TY - JOUR
T1 - Mechanistic insights into self-reinforcing processes driving abnormal histogenesis during the development of pancreatic cancer
AU - Iovanna, Juan L.
AU - Marks, David L.
AU - Fernandez-Zapico, Martin E.
AU - Urrutia, Raul
N1 - Funding Information:
Supported by grants from Ligue Contre le Cancer , INSERM , and INCA (Institute National du Cancer) (J.L.I.); the NIH ( DK52913 ), the Mayo Clinic Center for Cell Signaling in Gastroenterology ( P30DK084567 ), and the Translational Epigenomic Program, Center for Individualized Medicine , Mayo Clinic (R.U.); and by the Mayo Clinic SPORE in Pancreatic Cancer ( P50 CA102701 and CA136526 to M.E.F.-Z.).
PY - 2013/4
Y1 - 2013/4
N2 - Pancreatic ductal adenocarcinoma, one of the most feared lethal and painful diseases, is increasing in incidence. The poor prognosis of pancreatic ductal adenocarcinoma-affected patients primarily is owing to our inability to develop effective therapies. Mechanistic studies of genetic, epigenetic, and cell-to-cell signaling events are providing clues to molecular pathways that can be targeted in an attempt to cure this disease. The current review article seeks to draw inferences from available mechanistic knowledge to build a theoretical framework that can facilitate these approaches. This conceptual model considers pancreatic cancer as a tissue disease rather than an isolated epithelial cell problem, which develops and progresses in large part as a result of three positive feedback loops: i) genetic and epigenetic changes in epithelial cells modulate their interaction with mesenchymal cells to generate a dynamically changing process of abnormal histogenesis, which drives more changes; ii) the faulty tissue architecture of neoplastic lesions results in unsynchronized secretion of signaling molecules by cells, which generates an environment that is poor in oxygen and nutrients; and iii) the increased metabolic needs of rapidly dividing cells serve as an evolutionary pressure for them to adapt to this adverse microenvironment, leading to the emergence of resistant clones. We discuss how these concepts can guide mechanistic studies, as well as aid in the design of novel experimental therapeutics.
AB - Pancreatic ductal adenocarcinoma, one of the most feared lethal and painful diseases, is increasing in incidence. The poor prognosis of pancreatic ductal adenocarcinoma-affected patients primarily is owing to our inability to develop effective therapies. Mechanistic studies of genetic, epigenetic, and cell-to-cell signaling events are providing clues to molecular pathways that can be targeted in an attempt to cure this disease. The current review article seeks to draw inferences from available mechanistic knowledge to build a theoretical framework that can facilitate these approaches. This conceptual model considers pancreatic cancer as a tissue disease rather than an isolated epithelial cell problem, which develops and progresses in large part as a result of three positive feedback loops: i) genetic and epigenetic changes in epithelial cells modulate their interaction with mesenchymal cells to generate a dynamically changing process of abnormal histogenesis, which drives more changes; ii) the faulty tissue architecture of neoplastic lesions results in unsynchronized secretion of signaling molecules by cells, which generates an environment that is poor in oxygen and nutrients; and iii) the increased metabolic needs of rapidly dividing cells serve as an evolutionary pressure for them to adapt to this adverse microenvironment, leading to the emergence of resistant clones. We discuss how these concepts can guide mechanistic studies, as well as aid in the design of novel experimental therapeutics.
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U2 - 10.1016/j.ajpath.2012.12.004
DO - 10.1016/j.ajpath.2012.12.004
M3 - Short survey
C2 - 23375449
AN - SCOPUS:84875199836
SN - 0002-9440
VL - 182
SP - 1078
EP - 1086
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -