<i>DPC4</i>/Smad4 Expression and Outcome in Pancreatic Ductal Adenocarcinoma

Biankin, Andrew V.; Morey, Adrienne; Lee, C.-Soon; Kench, James G.; Biankin, Sandra A.; Hook, Henry C.; Head, Darren R.; Hugh, Thomas B.; Sutherland, Robert L.; Henshall, Susan M.

doi:10.1200/jco.2002.12.063

Cited by 157 publications

(119 citation statements)

References 31 publications

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“…There have also been several reports of various biological markers that may carry some prognostic significance. These include growth factors such as vascular endothelial growth factor and platelet-derived endothelial cell growth factor (Fujimoto et al, 1998), microsatellite instability (Nakata et al, 2002), tumour suppression gene expression such as SMAD4 (Biankin et al, 2002) and the expression of mutated genes controlling response to DNA damage, such as GADD45a and p53 (Yamasawa et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

CA19-9 as a prognostic factor in inoperable pancreatic cancer: the implication for clinical trials

et al. 2005

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In a multivariate analysis of 154 patients receiving chemotherapy, baseline CA19-9 was an independent prognostic factor for overall survival (OS) (HR 1.8; 95% CI: 1.3 -2.5, P ¼ 0.0004). The 1-year OS was 19 and 46%, respectively, for patients with a baseline CA19-9 above or below the median value. A fall of 20% in CA19-9 level from baseline was an independent prognostic factor for OS (HR 1.9; 95% CI: 1.1 -3.4, P ¼ 0.019).

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Section: Discussionmentioning

confidence: 99%

CA19-9 as a prognostic factor in inoperable pancreatic cancer: the implication for clinical trials

et al. 2005

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“…We identified a cohort of 128 patients with a diagnosis of pancreatic adenocarcinoma that underwent pancreatic resection or biopsy between January 1972 and November 2001 with available archived tissue. This cohort represents a subset of a previously described group of 348 patients (28). Archival formalin-fixed, paraffin-embedded tissue from all 128 pancreata that were resected or biopsied were used to construct seven pancreatic cancer tissue arrays, which contained up to 55 Â 1.6 mm cores per slide.…”

Section: Methodsmentioning

confidence: 99%

Expression of HOXB2, a Retinoic Acid Signaling Target in Pancreatic Cancer and Pancreatic Intraepithelial Neoplasia

Segara

Biankin

Kench

et al. 2005

Clinical Cancer Research

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Purpose: Despite significant progress in understanding the molecular pathology of pancreatic cancer and its precursor lesion: pancreatic intraepithelial neoplasia (PanIN), there remain no molecules with proven clinical utility as prognostic or therapeutic markers. Here, we used oligonucleotide microarrays to interrogate mRNA expression of pancreatic cancer tissue and normal pancreas to identify novel molecular pathways dysregulated in the development and progression of pancreatic cancer. Experimental Design: RNA was hybridized to Affymetrix Genechip HG-U133 oligonucleotide microarrays. A relational database integrating data from publicly available resources was created to identify candidate genes potentially relevant to pancreatic cancer. The protein expression of one candidate, homeobox B2 (HOXB2), in PanIN and pancreatic cancer was assessed using immunohistochemistry. Results: We identified aberrant expression of several components of the retinoic acid (RA) signaling pathway (RARa, MUC4, Id-1, MMP9, uPAR, HB-EGF, HOXB6, and HOXB2), many of which are known to be aberrantly expressed in pancreatic cancer and PanIN. HOXB2, a downstream target of RA, was up-regulated 6.7-fold in pancreatic cancer compared with normal pancreas. Immunohistochemistry revealed ectopic expression of HOXB2 in15% of early PanIN lesions and 48 of 128 (38%) pancreatic cancer specimens. Expression of HOXB2 was associated with nonresectable tumors and was an independent predictor of poor survival in resected tumors. Conclusions: We identified aberrant expression of RA signaling components in pancreatic cancer, including HOXB2, which was expressed in a proportion of PanIN lesions. Ectopic expression of HOXB2 was associated with a poor prognosis for all patients with pancreatic cancer and was an independent predictor of survival in patients who underwent resection.Pancreatic cancer is the fifth leading cause of cancer death in Western societies with a 5-year survival rate of <10% (1). Pancreatic cancer presents at an advanced stage; thus, only 10% to 20% of patients are suitable for surgical treatment at the time of presentation (1). Clinical management of these patients is complicated by inconsistencies in the influence of conventional clinicopathologic variables on outcome suggesting that some of these variables lack accuracy. In addition, preoperative assessment of some variables such as lymph node metastases is difficult. Whereas in other cancers assessment of aberrations in gene expression that cosegregate with therapeutic response and outcome are being adopted routinely to increase predictive power (e.g., ER and HER-2/neu in breast cancer), there remain no molecular markers of clinical utility in pancreatic cancer. This highlights the need for the identification of novel regulatory pathways important in pancreatic cancer that may also have diagnostic, therapeutic and prognostic utility.There is now compelling histopathologic and molecular evidence to support the evolution of pancreatic cancer through a series of noninvasive duct...

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“…47 P21 CIP1 overexpression is also a very early event in pancreatic neoplastic PanIN lesions, even before the aberrant expression of p53, cyclin D1, and DPC/Smad4 starts. 48 In pancreatic acinar cells it has been shown that p48/Ptf1 is directly responsible for growth suppression via transcriptional activation of p21 CIP1 30 . In that situation, p21 CIP1 thus functions as a cell-cycle inhibitory protein.…”

Section: 3mentioning

confidence: 99%

Expression of the Notch Signaling Pathway and Effect on Exocrine Cell Proliferation in Adult Rat Pancreas

Rooman

Medts

Baeyens

et al. 2006

The American Journal of Pathology

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When pancreatic tissue is injured after duct obstruction, acinoductal metaplasia is observed. Similar metaplastic changes occur when exocrine pancreatic cells are isolated and cultured. We demonstrate that under these experimental conditions the exocrine acinar cells lose their differentiated characteristics: expression of the acinar transcription factors p48/ Ptf1␣ and Mist1 is decreased or lost, whereas expression of the embryonic transcription factor Pdx1 is increased. The receptors Notch1 and Notch2, members of the DSL family of Notch ligands, and the target genes in the Notch-signaling pathway Hes1, Hey1, and Hey2 become strongly up-regulated. We noted also reduced expression of Sel1L, a Notch repressor that is normally highly expressed in exocrine pancreas. Stimulation of Notch by its ligand Jagged1 diminished the proliferation of cultured metaplastic exocrine cells. Chemical inhibition of Notch signaling resulted in increased proliferation and induction of the cell-cycle regulator p21Cip1 . This effect seems to be Hes1-independent and mainly coincides with decreased Hey1 and Hey2 mRNA expression. In conclusion , we demonstrate that during acinoductal metaplasia the Notch-signaling pathway is activated concomitantly with changes in transcription factor expression of pancreatic acinar cells. In addition, we show that Notch signaling is implicated in the suppression of proliferation of these metaplastic exocrine cells. The latter may be important in protection from neoplastic transformation.

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DPC4/Smad4 Expression and Outcome in Pancreatic Ductal Adenocarcinoma

Cited by 157 publications

References 31 publications

CA19-9 as a prognostic factor in inoperable pancreatic cancer: the implication for clinical trials

CA19-9 as a prognostic factor in inoperable pancreatic cancer: the implication for clinical trials

Expression of HOXB2, a Retinoic Acid Signaling Target in Pancreatic Cancer and Pancreatic Intraepithelial Neoplasia

Expression of the Notch Signaling Pathway and Effect on Exocrine Cell Proliferation in Adult Rat Pancreas

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