Gene expression in midgut carcinoid tumors: Potential targets for immunotherapy

Vikman, Sofia; Essand, Magnus; Cunningham, Janet L.; Torre, Manuel de la; Öberg, Kjell; Tötterman, Thomas H.; Giandomenico, Valeria

doi:10.1080/02841860510007404

Cited by 24 publications

(28 citation statements)

References 39 publications

(46 reference statements)

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“…Of the three most highly up-regulated genes in GI-NETs (VMAT1, ECM1, and LGALS4), VMAT1 and LGALS4 have been previously described in this context (Nilsson et al 2004, Vikman et al 2005, Rumilla et al 2006. Galectin 4 is expressed in the alimentary tract, where it is a component of adherens junctions or lipid rafts in the microvillus membrane (Huflejt & Leffler 2004) and is strongly expressed in ileal carcinoids (Rumilla et al 2006).…”

Section: E-m Duerr Et Al: Gene Expression In Netsmentioning

confidence: 99%

Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis

Duerr

Mizukami²,

Ng³

et al. 2008

Endocrine Related Cancer

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Current classifications of human gastroenteropancreatic neuroendocrine tumors (NETs) are inconsistent and based upon histopathologic but not molecular features. We sought to compare a molecular classification with the World Health Organization (WHO) histologic classification, identify genes that may be important for tumor progression, and determine whether gastrointestinal NETs (GI-NETs) differ in their molecular profile from pancreatic NETs (PNETs). DNA microarray analysis was performed to identify differentially expressed genes in PNETs and GI-NETs. Confirmation of expression levels was obtained by quantitative real-time PCR. Immunoblotting and mutational analysis were performed for selected genes. Hierarchical clustering of 19 PNETs revealed a 'benign' and 'malignant' cluster that corresponded well with the WHO categories of welldifferentiated endocrine tumor (WDET) and well-differentiated endocrine carcinoma (WDEC) respectively. FEV, adenylate cyclase 2 (ADCY2), nuclear receptor subfamily 4, group A, member 2 (NR4A2), and growth arrest and DNA-damage-inducible, beta (GADD45b) were the most highly up-regulated genes in the malignant group of PNETs. Platelet-derived growth factor receptor (PDGFR) was expressed in both WDETs and WDECs, and phosphorylation of PDGFR-b was observed in 83% of all PNETs. Malignant ileal GI-NETs exhibited a distinctive gene expression profile, and extracellular matrix protein 1 (ECM), vesicular monoamine member 1 (VMAT1), galectin 4 (LGALS4), and RET Proto-oncogene (RET) were highly up-regulated genes. Gene expression profiles reflect the current WHO classification and can distinguish benign from malignant PNETs and also PNETs from GI-NETs. This suggests that molecular profiling may enhance tumor classification schemes. Potential gene targets have also been identified, and PDGFR and RET are candidates that may represent novel therapeutic targets.

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Section: E-m Duerr Et Al: Gene Expression In Netsmentioning

confidence: 99%

Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis

Duerr

Mizukami²,

Ng³

et al. 2008

Endocrine Related Cancer

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“…These 8 genes that showed high expression levels but low variability among the 36 samples evaluated are indicated in Table 2. None of the conventional NET housekeeping genes [GAPDH (25,37,46), ACTB (37), HPRT1 (34), and glucose phosphate isomerase (4)] was present on this list. Proteins encoded by the eight novel candidate housekeeping genes have a diversity of functions, ranging from conversion of DNA to RNA (POLR2B) to transcriptional regulation (TFCP2, ZNF410, NCOR1) to glycosylation activity (ALG9), and are distributed over six chromosomes (chromosomes 4, 6, 11, 12, 14, and 17) ( Table 2).…”

Section: Genechip Analysesmentioning

confidence: 99%

“…Genes commonly used for normalization in neuroendocrine tumor (NET) tissue studies include GAPDH (23,25,37,46), ACTB (37), HPRT1 (34), and glucose phosphate isomerase (4). A growing body of evidence, however, indicates that transcript levels of these commonly used housekeeping genes may vary considerably in different tissue types or under different experimental conditions, and that a "universal control gene" does not exist (15,44,47,48).…”

mentioning

confidence: 99%

GeneChip, geNorm, and gastrointestinal tumors: novel reference genes for real-time PCR

Kidd

Nadler

Mane

et al. 2007

Physiological Genomics

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Accurate quantitation of target genes depends on correct normalization. Use of genes with variable tissue transcription ( GAPDH) is problematic, particularly in clinical samples, which are derived from different tissue sources. Using a large-scale gene database (Affymetrix U133A) data set of 36 gastrointestinal (GI) tumors and normal tissues, we identified 8 candidate reference genes and established expression levels by real-time RT-PCR in an independent data set ( n = 42). A geometric averaging method (geNorm) identified ALG9, TFCP2, and ZNF410 as the most robustly expressed control genes. Examination of raw CT values demonstrated that these genes were tightly correlated between themselves ( R2 > 0.86, P < 0.0001), with low variability [coefficient of variation (CV) <12.7%] and high interassay reproducibility ( r = 0.93, P = 0.001). In comparison, the alternative control gene, GAPDH, exhibited the highest variability (CV = 18.1%), was significantly differently expressed between tissue types ( P = 0.05), was poorly correlated with the three reference genes ( R2 < 0.4), and was considered the least stable gene. To illustrate the importance of correct normalization, the target gene, MTA1, was significantly overexpressed ( P = 0.0006) in primary GI neuroendocrine tumor (NET) samples (vs. normal GI samples) when normalized by geNormATZ but not when normalized using GAPDH. The geNormATZ approach was, in addition, applicable to adenocarcinomas; MTA1 was overexpressed ( P < 0.04) in malignant colon, pancreas, and breast tumors compared with normal tissues. We provide a robust basis for the establishment of a reference gene set using GeneChip data and provide evidence for the utility of normalizing a malignancy-associated gene ( MTA1) using novel reference genes and the geNorm approach in GI NETs as well as in adenocarcinomas and breast tumors.

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“…Probably combination with immunotherapies might be an option. We have identified some potential targets for immunotherapy in NE tumors [29]. The next step might be to combine hIFN-α2 gene therapy and engineered dendritic cells using these targets.…”

Section: Discussionmentioning

confidence: 99%

Efficient Human Interferon-α Gene Transfer to Neuroendocrine Tumor Cells with Long-Term and Stable Expression

et al. 2005

Self Cite

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Interferon (IFN)-α has been used in the treatment of neuroendocrine (NE) tumors; however, the feasibility of IFN-α gene therapy has not been evaluated in NE tumor cells. In this study, human IFN-α2 (hIFN-α2) gene has been transferred into a NE tumor cell line BON. hIFN-α2-expressing BON cells were subcutaneously inoculated in nude mice. The results demonstrated that hIFN-α2 exerted significant antiproliferative effects on NE tumor cell lines (BON and LCC18) and other tumor cell lines (CA46 and SW480) as well as porcine aorta cell line. Furthermore, hIFN-α2 demonstrated its antineovascular activity in mice tumor and a direct antiangiogenic effect in chicken chorioallantoic membrane assay. hIFN-α2-expressing BON cells had a stable and long-term expression. Mice implanted with hIFN-α2-expressing BON cells showed a lower incidence, a delayed development and a significantly longer doubling time of the tumor compared to both wild-type (WT) and vector group. In addition, IFN-α significantly inhibited cell adhesion of WT BON cells. hIFN-α2-expressing BON tumors had a high level of hIFN-α2 protein. Finally, mice implanted with a mixture of WT and hIFN-α2-expressing BON cells (1:1) presented a delayed tumor development and had an even lower incidence of tumors than those implanted with hIFN-α2-expressing BON cells only. The doubling time of tumor was also longest in the mixture group. Our data suggest that hIFN-α2 gene therapy might be possible to be used as a new treatment for NE tumor patients. Further studies on the regulation of hIFN-α expression are needed, especially in combination with other cytokines, which could lead to a better understanding and improvements of hIFN-α gene therapy.

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Gene expression in midgut carcinoid tumors: Potential targets for immunotherapy

Cited by 24 publications

References 39 publications

Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis

Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis

GeneChip, geNorm, and gastrointestinal tumors: novel reference genes for real-time PCR

Efficient Human Interferon-α Gene Transfer to Neuroendocrine Tumor Cells with Long-Term and Stable Expression

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