Mechanistic insights into self-reinforcing processes driving abnormal histogenesis during the development of pancreatic cancer

Juan L. Iovanna, David L. Marks, Martin E Fernandez-Zapico, Raul Urrutia

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1078-1086
Number of pages9
JournalAmerican Journal of Pathology
Volume182
Issue number4
DOIs
StatePublished - Apr 2013

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Pancreatic Neoplasms
Epigenomics
Adenocarcinoma
Epithelial Cells
Research Design
Clone Cells
Oxygen
Pressure
Food
Incidence
Therapeutics

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Mechanistic insights into self-reinforcing processes driving abnormal histogenesis during the development of pancreatic cancer. / Iovanna, Juan L.; Marks, David L.; Fernandez-Zapico, Martin E; Urrutia, Raul.

In: American Journal of Pathology, Vol. 182, No. 4, 04.2013, p. 1078-1086.

Research output: Contribution to journalArticle

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