Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets

Abstract

The intrinsic nature of tumour behaviour (stable vs progressive) and the presence of liver metastases are key factors in determining the outcome of patients with a pancreatic endocrine tumour (PET). Previous expression profile analyses of PETs were limited to non-homogeneous groups or to primary lesions only. The aim of this study was to investigate the gene expression profiles of a more uniform series of sporadic, non-functioning (NF) PETs with progressive disease and, for the first time, their liver metastases, on the Affymetrix human genome U133A and B GeneChip set. Thirteen NF PET samples (eight primaries and five liver metastases) from ten patients with progressive, metastatic disease, three cell lines (BON, QGP and CM) and four purified islet samples were analysed. The same samples were employed for confirmation of candidate gene expression by means of quantitative RT-PCR, while a further 37 PET and 15 carcinoid samples were analysed by immunohistochemistry. Analysis of genes differentially expressed between islets and primaries and metastases revealed 667 up-and 223 down-regulated genes, most of which have not previously been observed in PETs, and whose gene ontology molecular function has been detailed. Overexpression of bridging integrator 1 (BIN1) and protein Z dependent protease inhibitor (SERPINA10) which may represent useful biomarkers, and of lymphocyte specific protein tyrosine kinase (LCK) and bone marrow stromal cell antigen (BST2) which could be used as therapeutic targets, has been validated. When primary tumours were compared with metastatic lesions, no significantly differentially expressed genes were found, in accord with cluster analysis which revealed a striking similarity between primary and metastatic lesions, with the cell lines clustering separately. We have provided a comprehensive list of differentially expressed genes in a uniform set of aggressive NF PETs. A number of dysregulated genes deserve further in-depth study as potentially promising candidates for new diagnostic and treatment strategies. The analysis of liver metastases revealed a previously unknown high level of similarity with the primary lesions.

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

“…Nevertheless, it should be noted that there were some similarities, as one study also identified an up-regulation of PDGFR-b in WDECs (Couvelard et al 2006). In addition, GO analysis in one study also revealed the molecular function classifier 'binding' as the most frequent in their up-regulated genes (Capurso et al 2006). In aggregate, our results enhance the spectrum of genes implicated in NET pathogenesis.…”

“…Previous studies compared WDETs with normal islet controls (Maitra et al 2003), MEN-1 associated NETs with normal islets (Dilley et al 2005), PNETs with normal pancreas, pancreatitis, and pancreatic adenocarcinoma (Bloomston et al 2004), non-functioning PNETs and their metastases with normal islets (Capurso et al 2006), and metastatic with non-metastatic PNETs, primarily nonfunctioning (Hansel et al 2004, Couvelard et al 2006. Interestingly, there was no significant overlap between the identified genes in these studies and our current analysis.…”

“…We hypothesize that this poor concordance is most likely a reflection of the different study designs, software platforms, data analysis parameters, and sample subtypes. In contrast to three reports that are most similar to ours (Hansel et al 2004, Capurso et al 2006, Couvelard et al 2006, we studied a broader mix of PNET subtypes, not exclusively non-functioning PNETs, and this may potentially explain the disparity. With respect to technical differences, we utilized an Affymetrix platform, whereas Couvelard et al obtained microarray chips from the Sanger center.…”

“…Thus far, only a few studies have investigated gene expression profiles in PNETs. Most of these have focused on differences between tumors and normal tissue (Maitra et al 2003, Bloomston et al 2004, Capurso et al 2006. In the present study, we sought to compare molecular classifications with the WHO histologic classification, identify genes that may be important for tumor progression, and determine whether GI-NETs differ in their molecular profile from PNETs.…”

HM1.24 Is Internalized from Lipid Rafts by Clathrin-mediated Endocytosis through Interaction with α-Adaptin

“…Recently, HM1.24 was designated CD317 and found to be highly expressed in all B cell stages of differentiation, on bone marrow CD34 ϩ cells, and also on T cells (6). In addition to myeloma cells, overexpression of HM1.24 has also been described in a wide variety of invasive solid tumor cell lines (7), in pancreatic ductal adenocarcinoma (8), and in pancreatic endocrine tumors (9). Although the mechanism by which HM1.24 is overexpressed remains to be elucidated, in the promoter region of the HM1.24 gene (BST2), a tandem repeat of three cis elements for a transcription factor, signal transducers and activators of transcription 3, which mediates interleukin-6 response gene expression, is contained upstream of the transcription initiation site.…”