Exocrine Pancreatic Carcinogenesis and Autotaxin Expression

Abstract

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.

Toluene diisocyanate: Induction of the autotaxin-lysophosphatidic acid axis and its association with airways symptoms

“…1A). In a previous work we documented increased mRNA levels of the gene coding for ATX (ENPP2) in pancreatic cancer cells in response to 10 μM TDI (Kadekar et al, 2012). Fig.…”

“…e l s e v i e r . c o m / l o c a t e / y t a a p ATX induction has been associated with cancer progression (Tabchy et al, 2011;Kadekar et al, 2012), rheumatoid arthritis (Nikitopoulou et al, 2012), idiopathic pulmonary fibrosis and also with lung fibrosis induced by the cancer drug bleomycine (Budd and Qian, 2013). Recently a study indicated a role for ATX in allergic airway inflammation after allergen challenge (Park et al, 2013) and remaining questions include cellular mechanisms behind ATX induction (Georas, 2013).…”

The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer

“…63 In addition, genomic alterations in ATX have been observed across multiple cancers. Information obtained from the Cancer Genome Atlas (TCGA) data shows that most of the genomic alterations are ENPP2 amplifications, which could potentially elucidate dysregulation of ATX/LPAmediated signaling pathways in various cancers.…”

Autotaxin signaling, purinergic receptors and lung damage

“…These chemicals were selected because they induced rat pancreatic acinar carcinomas in cancer bioassays performed by the National Toxicology Program (NTP). Based on the observed ATX induction, we suggested that these chemicals facilitated pancreatic carcinogenesis via ATX [21] . Of these eight chemicals, TDI is so far the only one that we have studied in some detail, but the potency of TDI to induce ATX is now a stimulus for further investigations.…”