Mechanistic insights into self-reinforcing processes driving abnormal histogenesis during the development of pancreatic cancer. Am J Pathol 2013 Apr;182(4):1078-86
Date
02/05/2013Pubmed ID
23375449Pubmed Central ID
PMC3969507DOI
10.1016/j.ajpath.2012.12.004Scopus ID
2-s2.0-84875199836 (requires institutional sign-in at Scopus site) 16 CitationsAbstract
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.
Author List
Iovanna JL, Marks DL, Fernandez-Zapico ME, Urrutia RAuthor
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Hypoxia
Epithelial-Mesenchymal Transition
Feedback, Physiological
Humans
Pancreatic Neoplasms
Precancerous Conditions
Stromal Cells
