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Exocrine pancreatic cancer is an aggressive disease with an exceptionally high mortality rate. Genetic analysis suggests a causative role for environmental factors, but consistent epidemiological support is scarce and no biomarkers for monitoring the effects of chemical pancreatic carcinogens are available. With the objective to identify common traits for chemicals inducing pancreatic tumors we studied the National Toxicology Program (NTP) bioassay database. We found that male rats were affected more often than female rats and identified eight chemicals that induced exocrine pancreatic tumors in males only. For a hypothesis generating process we used a text mining tool to analyse published literature for suggested mode of actions (MOA). The resulting MOA analysis suggested inflammatory responses as common feature. In cell studies we found that all the chemicals increased protein levels of the inflammatory protein autotaxin (ATX) in Panc-1, MIA PaCa-2 or Capan-2 cells. Induction of MMP-9 and increased invasive migration were also frequent effects, consistent with ATX activation. Testosterone has previously been implicated in pancreatic carcinogenesis and we found that it increased ATX levels. Our data show that ATX is a target for chemicals inducing pancreatic tumors in rats. Several lines of evidence implicate ATX and its product lysophosphatidic acid in human pancreatic cancer. Mechanisms of action may include stimulated invasive growth and metastasis. ATX may interact with hormones or onco- or suppressor-genes often deregulated in exocrine pancreatic cancer. Our data suggest that ATX is a target for chemicals promoting pancreatic tumor development.
Pubmed ID: 22952646 RIS Download
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The NTP is an interagency program whose mission is to evaluate agents of public health concern by developing and applying tools of modern toxicology and molecular biology. The program maintains an objective, science-based approach in dealing with critical issues in toxicology and is committed to using the best science available to prioritize, design, conduct, and interpret its studies. To that end, the NTP is continually evolving to remain at the cutting edge of scientific research and to develop and apply new technologies. More than 80,000 chemicals are registered for use in the United States. Each year, an estimated 2,000 new ones are introduced for use in such everyday items as foods, personal care products, prescription drugs, household cleaners, and lawn care products. We do not know the effects of many of these chemicals on our health, yet we may be exposed to them while manufacturing, distributing, using, and disposing of them or when they become pollutants in our air, water, or soil. Relatively few chemicals are thought to pose a significant risk to human health. However, safeguarding public health depends on identifying both what the effects of these chemicals are and at what levels of exposure they may become hazardous to humansthat is, understanding their toxicology. The program was created as a cooperative effort to: 1. Coordinate toxicology testing programs within the federal government. 2. Strengthen the science base in toxicology. 3. Develop and validate improved testing methods. 4. Provide information about potentially toxic chemicals to health, regulatory, and research agencies, scientific and medical communities, and the public. The need for a program like the NTP arose because of increasing scientific, regulatory, and Congressional concerns about the human health effects of chemical agents in our environment. Many human diseases were thought to be directly or indirectly related to chemical exposures; therefore, it was thought that decreasing or eliminating human exposures to those chemicals would help prevent some human disease and disability. Testing Information The NTP is an interagency program whose mission is to evaluate agents of public health concern by developing and applying the tools of modern toxicology and molecular biology. This involves conducting toxicological evaluations of substances of public health concern, developing and validating improved (sensitive, specific, rapid) testing methods, developing approaches and generating data to strengthen the science base for risk assessment, and communicating with all stakeholders. The NTP plays a critical role in providing needed scientific data, interpretations, and guidance concerning the appropriate uses of data to regulatory agencies and other groups involved with health-related research. Through its interactive relationship with regulatory agencies, the NTP plays an indirect, but important role in shaping public health policy. Study Data Searches The National Toxicology Program makes available data from more than 500 two-year, two species, toxicology and carcinogenesis studies collected by the NTP and its predecessor, the National Cancer Institute's Carcinogenesis Testing Program, are stored in a database at NIEHS. The NTP database also contains the results collected on approximately 300 toxicity studies from shorter duration tests and from genetic toxicity studies, which includes both in vitro and in vivo tests. In addition, test data from the immunotoxicity, developmental toxicity and reproductive toxicity studies are continually being added to this database. Partnerships Through relationships with regulatory agencies, the NTP has an indirect role in shaping public health policy. Federal and state government agencies rely on the scientific knowledge and its interpretation provided by the NTP to make credible decisions that protect public health and the environment. The NTP also plays a critical role in: 1. Fostering interagency collaborations in research and exposure assessment 2. Providing information to regulatory agencies about alternative methods for toxicity testing, interpretation 3. Exploring new technologies for evaluating how environmental agents cause disease NTP conferences and workshops provide an opportunity for researchers, regulatory, policy makers, and the public to examine issues together, exchange information, and reach agreement on future directions of toxicology and risk assessment. Postdoctoral Training Program Opportunities Applied Toxicology and Carcinogenesis Training Program Fellowship in Toxicological Pathology Fellowship in Laboratory Animal Medicine
View all literature mentionsPublic database with millions of high-resolution images showing the spatial distribution of proteins in different normal human tissues and cancer types, as well as different human cell lines. The data is released together with application-specific validation performed for each antibody, including immunohistochemisty, Western blot analysis and, for a large fraction, a protein array assay and immunofluorescent based confocal microscopy. The database has been developed in a gene-centric manner with the inclusion of all human genes predicted from genome efforts. Search functionalities allow for complex queries regarding protein expression profiles, protein classes and chromosome location. Antibodies included have been analyzed using a standardized protocol in a single attempt without further efforts to optimize the procedure and therefore it cannot be excluded that certain observed binding properties are due to technical rather than biological reasons and that further optimization could result in a different outcome. Submission of antibodies: The Swedish Human Proteome Atlas (HPA) program, invites submission of antibodies from both academic and commercial sources to be included in the human protein atlas. All antibodies will be validated by the HPA-program by a standard procedure and antibodies that are accepted will be use in the tissue- profiling program to generate high-resolution immunohistochemistry images representing a wide spectrum of normal tissues and cancer types.
View all literature mentionsCell line PANC-1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line MIA PaCa-2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThe SciCrunch Infrastructure was developed as a cooperative data platform to be used by diverse communities in making data more FAIR.
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