Discovery of Novel Tumor Markers of Pancreatic Cancer using Global Gene Expression Technology

Iacobuzio‐Donahue, Christine A.; Maitra, Anirban; Shen-Ong, G L; Heek, Tjarda van; Ashfaq, Raheela; Meyer, Renee; Walter, Kimberly; Berg, Karin D.; Hollingsworth, Michael A.; Cameron, John L.; Yeo, Charles J.; Kern, Scott E.; Goggins, Michael; Hruban, Ralph H.

doi:10.1016/s0002-9440(10)62551-5

Cited by 268 publications

(166 citation statements)

References 35 publications

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“…For example, osteopontin, a secreted glycoprotein expressed prominently in bone and by lining epithelial cells, was first identified as overexpressed in pancreatic cancers by oligonucleotide microarrays 14 and we have recently found that osteopontin protein levels are significantly elevated in patients with resectable pancreatic adenocarcinoma compared to healthy controls (Po0.001). 15 Other interesting genes identified as overexpressed in the parenchyma of pancreatic cancer and chronic pancreatitis are lactoferrin and fibrinogen.…”

Section: Discussionmentioning

confidence: 95%

Gene expression alterations in the non-neoplastic parenchyma adjacent to infiltrating pancreatic ductal adenocarcinoma

et al. 2005

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The non-neoplastic pancreatic parenchyma adjacent to infiltrating ductal adenocarcinoma demonstrates inflammation, fibrosis, acinar cell loss and small duct-like metaplasia of acinar cells. Similar morphologic changes are also observed in the setting of chronic pancreatitis. In addition, peritumoral acini have been shown to have alterations in gene expression even in the absence of morphological changes. To better understand the pancreatic acinar responses to infiltrating pancreatic ductal adenocarcinoma, we characterized gene expression patterns of pancreatic acinar tissue adjacent to infiltrating pancreatic ductal adenocarcinomas and compared them to gene expression patterns of acinar tissue affected by chronic pancreatitis as well as to those of normal pancreatic acini. Fresh-frozen pancreatic acinar tissue was microdissected from nine patients (three with pancreatic cancer, three with chronic pancreatitis, three with normal pancreata) using laser capture microdissection, and extracted RNA from each microdissection was subjected to two rounds of linear amplification and hybridized to oligonucleotide microarrays. Gene expression patterns were confirmed using quantitative RT-PCR and/or immunohistochemistry. A total of 20 genes was found to be overexpressed in peritumoral acinar tissue compared to normal acinar tissue and to acini affected by chronic pancreatitis. These 20 genes included pancreatitis-associated protein (HIP/PAP), a gene known to be overexpressed in acini adjacent to infiltrating pancreatic cancer, and the gene cartilage glycoprotein-39 (HC gp-39 or TKL-40). Serum HC gp-39 protein levels were significantly higher in patients with pancreatic cancer and in those with chronic pancreatitis than in controls without pancreatic disease. There was no significant difference in the levels of serum HC gp-39 in patients with pancreatic cancer and those with chronic pancreatitis. Our results demonstrate some of the molecular alterations in acinar cells that occur in response to adjacent infiltrating pancreatic ductal adenocarcinoma and reveal that such alterations can provide a rich source of markers of pancreatic cancer.

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Section: Discussionmentioning

confidence: 95%

Gene expression alterations in the non-neoplastic parenchyma adjacent to infiltrating pancreatic ductal adenocarcinoma

et al. 2005

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“…Half of them (26 genes indicated by asterisks in Supplementary Table 1) have been listed as overexpressed genes in pancreatic cancers by microarray analyses in published papers. [13][14][15][16][17][18] This agreement suggested that xenografted specimens are able to serve as a panel for pancreatic cancer.…”

Section: Gene-expression Profiling Of Pancreatic Cancer Xenograftsmentioning

confidence: 94%

“…[13][14][15][16][17][18] In this study, xenografts of clinical specimens orthotopically transplanted into severe combined immunodeficient (SCID) mice 19 were utilized as a panel for gene-expression profiling of pancreatic cancer. Among commonly overexpressed genes in pancreatic cancer xenografts, we further evaluated the adenylate cyclaseassociated protein 1 (CAP1) gene, which encodes an actin monomer-binding protein (reviewed in reference 20 ).…”

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confidence: 99%

Adenylate cyclase-associated protein 1 overexpressed in pancreatic cancers is involved in cancer cell motility

Yamazaki

Takamura

Masugi

et al. 2009

Laboratory Investigation

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Pancreatic cancer has the worst prognosis among cancers due to the difficulty of early diagnosis and its aggressive behavior. To characterize the aggressiveness of pancreatic cancers on gene expression, pancreatic cancer xenografts transplanted into severe combined immunodeficient mice served as a panel for gene-expression profiling. As a result of profiling, the adenylate cyclase-associated protein 1 (CAP1) gene was shown to be overexpressed in all of the xenografts. The expression of CAP1 protein in all 73 cases of pancreatic cancer was recognized by immunohistochemical analyses. The ratio of CAP1-positive tumor cells in clinical specimens was correlated with the presence of lymph node metastasis and neural invasion, and also with the poor prognosis of patients. Immunocytochemical analyses in pancreatic cancer cells demonstrated that CAP1 colocalized to the leading edge of lamellipodia with actin. Knockdown of CAP1 by RNA interference resulted in the reduction of lamellipodium formation, motility, and invasion of pancreatic cancer cells. This is the first report demonstrating the overexpression of CAP1 in pancreatic cancers and suggesting the involvement of CAP1 in the aggressive behavior of pancreatic cancer cells. Pancreatic cancer is a leading cause of cancer death worldwide. 1,2 Only about 20% of pancreatic cancer can be surgically resected with curative intent at the time of diagnosis. 3 Mainly due to the difficulty in early detection and frequent metastatic dissemination, the 5-year survival rate for pancreatic cancer patients remains below 5%. 3,4 Considering that vascular involvement, lymph node metastasis, and neural invasion have been proposed as prognostic factors, 5-7 it seems that metastasis is responsible for the aggressive behavior of pancreatic cancer. Pancreatic cancer appears to acquire genetic aberrations with successive alteration of genes involved in the regulation of cell proliferation. The alterations include activating mutations of the KRAS gene 8,9 that occur early in the stage of pancreatic carcinogenesis, and inactivations by the deletion and mutation of the CDKN2A, 10 TP53, 11 and SMAD4 genes. 12 In addition to cell proliferation, cell motility is one of the factors associated with cancer metastasis; however, no alteration of such genes has been revealed in pancreatic cancer. Therefore, alteration of the expression level of genes by epigenetic or transcriptional manner may be a cue to elucidate the mechanism of cancer metastasis.Recent developments in the technology of human genome research enabled us to obtain genome-wide gene-expression profiles, and vast numbers of marker molecule candidates for pancreatic cancer have been proposed. [13][14][15][16][17][18] In this study, xenografts of clinical specimens orthotopically transplanted into severe combined immunodeficient (SCID) mice 19 were utilized as a panel for gene-expression profiling of pancreatic cancer. Among commonly overexpressed genes in pancreatic cancer xenografts, we further evaluated the adenylate cyclaseassociated pr...

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“…Several similar genetic and/or epigenetic abnormalities have also been described in IPMNs including alteration of the K-ras, p53 and STK11/LKB1 genes (Sessa et al, 1994;Sato et al, 2001Sato et al, , 2002. Global gene expression profiles of pancreatic ductal adenocarcinomas and of IPMNs have provided information about candidate molecular markers of these neoplasms as well as providing information as to their tumor biology (Ryu et al, 2001(Ryu et al, , 2002Iacobuzio-Donahue et al, 2002Terris et al, 2002;Logsdon et al, 2003;Sato et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Characterization of gene expression in mucinous cystic neoplasms of the pancreas using oligonucleotide microarrays

et al. 2004

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Discovery of Novel Tumor Markers of Pancreatic Cancer using Global Gene Expression Technology

Cited by 268 publications

References 35 publications

Gene expression alterations in the non-neoplastic parenchyma adjacent to infiltrating pancreatic ductal adenocarcinoma

Gene expression alterations in the non-neoplastic parenchyma adjacent to infiltrating pancreatic ductal adenocarcinoma

Adenylate cyclase-associated protein 1 overexpressed in pancreatic cancers is involved in cancer cell motility

Characterization of gene expression in mucinous cystic neoplasms of the pancreas using oligonucleotide microarrays

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