All-<i>Trans</i> Retinoic Acid Induces Differentiation of Ducts and Endocrine Cells by Mesenchymal/Epithelial Interactions in Embryonic Pancreas

Tulachan, Sidhartha; Doi, Ryuichiro; Kawaguchi, Yoshiya; Tsuji, S.; Nakajima, Saeko; Masui, Toshihiko; Koizumi, Masayuki; Toyoda, Eiji; Mori, Tomohiko; Ito, Daisuke; Kami, Katsuya; Fujimoto, Koji; Imamura, Masayuki

doi:10.2337/diabetes.52.1.76

Cited by 70 publications

(58 citation statements)

References 54 publications

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“…However, in control experiments, they were detected in other tissues in which each was already known to be expressed (Sladek et al, 1990;Zennaro et al, 1997;Zineb et al, 1998;Tulachan et al, 2003;Jeyasuria et al, 2004;Tanaka et al, 2006). These results suggest that they are not expressed or expressed at a very low level in the cerebellum at this stage of development.…”

Section: Nuclear Receptors Expression Patterns In the P21 Cerebellummentioning

confidence: 73%

The expression pattern of nuclear receptors during cerebellar development

Qin

Suh

Kim

et al. 2007

Developmental Dynamics

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Section: Nuclear Receptors Expression Patterns In the P21 Cerebellummentioning

confidence: 73%

The expression pattern of nuclear receptors during cerebellar development

Qin

Suh

Kim

et al. 2007

Developmental Dynamics

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“…RA regulates early instructive signals from lateral plate mesoderm that is essential for specification of endoderm towards a pancreatic fate (41). RARs also regulate exocrine pancreatic development at later stages (42), by modulating lineage selection favoring ductal rather than acinar differentiation primarily through RAR-a (10,11). Reactivation of developmental pathways, specifically those that regulate exocrine cell lineage, have been implicated previously in the early development of pancreatic cancer (25) and other pathways that determine duct cell versus acinar cell differentiation involving RA signaling, may also be important.…”

Section: Discussionmentioning

confidence: 99%

“…Endodermal expression of pdx-1 (a homeobox-containing transcription factor essential for pancreatic development) is induced by RA (10) and marks a pluripotent population of cells that give rise to all cell types in the pancreas. RA signaling regulates pancreas exocrine lineage selection, and treatment with RA analogues can effect a shift from an acinar to a ductal phenotype through epithelial-mesenchymal interactions (11).…”

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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

150

118

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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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“…5 The mesenchyme has been considered to contribute cells only to connective tissue and smooth muscle of the definitive pancreas. While signals from the mesenchyme are recognised as important for branching and differentiation of the pancreatic epithelium, [6][7][8][9][10][11][12][13][14][15] and the epithelium is known to send regulatory signals to the mesenchyme, 16 any exchange of cells between these two early tissues does not appear to have been documented.…”

Section: Introductionmentioning

confidence: 99%