One reason why pancreatic cancer is so aggressive and unresponsive to treatments is its resistance to apoptosis. We report here that reactive oxygen species (ROS) are a prosurvival, antiapoptotic factor in pancreatic cancer cells. Human pancreatic adenocarcinoma MIA PaCa-2 and PANC-1 cells generated ROS, which was stimulated by growth factors (serum, insulin-like growth factor I, or fibroblast growth factor-2). Growth factors also stimulated membrane NAD(P)H oxidase activity in these cells. Both intracellular ROS and NAD(P)H oxidase activity were inhibited by antioxidants tiron and N-acetylcysteine and the inhibitor of flavoprotein-dependent oxidases, diphenylene iodo- Pancreatic adenocarcinoma is an aggressive malignancy resistant to chemotherapy and radiotherapy (1). One mechanism mediating pancreatic cancer aggressiveness and unresponsiveness to treatment is its resistance to apoptosis. Constitutive activation of antiapoptotic proteins such as transcription factors NF-B (2) and signal transducers and activators of transcription (3), heat shock proteins (4), or phosphatidylinositide 3-kinase (5) is thought to contribute to pancreatic cancer resistance to apoptosis. We hypothesized that a key factor mediating this resistance is ROS 1 generated in pancreatic cancer cells. Although ROS have long been thought to promote cell death (6 -8), recent data (9 -12) suggest that they may also play a prosurvival role. ROS can activate the above mentioned antiapoptotic signaling pathways. In this regard, we recently showed (13) (12, 19 -21). Furthermore, functional components of the phagocytic NAD(P)H oxidase have been found to mediate superoxide production in some nonphagocytic cells (22,23). Other ROS-generating enzymes are xanthine oxidase, nitric-oxide synthase (NOS), phospholipase A 2 (PLA 2 ), and lipoxygenases (14). A growing body of evidence indicates that ROS play signaling roles in physiologic and pathophysiologic processes, including proliferation (24), adhesion (25), and hypertension (17, 26). In particular, growth factors are known to stimulate ROS in a variety of cell types through receptor-transducing pathways,

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and is characterized by remarkable desmoplasia. The desmoplasia is composed of extracellular matrix (ECM) proteins, myofibroblastic pancreatic stellate cells, and immune cells associated with a multitude of cytokines, growth factors, and ECM metabolizing enzymes. The mechanisms of participation of this complex matrix process in carcinogenesis are only starting to be appreciated. Recent studies showed key roles for stellate cells in the production of ECM proteins as well as cytokines and growth factors that promote the growth of the cancer cells all present in the desmoplastic parts of PDAC. In addition, interactions of ECM proteins and desmoplastic secreted growth factors with the cancer cells of PDAC activate intracellular signals including reactive oxygen species that act to make the cancer cells resistant to dying. These findings suggest that the desmoplasia of PDAC is a key factor in regulating carcinogenesis of PDAC as well as responses to therapies. A better understanding of the biology of desmoplasia in the mechanism of PDAC will likely provide significant opportunities for better treatments for this devastating cancer.

No abstract