6K/IRS-1 feedback loop. Interestingly, resistance of prostate CSCs to selective mTOR inhibitors was observed because of H...

Anticancer research, 2009

Loss of cyclin-dependent kinase (CDK) 10 expression may be an important mechanism of tamoxifen re... more Loss of cyclin-dependent kinase (CDK) 10 expression may be an important mechanism of tamoxifen resistance and the 5' CpG island associated with the CDK10 gene has been suggested to be a target for aberrant methylation in breast cancer. The methylation status of CDK10, RASSF1A (Ras association domain family 1A) and DAL-1 (differentially expressed in adenocarcinoma of the lung) was determined by means of methylation-specific PCR (MSP) in the formalin-fixed, paraffin-embedded (FFPE) surgical specimens of 96 breast carcinoma patients. Reverse transcription kinetic PCR (RT-kPCR) was used for assessment of the expression of CDK10. The unmethylated form of CDK10, RASSF1A and DAL-1 was detected in all the samples analyzed. Methylation of the CDK10 5' region was not found in any of the 96 breast cancer samples. RASSF1A methylation was detected in 75 out of 96 (78%) and DAL-1 in 9 out of 15 (60%) breast cancer samples, respectively. Consistent with the methylation results, the express...

Cancer and Metastasis Reviews, 2010

Ash Annual Meeting Abstracts, Nov 18, 2011

Oncotarget, 2011

A novel way by which the AP-1 factor c-JUN interferes with tumorigenesis has recently been elucid... more A novel way by which the AP-1 factor c-JUN interferes with tumorigenesis has recently been elucidated [1]. In a model of murine leukemia, c-JUN prevents the epigenetic silencing of the cell cycle kinase CDK6. In the absence of c-JUN, CDK6 is down-regulated and the 5’region of the gene is methylated. Down-regulation of CDK6 results in significantly delayed leukemia formation. Here we show that c-JUN is also involved in protecting the promoter region of the tumor suppressor p16(INK4a), which is consistently methylated over time in c-JUN deficient cells. In cells expressing c-JUN, p16(INK4a) promoter methylation is a less frequent event. Our study unravels a novel mechanism by which the AP-1 factor c-JUN acts as a “bodyguard”,and preventing methylation of a distinct set of genes after oncogenic transformation.

Molecular carcinogenesis, Jan 9, 2014

Even though a large proportion of patients with acute myeloid leukemia (AML) achieve a complete r... more Even though a large proportion of patients with acute myeloid leukemia (AML) achieve a complete remission upon initial therapy, the majority of them eventually relapse with resistant disease. Overexpression of the gene coding for the transcription factor Ecotropic Virus Integration site 1 (EVI1) is associated with rapid disease recurrence and shortened survival. We therefore sought to identify EVI1 target genes that may play a role in chemotherapy resistance using a previously established in vitro model system for EVI1 positive myeloid malignancies. Gene expression microarray analyses uncovered the Cell Adhesion Molecule 1 (CADM1) gene as a candidate whose deregulation by EVI1 may contribute to drug refractoriness. CADM1 is an apoptosis inducing tumor suppressor gene that is inactivated by methylation in a variety of tumor types. In the present study we provide evidence that it may play a role in chemotherapy induced cell death in AML: CADM1 was induced by drugs used in the treatmen...

Journal of Hematology & Oncology, 2015

The transcription factor Ecotropic Virus Integration site 1 (EVI1) regulates cellular proliferati... more The transcription factor Ecotropic Virus Integration site 1 (EVI1) regulates cellular proliferation, differentiation, and apoptosis, and its overexpression contributes to an aggressive course of disease in myeloid leukemias and other malignancies. Notwithstanding, knowledge about the target genes mediating its biological and pathological functions remains limited. We therefore aimed to identify and characterize novel EVI1 target genes in human myeloid cells. U937T_EVI1, a human myeloid cell line expressing EVI1 in a tetracycline regulable manner, was subjected to gene expression profiling. qRT-PCR was used to confirm the regulation of membrane-spanning-4-domains subfamily-A member-3 (MS4A3) by EVI1. Reporter constructs containing various parts of the MS4A3 upstream region were employed in luciferase assays, and binding of EVI1 to the MS4A3 promoter was investigated by chromatin immunoprecipitation. U937 derivative cell lines experimentally expressing EVI1 and/or MS4A3 were generated by retroviral transduction, and tested for their tumorigenicity by subcutaneous injection into severe combined immunodeficient mice. Gene expression microarray analysis identified 27 unique genes that were up-regulated, and 29 unique genes that were down-regulated, in response to EVI1 induction in the human myeloid cell line U937T. The most strongly repressed gene was MS4A3, and its down-regulation by EVI1 was confirmed by qRT-PCR in additional, independent experimental model systems. MS4A3 mRNA levels were also negatively correlated with those of EVI1 in several published AML data sets. Reporter gene assays and chromatin immunoprecipitation showed that EVI1 regulated MS4A3 via direct binding to a promoter proximal region. Experimental re-expression of MS4A3 in an EVI1 overexpressing cell line counteracted the tumor promoting effect of EVI1 in a murine xenograft model by increasing the rate of apoptosis. Our data reveal MS4A3 as a novel direct target of EVI1 in human myeloid cells, and show that its repression plays a role in EVI1 mediated tumor aggressiveness.

Oncotarget, 2015

In our study, we investigated the role of ZNF677 in non-small cell lung cancers (NSCLC). By compa... more In our study, we investigated the role of ZNF677 in non-small cell lung cancers (NSCLC). By comparing ZNF677 expression in primary tumor (TU) and in the majority of cases also of corresponding non-malignant lung tissue (NL) samples from > 1,000 NSCLC patients, we found tumor-specific downregulation of ZNF677 expression (adjusted p-values < 0.001). We identified methylation as main mechanism for ZNF677 downregulation in NSCLC cells and we observed tumor-specific ZNF677 methylation in NSCLC patients (p < 0.0001). In the majority of TUs, ZNF677 methylation was associated with loss of ZNF677 expression. Moreover, ZNF677 overexpression in NSCLC cells was associated with reduced cell proliferation and cell migration. ZNF677 was identified to regulate expression of many genes mainly involved in growth hormone regulation and interferon signalling. Finally, patients with ZNF677 methylated TUs had a shorter overall survival compared to patients with ZNF677 not methylated TUs (p = 0.0...