Exocrine Pancreatic Carcinogenesis and Autotaxin Expression

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.

[1]  S. Larsson,et al.  Red Meat Consumption and Risk of Stroke: A Meta-Analysis of Prospective Studies , 2012, Stroke.

[2]  Anna Korhonen,et al.  Data and literature gathering in chemical cancer risk assessment , 2012, Integrated environmental assessment and management.

[3]  J. French,et al.  Gender Differences in Chemical Carcinogenesis in National Toxicology Program 2-Year Bioassays , 2012, Toxicologic pathology.

[4]  A. Korhonen,et al.  Text Mining for Literature Review and Knowledge Discovery in Cancer Risk Assessment and Research , 2012, PloS one.

[5]  S. Larsson,et al.  Red and processed meat consumption and risk of pancreatic cancer: meta-analysis of prospective studies , 2012, British Journal of Cancer.

[6]  H. Papadaki,et al.  Androgen Receptor in Laryngeal Carcinoma: Could There Be an Androgen-Refractory Tumor? , 2011, ISRN oncology.

[7]  W. Gerald,et al.  Stat3 Mediates Expression of Autotaxin in Breast Cancer , 2011, PloS one.

[8]  Tao Jiang,et al.  STAT3 Knockdown Reduces Pancreatic Cancer Cell Invasiveness and Matrix Metalloproteinase-7 Expression in Nude Mice , 2011, PloS one.

[9]  P. A. van den Brandt,et al.  A pooled analysis of 14 cohort studies of anthropometric factors and pancreatic cancer risk , 2011, International journal of cancer.

[10]  P. Mazur,et al.  Early requirement of Rac1 in a mouse model of pancreatic cancer. , 2011, Gastroenterology.

[11]  B. Bao,et al.  Activated K-ras and INK4a/Arf Deficiency Cooperate During the Development of Pancreatic Cancer by Activation of Notch and NF-κB Signaling Pathways , 2011, PloS one.

[12]  Daniel Morton,et al.  An Analysis of Pharmaceutical Experience with Decades of Rat Carcinogenicity Testing , 2011, Toxicologic pathology.

[13]  N. Sasahira,et al.  Specific increase in serum autotaxin activity in patients with pancreatic cancer. , 2011, Clinical Biochemistry.

[14]  G. Mills,et al.  Lysophosphatidic acid augments human hepatocellular carcinoma cell invasion through LPA1 receptor and MMP-9 expression , 2011, Oncogene.

[15]  Yan Xu,et al.  Autotaxin is induced by TSA through HDAC3 and HDAC7 inhibition and antagonizes the TSA-induced cell apoptosis , 2011, Molecular Cancer.

[16]  Jianhua Yang,et al.  Molecular basis of lysophosphatidic acid-induced NF-κB activation. , 2010, Cellular signalling.

[17]  B. Boyan,et al.  24R,25-Dihydroxyvitamin D3, lysophosphatidic acid, and p53: A signaling axis in the inhibition of phosphate-induced chondrocyte apoptosis , 2010, The Journal of Steroid Biochemistry and Molecular Biology.

[18]  M. Hebrok,et al.  KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma , 2010, Nature Reviews Cancer.

[19]  B. Kaina,et al.  The aryl hydrocarbon receptor (AhR) in the regulation of cell-cell contact and tumor growth. , 2010, Carcinogenesis.

[20]  J. Aoki,et al.  Autotaxin--an LPA producing enzyme with diverse functions. , 2010, Journal of biochemistry.

[21]  D. Lauffenburger,et al.  Structure of the EGF receptor transactivation circuit integrates multiple signals with cell context. , 2010, Molecular bioSystems.

[22]  J. Aoki,et al.  Biological roles of lysophosphatidic acid signaling through its production by autotaxin. , 2010, Biochimie.

[23]  K. Harper,et al.  Autotaxin promotes cancer invasion via the lysophosphatidic acid receptor 4: participation of the cyclic AMP/EPAC/Rac1 signaling pathway in invadopodia formation. , 2010, Cancer research.

[24]  U. Nöthlings,et al.  Cigarette smoking, environmental tobacco smoke exposure and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition , 2010, International journal of cancer.

[25]  J. Shea,et al.  Phenotype and Genotype of Pancreatic Cancer Cell Lines , 2010, Pancreas.

[26]  J. Davila,et al.  Incidence and Survival of Pancreatic Head and Body and Tail Cancers: A Population-Based Study in the United States , 2010, Pancreas.

[27]  Paolo Vineis,et al.  Alcohol intake and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium (PanScan) , 2010, Cancer Causes & Control.

[28]  D. Klimstra,et al.  Pancreatic Acinar Cell Carcinomas With Prominent Ductal Differentiation: Mixed Acinar Ductal Carcinoma and Mixed Acinar Endocrine Ductal Carcinoma , 2010, The American journal of surgical pathology.

[29]  David A. Egan,et al.  Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation , 2010, Proceedings of the National Academy of Sciences.

[30]  M. Hebrok,et al.  Cellular plasticity within the pancreas--lessons learned from development. , 2010, Developmental cell.

[31]  J. Potter,et al.  Incidence rates of exocrine and endocrine pancreatic cancers in the United States , 2010, Cancer Causes & Control.

[32]  Mark A Pereira,et al.  Soft Drink and Juice Consumption and Risk of Pancreatic Cancer: The Singapore Chinese Health Study , 2010, Cancer Epidemiology, Biomarkers & Prevention.

[33]  Kyoko Noguchi,et al.  LPA receptors: subtypes and biological actions. , 2010, Annual review of pharmacology and toxicology.

[34]  L. Tanoue.  Cancer Statistics, 2009 , 2010 .

[35]  Patrick Maisonneuve,et al.  Epidemiology of pancreatic cancer: an overview , 2009, Nature Reviews Gastroenterology &Hepatology.

[36]  B. Ji,et al.  Ras activity in acinar cells links chronic pancreatitis and pancreatic cancer. , 2009, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[37]  E. Thrower,et al.  The acinar cell and early pancreatitis responses. , 2009, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[38]  Gerald C. Chu,et al.  Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. , 2009, Cancer cell.

[39]  D. Jain,et al.  Protease activation during in vivo pancreatitis is dependent on calcineurin activation. , 2009, American journal of physiology. Gastrointestinal and liver physiology.

[40]  Anna Korhonen,et al.  The first step in the development of text mining technology for cancer risk assessment: identifying and organizing scientific evidence in risk assessment literature , 2009, BMC Bioinformatics.

[41]  B. Mroczko,et al.  Clinical Significance of the Measurements of Serum Matrix Metalloproteinase-9 and Its Inhibitor (Tissue Inhibitor of Metalloproteinase-1) in Patients With Pancreatic Cancer: Metalloproteinase-9 as an Independent Prognostic Factor , 2009, Pancreas.

[42]  Anna Korhonen,et al.  User-Driven Development of Text Mining Resources for Cancer Risk Assessment , 2009, BioNLP@HLT-NAACL.

[43]  Yiling Lu,et al.  Expression of autotaxin and lysophosphatidic acid receptors increases mammary tumorigenesis, invasion, and metastases. , 2009, Cancer cell.

[44]  K. Mundt,et al.  Mortality in the German Porcelain Industry 1985–2005: First Results of an Epidemiological Cohort Study , 2009, Journal of occupational and environmental medicine.

[45]  I. Takeyoshi,et al.  LPA1 receptors mediate stimulation, whereas LPA2 receptors mediate inhibition, of migration of pancreatic cancer cells in response to lysophosphatidic acid and malignant ascites. , 2009, Carcinogenesis.

[46]  A. Osunkoya,et al.  Reciprocal regulation of ZEB1 and AR in triple negative breast cancer cells , 2009, Breast Cancer Research and Treatment.

[47]  B. Fischer,et al.  TCDD induces cell migration via NFATc1/ATX-signaling in MCF-7 cells. , 2009, Toxicology letters.

[48]  D Hattis,et al.  A preliminary operational classification system for nonmutagenic modes of action for carcinogenesis. , 2009, Critical reviews in toxicology.

[49]  J. L. Goodman,et al.  Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia , 2008, Proceedings of the National Academy of Sciences.

[50]  G. Feldmann,et al.  Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice , 2008, Proceedings of the National Academy of Sciences.

[51]  Yiling Lu,et al.  Lysophosphatidic acid receptors determine tumorigenicity and aggressiveness of ovarian cancer cells. , 2008, Journal of the National Cancer Institute.

[52]  H. Boshuizen,et al.  Abstract A98: Cigarette smoking, environmental tobacco smoke exposure, and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition , 2008 .

[53]  H. Weir,et al.  Surveillance for cancers associated with tobacco use--United States, 1999-2004. , 2008, Morbidity and mortality weekly report. Surveillance summaries.

[54]  R. Bernards,et al.  Suppression of the p53-Dependent Replicative Senescence Response by Lysophosphatidic Acid Signaling , 2008, Molecular Cancer Research.

[55]  R. Takayanagi,et al.  Lysophosphatidic acid induced nuclear translocation of nuclear factor-kappaB in Panc-1 cells by mobilizing cytosolic free calcium. , 2008, World Journal of Gastroenterology.

[56]  S. M. Sims,et al.  P2X7 receptors on osteoblasts couple to production of lysophosphatidic acid: a signaling axis promoting osteogenesis , 2008, The Journal of cell biology.

[57]  A. Maitra,et al.  Pancreatic Carcinogenesis , 2008, Pancreatology.

[58]  R. García-Becerra,et al.  Regulation of LPA receptor function by estrogens. , 2008, Biochimica et biophysica acta.

[59]  R. Hruban,et al.  Tumorigenesis and Neoplastic Progression Acinar Cells Contribute to the Molecular Heterogeneity of Pancreatic Intraepithelial Neoplasia , 2007 .

[60]  G. Halldén,et al.  GPR93 activation by protein hydrolysate induces CCK transcription and secretion in STC-1 cells. , 2007, American journal of physiology. Gastrointestinal and liver physiology.

[61]  M. Barbacid,et al.  Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. , 2007, Cancer cell.

[62]  S. M. Sims,et al.  P2X7 Nucleotide Receptors Mediate Blebbing in Osteoblasts through a Pathway Involving Lysophosphatidic Acid* , 2007, Journal of Biological Chemistry.

[63]  H. Friess,et al.  Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease. , 2007, American journal of physiology. Gastrointestinal and liver physiology.

[64]  Hiroshi Suzuki,et al.  Lysophosphatidic receptor, LPA3, is positively and negatively regulated by progesterone and estrogen in the mouse uterus. , 2006, Life sciences.

[65]  J. Wiley,et al.  Rapid ATP-induced release of matrix metalloproteinase 9 is mediated by the P2X7 receptor. , 2006, Blood.

[66]  Pei-Shan Liu,et al.  Effect of toluene diisocyanate on homeostasis of intracellular-free calcium in human neuroblastoma SH-SY5Y cells. , 2006, Toxicology and applied pharmacology.

[67]  Pei-Shan Liu,et al.  2,4-Toluene diisocyanate suppressed the calcium signaling of ligand gated ion channel receptors. , 2006, Toxicology.

[68]  C. Malbon.  β-Catenin, Cancer, and G Proteins: Not Just for Frizzleds Anymore , 2005, Science's STKE.

[69]  B. Giepmans,et al.  The ins and outs of lysophosphatidic acid signaling , 2004, BioEssays : news and reviews in molecular, cellular and developmental biology.

[70]  J. Haseman,et al.  Exocrine pancreatic pathology in female Harlan Sprague-Dawley rats after chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds. , 2004, Environmental health perspectives.

[71]  Y. Morishita,et al.  Lysophosphatidic Acid (LPA) in Malignant Ascites Stimulates Motility of Human Pancreatic Cancer Cells through LPA1* , 2004, Journal of Biological Chemistry.

[72]  R. Maronpot,et al.  Relevance of Animal Carcinogenesis Findings to Human Cancer Predictions and Prevention , 2004, Toxicologic pathology.

[73]  M. Rao.  Animal models of exocrine pancreatic carcinogenesis , 1987, Cancer and Metastasis Reviews.

[74]  C. la Vecchia,et al.  Pancreatic Cancer Mortality in Europe: The Leveling of an Epidemic , 2003, Pancreas.

[75]  D. Longnecker,et al.  Preinvasive pancreatic neoplasia of ductal phenotype induced by acinar cell targeting of mutant Kras in transgenic mice. , 2003, Cancer research.

[76]  J. Winer,et al.  Synergistic Induction of Tumor Antigens by Wnt-1 Signaling and Retinoic Acid Revealed by Gene Expression Profiling* , 2002, The Journal of Biological Chemistry.

[77]  J. Crawford,et al.  Enhancement of survival by LPA via Erk1/Erk2 and PI 3-kinase/Akt pathways in a murine hepatocyte cell line. , 2001, American journal of physiology. Cell physiology.

[78]  Suk Woo Nam,et al.  Autotaxin (ATX), a potent tumor motogen, augments invasive and metastatic potential of ras-transformed cells , 2000, Oncogene.

[79]  T. Tosteson,et al.  K-ras mutation in focal proliferative lesions of human pancreas. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[80]  D. Longnecker,et al.  Evaluation of p53 mutation in pancreatic acinar cell carcinomas of humans and transgenic mice. , 1998, Pancreas.

[81]  V. Tuohy,et al.  Phosphodiesterase I, A Novel Adhesion Molecule and/or Cytokine Involved in Oligodendrocyte Function , 1997, The Journal of Neuroscience.

[82]  G. Nuovo,et al.  Matrix Metalloproteinase‐9 in Tumor Cell Invasion , 1994, Annals of the New York Academy of Sciences.

[83]  C. Heffess,et al.  Only wild‐type c‐ki‐ras codons 12, 13, and 61 in human pancreatic acinar cell carcinomas , 1994, Molecular carcinogenesis.

[84]  R. Woutersen,et al.  Early indicators of exocrine pancreas carcinogenesis produced by non-genotoxic agents. , 1991, Mutation research.

[85]  D. Longnecker,et al.  Effects of sex steroid hormones on pancreatic cancer in the rat , 1990, International journal of pancreatology : official journal of the International Association of Pancreatology.

[86]  Longnecker Ds,et al.  Pathology of tumours in laboratory animals. Tumours of the rat. Tumours of the pancreas. , 1990 .

[87]  D. Longnecker,et al.  Pathology of tumours in laboratory animals. Tumours of the rat. Tumours of the pancreas. , 1990, IARC scientific publications.

[88]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[89]  E. Lhoste,et al.  Effect of castration and hormone replacement on azaserine-induced pancreatic carcinogenesis in male and female Fischer rats. , 1987, Carcinogenesis.

[90]  E. Lhoste,et al.  Effect of Orchiectomy and Testosterone on the Early Stages of Azaserine‐Induced Pancreatic Carcinogenesis in the Rat , 1987, Pancreas.

[91]  J. Barrowman,et al.  Effect of experimental pancreatic growth on the content of xenobiotic-metabolising enzymes in the pancreas. , 1987, Gut.