TY - JOUR
T1 - Ontogenic growth as the root of fundamental differences between childhood and adult cancer
AU - Werner, Benjamin
AU - Traulsen, Arne
AU - Dingli, David
N1 - Publisher Copyright:
© AlphaMed Press.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - Cancer, the unregulated proliferation of cells, can occur at any age and may arise from almost all cell types. However, the incidence and types of cancer differ with age. Some cancers are predominantly observed in children, others are mostly restricted to older ages. Treatment strategies of some cancers are very successful and cure is common in childhood, while treatment of the same cancer type is much more challenging in adults. Here, we develop a stochastic model of stem cell proliferation that considers both tissue development and homeostasis and discuss the disturbance of such a system by mutations. Due to changes in population size, mutant fitness becomes context dependent and consequently the effects of mutations on the stem cell population can vary with age. We discuss different mutant phenotypes and show the age dependency of their expected abundances. Most importantly, fitness of particular mutations can change with age and advantageous mutations can become deleterious or vice versa. This perspective can explain unique properties of childhood disorders, for example, the frequently observed phenomenon of a self-limiting leukemia in newborns with trisomy 21, but also explains other puzzling observations such as the increased risk of leukemia in patients with bone marrow failure or chemotherapy induced myelodysplasia.
AB - Cancer, the unregulated proliferation of cells, can occur at any age and may arise from almost all cell types. However, the incidence and types of cancer differ with age. Some cancers are predominantly observed in children, others are mostly restricted to older ages. Treatment strategies of some cancers are very successful and cure is common in childhood, while treatment of the same cancer type is much more challenging in adults. Here, we develop a stochastic model of stem cell proliferation that considers both tissue development and homeostasis and discuss the disturbance of such a system by mutations. Due to changes in population size, mutant fitness becomes context dependent and consequently the effects of mutations on the stem cell population can vary with age. We discuss different mutant phenotypes and show the age dependency of their expected abundances. Most importantly, fitness of particular mutations can change with age and advantageous mutations can become deleterious or vice versa. This perspective can explain unique properties of childhood disorders, for example, the frequently observed phenomenon of a self-limiting leukemia in newborns with trisomy 21, but also explains other puzzling observations such as the increased risk of leukemia in patients with bone marrow failure or chemotherapy induced myelodysplasia.
KW - Acute lymphocytic leukemia
KW - Acute myelogenous leukemia
KW - Adult haematopoietic stem cells
KW - Cancer stem cells
KW - Hemopoietic stem cells
KW - Self-renewal
UR - http://www.scopus.com/inward/record.url?scp=84952683484&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84952683484&partnerID=8YFLogxK
U2 - 10.1002/stem.2251
DO - 10.1002/stem.2251
M3 - Article
C2 - 26689724
AN - SCOPUS:84952683484
VL - 34
SP - 543
EP - 550
JO - Stem Cells
JF - Stem Cells
SN - 1066-5099
IS - 3
ER -