Epidemiology and molecular pathology at crossroads to establish causation: molecular mechanisms of malignant transformation

Bocchetta, Maurizio; Carbone, Michele

doi:10.1038/sj.onc.1207855

Cited by 21 publications

(7 citation statements)

References 65 publications

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“…p53 signaling is believed to be disrupted in virtually all metastatic cancers (52)(53)(54)(55). In contrast to Madh4 and p21-Cip1/Waf1, we could not detect any obvious downregulation and p19-Arf expression levels were unchanged in the tumor tissue.…”

Section: Molecular Analysis Of Pancreatic Adenocarcinomascontrasting

confidence: 75%

Ductal origin of pancreatic adenocarcinomas induced by conditional activation of a human Ha- ras oncogene in rat pancreas

et al. 2006

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Pancreatic ductal adenocarcinoma is one of the most debilitating malignancies in humans. Currently, radiation and chemotherapy are ineffective, with median survival times after treatment of <12 months. Animal models that reflect the human condition and can be used to explore screening and therapeutic approaches are clearly desirable. One feature of human pancreatic adenocarcinoma is an exceedingly high frequency of K-ras mutation. The present study was conducted to determine if targeted activation of a human oncogenic-ras transgene in rat pancreas would induce carcinomas correspondent to human pancreatic ductal adenocarcinomas. We established transgenic (Hras250) rats in which expression of a human Ha-rasG12V oncogene is regulated by the Cre/lox system. Targeted pancreatic activation of the transgene was accomplished by injection of Cre-carrying adenovirus into the pancreatic ducts and acini through the common bile duct. Adenoviral infection of injected animals was exclusive to the pancreas; infected cells could be identified in duct, intercalated duct, centroacinar and, less frequently, acinar cells, but not in endocrine islet cells. Four weeks after injection, proliferative lesions in the duct epithelium, intercalated ducts and centroacinar cells, but not acinar cells, were widespread. Tumorigenesis in other tissues was not observed. Most lesions, including atypical duct proliferative lesions, PanIN-like lesions and carcinomas, were positive for cytokeratins 19 and 7, cyclooxygenase 2 and MMP-7 but negative for amylase and chymotrypsin. Many adenocarcinoma lesions were positive for EGF and EGFR. Duct epithelial and atypical duct proliferative lesions and carcinoma lesions were all positive for transduced Ha-rasG12V oncogene expression. The cytogenesis of pancreatic ductal type carcinoma was depicted. This model exhibits important similarities to the human disease and promises to advance our understanding of the behavior of pancreas adenocarcinomas and expedite screening and therapy.

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Section: Molecular Analysis Of Pancreatic Adenocarcinomascontrasting

confidence: 75%

Ductal origin of pancreatic adenocarcinomas induced by conditional activation of a human Ha- ras oncogene in rat pancreas

et al. 2006

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“…Although it was reported that overexpression of Acrogranin in a cancer cell line (SW-13) augmented the tumorigenicity in nude mice (17), this is the first study showing that Acrogranin endows tumorigenicity to phenotypically normal cells which originally did not form tumors in nude mice. Studies on in vitro-malignant transformation have revealed that, in order to transform primary human cells, the following four signals are necessary: 1) maintenance of telomere length by hTERT expression, 2) perturbation of p53 and RB by SV40LT expression or other methods, 3) perturbation of PP2A by SV40 ST expression or other methods, 4) constitutive RAS signaling by transfection of the oncogenic allele of RAS (18)(19)(20)(21). In general, signals from growth factors are transmitted through tyrosine kinase-type receptors to RAS (22).…”

Section: Discussionmentioning

confidence: 99%

Immortalized ovarian surface epithelial cells acquire tumorigenicity by Acrogranin gene overexpression

Miyanishi

Mandai²,

Matsumura³

et al. 2007

Oncol Rep

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Malignant transformation is caused by multi-step genetic mutations, and growth factors are believed to play important roles in developing and maintaining malignant phenotype. However, there is no direct evidence that a specific growth factor contributes to malignant transformation of phenotypically normal cells. In order to assess the function of Acrogranin (also known as granulin epithelial precursor; GEP) in ovarian carcinogenesis, ovarian surface epithelial (OSE) cells, which are supposed to be the origin of primary ovarian epithelial cancer, were transfected with combined genes of hTERT, SV40 LT, and Acrogranin. Introduction of hTERT and SV40 LT was sufficient for immortalizing OSE cells but not enough for tumor formation in nude mice. In contrast, transfection and overexpression of Acrogranin in immortalized OSE cells showed augmented clonogenicity in soft agar and obvious tumorigenicity in nude mice. This is the first study showing evidence that a specific growth factor plays a direct role in malignant transformation in ovarian cancer development.

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“…Typically, the measurements of response in epidemiologic studies reflect late-stage end points of morbidity, mortality, body weight decrease, tumor development, and tissue pathology (Bocchetta and Carbone 2004; Maier et al 2004). Defining risk at a late stage in the disease process provides little opportunity to intervene and redirect the outcome.…”

Section: Exposure Assessment Methodsmentioning

confidence: 99%

Personalized Exposure Assessment: Promising Approaches for Human Environmental Health Research

Weis

Balshaw

Barr

et al. 2005

Environ Health Perspect

119

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New technologies and methods for assessing human exposure to chemicals, dietary and lifestyle factors, infectious agents, and other stressors provide an opportunity to extend the range of human health investigations and advance our understanding of the relationship between environmental exposure and disease. An ad hoc Committee on Environmental Exposure Technology Development was convened to identify new technologies and methods for deriving personalized exposure measurements for application to environmental health studies. The committee identified a “toolbox” of methods for measuring external (environmental) and internal (biologic) exposure and assessing human behaviors that influence the likelihood of exposure to environmental agents. The methods use environmental sensors, geographic information systems, biologic sensors, toxicogenomics, and body burden (biologic) measurements. We discuss each of the methods in relation to current use in human health research; specific gaps in the development, validation, and application of the methods are highlighted. We also present a conceptual framework for moving these technologies into use and acceptance by the scientific community. The framework focuses on understanding complex human diseases using an integrated approach to exposure assessment to define particular exposure–disease relationships and the interaction of genetic and environmental factors in disease occurrence. Improved methods for exposure assessment will result in better means of monitoring and targeting intervention and prevention programs.

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Epidemiology and molecular pathology at crossroads to establish causation: molecular mechanisms of malignant transformation

Cited by 21 publications

References 65 publications

Ductal origin of pancreatic adenocarcinomas induced by conditional activation of a human Ha- ras oncogene in rat pancreas

Ductal origin of pancreatic adenocarcinomas induced by conditional activation of a human Ha- ras oncogene in rat pancreas

Immortalized ovarian surface epithelial cells acquire tumorigenicity by Acrogranin gene overexpression

Personalized Exposure Assessment: Promising Approaches for Human Environmental Health Research

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