Analysis of gene expression in cancer cell lines identifies candidate markers for pancreatic tumorigenesis and metastasis

Abstract

Pancreatic cancer is a highly aggressive type of malignancy and the prognosis for disease presenting typically at a late stage is extremely poor. A comprehensive understanding of its molecular genetics is required in order to develop new approaches to clinical management. To date, serial analysis of gene expression and more recently oligo/cDNA microarray technologies have been employed in order to identify genes involved in pancreatic neoplasia that can be developed as diagnostic markers and drug targets for this dismal disease. This study describes the expression profile obtained from 20 pancreatic cell lines using cDNA microarrays containing 9,932 human gene elements. Numerous genes were identified as being differentially expressed, some of which have been previously implicated in pancreatic adenocarcinoma (S100P, S100A4, prostate stem cell antigen, lipocalin 2, claudins 3 and 4, trefoil factors 1 and 2) as well as several novel genes. The differentially expressed genes identified are involved in a variety of cellular functions, including control of transcription, regulation of the cell cycle, proteolysis, cell adhesion and signaling. Validation of our array results was performed by exploring the SAGEmap database and by immunohistochemistry for a selection of 4 genes that have not previously been studied in pancreatic cancer: anterior gradient 2 homologue (Xenopus laevis), insulin-like growth factor binding protein 3 and 4 and Forkhead box J1. Immunostaining was performed using pancreas-specific tissue microarrays containing core biopsies from 305 clinical specimens. In addition, using statistical group comparison and hierarchical clustering, a selection of genes was identified that may be linked to the site of metastasis from which these cell lines were isolated.

Sperm-associated antigen 1 is expressed early in pancreatic tumorigenesis and promotes motility of cancer cells

“…We and others have recently undertaken such analyses of normal pancreas and pancreatic adenocarcinoma (Crnogorac-Jurcevic et al, 2003;Logsdon et al, 2003;Hustinx et al, 2004;Grutzmann et al, 2005) and our cDNA array data showed overexpression of spermassociated antigen 1 (SPAG1) in cancer cells (Missiaglia et al, 2004).…”

Identification of genetic alterations in pancreatic cancer by the combined use of tissue microdissection and array-based comparative genomic hybridisation

“…This gene lies adjacent to the AGR2 gene (7p21.1) and both genes are classified as members of the same family (AGR family) due to highly similar (approximately 70%) protein sequences. Interestingly, several gene expression analyses have shown that AGR2 is upregulated in the majority of PDACs as well as pancreatic intraepithelial neoplasia (PanIN) lesions (Crnogorac-Jurcevic et al, 2003;IacobuzioDonahue et al, 2003a;Iacobuzio-Donahue et al, 2003b;Missiaglia et al, 2004;Buchholz et al, 2005). Taken together, BCMP11 is also likely to be involved in the development of PDAC.…”

The metastasis associated protein S100A4: role in tumour progression and metastasis

“…In addition to these data for breast cancer, an increase in S100A4 protein expression has been correlated with a worse prognosis for patients with colorectal, gallbladder, bladder, esophageal, nonsmall-cell lung, gastric, medulloblastoma, pancreatic and hepatocellular cancers Mazzucchelli, 2002;Cho et al, 2003;Heman et al, 2003;Cui et al, 2004;Missiaglia et al, 2004). Since tumour size and histological grade do not sufficiently predict metastatic potential, there is a need to identify markers to devise treatment algorithms that guide physicians regarding which patients should receive adjuvant chemotherapy treatment.…”