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Pancreatic cancer biology and genetics from an evolutionary perspective
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Journal Article
Pancreatic cancer biology and genetics from an evolutionary perspective
2016
Overview
Key Points
Pancreatic cancer evolves in three stages: initiation, expansion and survival in foreign microenvironments.
Factors that contribute to initiation are inherited (germline) mutations, somatic mutations acquired during organ growth and renewal, ageing, chronic inflammation, obesity and smoking.
Genetic mutations in
KRAS
, cyclin-dependent kinase inhibitor 2A (
CDKN2A
),
TP53
and
SMAD4
drive clonal expansion by conferring a selective growth advantage on pancreatic cancer cells.
Selection pressures and bottlenecks result from extension into new microenvironments of immune cells, stroma, organ-specific cell types and resource gradients that vary spatially and temporally. Metastasis requires dispersal, invasion and colonization of microenvironments distant from the pancreatic primary site.
Remaining questions include the order of early cancer-promoting events, the phenotypic importance of late-occurring mutations and the clinical relevance of genetic, microenvironmental and cellular heterogeneity.
Evolutionary thinking provides a framework for the biology of pancreatic cancer, revealing how and why this lethal tumour evolves.
This Review brings many aspects of pancreatic ductal adenocarcinoma research into a single concept rooted in Darwinian evolution, with the goal of identifying novel insights and opportunities for future study.
Cancer is an evolutionary disease, containing the hallmarks of an asexually reproducing unicellular organism subject to evolutionary paradigms. Pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer) is a particularly robust example of this phenomenon. Genomic features indicate that pancreatic cancer cells are selected for fitness advantages when encountering the geographic and resource-depleted constraints of the microenvironment. Phenotypic adaptations to these pressures help disseminated cells to survive in secondary sites, a major clinical problem for patients with this disease. In this Review we gather the wide-ranging aspects of pancreatic cancer research into a single concept rooted in Darwinian evolution, with the goal of identifying novel insights and opportunities for study.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Carcinoma, Pancreatic Ductal - genetics
/ Carcinoma, Pancreatic Ductal - immunology
/ Carcinoma, Pancreatic Ductal - pathology
/ Cell Transformation, Neoplastic - genetics
/ Humans
/ Mutation
/ Neoplasm Proteins - genetics
/ Neoplasm Proteins - physiology
/ Pancreatic Neoplasms - genetics
/ Pancreatic Neoplasms - immunology
