Identification and sequencing of the Syrian Golden hamster (Mesocricetus auratus) p16INK4a and p15INK4b cDNAs and their homozygous gene deletion in cheek pouch and pancreatic tumor cells

Muscarella, Peter; Knobloch, Thomas J.; Ulrich, Alexis; Casto, Bruce C.; Moniaux, Nicolas; Wittel, Uwe A.; Melvin, W. Scott; Pour, Parviz M.; Song, Huijuan; Gold, Barry; Batra, Surinder K.; Weghorst, Christopher M.

doi:10.1016/s0378-1119(01)00728-4

Cited by 21 publications

(16 citation statements)

References 30 publications

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“…p16 expression decreases sharply during oral mucosal dysplasia and remains at low levels in subsequent stages of oral oncogenesis [47]; this is consistent with our findings. Possible mechanisms of p16 INK4A gene inactivation may include accumulation of events, such as homozygous gene deletion, mutations and hypermethylation of the promoter region of the p16 gene [48][49][50][51][52]. In addition, the fact that no difference in p16 INK4A expression was observed among the groups, irrespective of the oral administration of HERP, indicates that the inhibitory effects of the extract on the progression of the epithelial dysplasia to invasive carcinoma were not associated with the inactivation of this protein.…”

Section: Experimental Animalmentioning

confidence: 99%

Inhibition of DMBA‐induced Oral Squamous Cells Carcinoma Growth by Brazilian Red Propolis in Rodent Model

Ribeiro

Alves

Santos

et al. 2015

Basic Clin Pharma Tox

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Abstract:We investigated the effect of oral administration of hydroalcoholic extract of Brazilian red propolis (HERP) on DMBA-induced oral squamous cell carcinomas (OSCC) in rodents. The chemical components of the HERP were assessed by high-performance liquid chromatography (HPLC). Carcinogenesis was topically induced in the lower lip of 25 rats using 9,10-dimethyl-1,2-benzanthracene (DMBA); the tumour was treated with saline (TUM1) and Tween 80 (TUM2) as well as HERP at 10, 50 and 100 mg/kg (HERP10, HERP50 and HERP100, respectively) for 20 weeks. Topical application of saline and oral administration of 100 mg/kg HERP was used in five rats as a control group (CTR). After 26 weeks, the histological malignancy grading and immunohistochemical expression of INK4A were assessed in the tumours/tissue samples. The compounds identified were propyl gallate, daidzein, catechin, epicatechin, formononetin and biochanin A. Formononetin, daidzein and biochanin A showed concentration of 23.29, 0.38 and 0.67 mg/g of HERP, respectively. HERP at doses of 50 and 100 mg/ kg inhibited 40% of OSCC growth and promoted a 3-week delay in development of clinically detectable tumours. Epithelial dysplasia was observed in all samples with no clinical tumour, except in CTR. No significant difference in the immunoexpression of INK4A was observed between HERP-treated and saline/Tween 80-treated groups (p > 0.05). Our results suggest that HERP exerts chemopreventive activity on the progression of DMBA-induced epithelial dysplasia to OSCC in an experimental model of labial carcinogenesis; however, this effect is not associated with Ki-67 and p16INK4A immunoexpression.Propolis is a natural, resinous hive product that honeybees manufacture by mixing their own waxes and salivary secretions with resins collected from cracks in tree barks and leaf buds [1]. Propolis samples from different regions of Brazil display different colours and chemical compositions, depending on the local flora at the site of collection [2]. Brazilian green propolis, derived from Baccharis dracunculifolia (Asteraceae) [3], is the most popular and well-studied Brazilian propolis.In the last few years, a red variety of Brazilian propolis has been described and characterized by various authors [4][5][6], demonstrating that the botanical origin influences directly its chemical composition. Isoflavones are chemical constituents usually identified in ethanolic extracts of red propolis, being formononetin, daidzein and biochanin A more often found [5,7].Brazilian

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Section: Experimental Animalmentioning

confidence: 99%

Inhibition of DMBA‐induced Oral Squamous Cells Carcinoma Growth by Brazilian Red Propolis in Rodent Model

Ribeiro

Alves

Santos

et al. 2015

Basic Clin Pharma Tox

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“…Transdifferentiation of islet cells, specifically ␤ cells, is proposed as a likely source of metaplasia/neoplasia in several in vitro and in vivo studies (17). In vitro, isolated pancreatic islets have been reported to transform to duct-like structures expressing ductal markers and to acquire genetic alterations typical of pancreatic cancer, such as K-ras mutations and p16 deletion (18)(19)(20). However, in vitro studies do not necessarily mirror in vivo events.…”

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confidence: 99%

β cell transdifferentiation does not contribute to preneoplastic/metaplastic ductal lesions of the pancreas by genetic lineage tracing in vivo

Strobel

Dor²,

Stirman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Inflammatory injury to the pancreas results in regeneration of normal tissue and formation of metaplastic lesions of a ductal phenotype. These metaplastic ductal lesions (MDL) are called tubular complexes (TC), mucinous metaplasia, or pancreatic intraepithelial neoplasia. Because they are regularly found in chronic pancreatitis and pancreatic cancer, their formation is thought to represent a step in inflammation-mediated carcinogenesis. Despite these lesions' ductal character, their origin is controversial. All known pancreatic cell lineages have been suggested as the origin. In vitro studies suggest that differentiated cells in the pancreas remain highly plastic and can transdifferentiate as a mechanism of regeneration and metaplasia. In vivo studies suggest that islets, specifically ␤ cells, may be the cell of origin. However, in vitro studies are subject to ductal cell contamination, and previous in vivo studies interpret static data rather than direct evidence. Using genetic lineage tracing in vivo, we investigate whether transdifferentiation of ␤ cells contributes to regeneration or metaplasia in pancreatitis. RIP-CreER;Z/AP mice were used to heritably tag ␤ cells in the adult pancreas. Injury by cerulein pancreatitis resulted in regeneration of normal tissue and metaplasia with formation of two distinct types of TC and mucinous lesions. Lineage tracing revealed that none of these MDL are of ␤ cell origin; nor do ␤ cells contribute to regeneration of normal acinar and ductal tissue, which indicates that the plasticity of differentiated pancreatic islet cells, suggested by earlier static and in vitro studies, plays no role in regeneration, metaplasia, and carcinogenesis in vivo.metaplasia ͉ pancreatitis ͉ pancreatic intraepithelial neoplasia T issue injury can result in regeneration of normal tissue and in metaplasia. Metaplasia is often seen in response to chronic injury and can occur by selective cellular proliferation or death or by transdifferentiation. Cell lineages in the pancreas include exocrine (acinar and ductal) and endocrine cells. Inflammation of the pancreas results in the formation of metaplastic lesions of a ductal phenotype (MDL) that are consistently found in chronic pancreatitis (CP) and specimens of pancreatic cancer. Therefore, this ''ductal'' metaplasia is thought to represent a condition with increased risk of neoplasia. In the literature, two definitions have been used to describe MDL in the pancreas: tubular complexes (TC) and mucinous metaplasia or pancreatic intraepithelial neoplasia (PanIN) (1, 2). TC, defined as cylindrical tubes with a wide lumen lined by a monolayer of flat duct-like cells (3-5), are found in pancreatic development, regeneration, in CP, and in cancer (5-8). In some studies, TC exhibited a high cell turnover and were thought to have regenerative potential, including islet regeneration (5, 9). A progression of TC to neoplasia has been suggested in rodent models of chemical carcinogenesis (1, 10, 11) and transgenic mouse models (12). Misexpression of mucins in pan...

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“…Determination of the genetic abnormalities in the premalignant neoplastic lesion, as identified by Markovian and DNA ploidy analysis, will help elucidate adenocarcinoma development in this hamster model. Recent studies in hamster pancreatic adenocarcinoma cell lines have generated data demonstrating that p16, a tumor suppressor gene, and the associated p15 gene are homozygously deleted in these lines, implying that these deletions may be important in hamster tumorigenesis (Muscarella et al 2001). This offers further evidence that the hamster pancreatic cancer model may yield mechanistic data relative to the human disease because these deletions are also found in human pancreatic adenocarcinomas and cell lines (Naumann et al 1996;Kaino 1997;Capella et al 1999).…”

Section: Discussionmentioning

confidence: 91%

DNA Ploidy and Markovian Analysis of Neoplastic Progression in Experimental Pancreatic Cancer

Postier¹,

Lerner

Lightfoot

et al. 2003

J Histochem Cytochem.

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S U M M A R YComputer-assisted analysis of DNA ploidy and nuclear morphology were used to elucidate changes in the cell nucleus that occur during the development of experimental pancreatic cancer. Ductal pancreatic adenocarcinoma was induced in 49 Syrian hamsters by SC injection of N -nitrosobis (2-oxopropyl) amine; twenty hamsters served as controls. Groups of animals were sacrificed every 4 weeks for 20 weeks and adjacent sections of pancreatic tissue were H&E and Feulgen-stained for light microscopy and computer assisted cytometry. Pancreatic ductal cells were classified as normal, atypical, or malignant; tissue inflammation (pancreatitis) was also noted when present. DNA ploidy and nuclear morphology evaluation (Markovian analysis) identified an atypical cell stage clearly distinguishable from either normal or malignant cells; pancreatitis preceded this atypia. The DNA ploidy histogram of these atypical cells revealed a major diploid peak and a minor aneuploid peak. The receiver operator characteristic curve areas for a logistic regression model of normal vs atypical cells was 0.94 and for atypical vs malignant was 0.98, numbers indicative of near-perfect discrimination among these three cell types. The ability to identify an atypical cell population should be useful in establishing the role of these cells in the progression of human pancreatic adenocarcinoma.

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Identification and sequencing of the Syrian Golden hamster (Mesocricetus auratus) p16INK4a and p15INK4b cDNAs and their homozygous gene deletion in cheek pouch and pancreatic tumor cells

Cited by 21 publications

References 30 publications

Inhibition of DMBA‐induced Oral Squamous Cells Carcinoma Growth by Brazilian Red Propolis in Rodent Model

Inhibition of DMBA‐induced Oral Squamous Cells Carcinoma Growth by Brazilian Red Propolis in Rodent Model

β cell transdifferentiation does not contribute to preneoplastic/metaplastic ductal lesions of the pancreas by genetic lineage tracing in vivo

DNA Ploidy and Markovian Analysis of Neoplastic Progression in Experimental Pancreatic Cancer

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