Ontogenic growth as the root of fundamental differences between childhood and adult cancer

Abstract

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. STEM CELLS 2016;34:543-550 SIGNIFICANCE STATEMENTWe use a mathematical model to show that the stage of development of a person from a newborn until they reach adult life has a major impact on the behavior of mutations within stem cells that can lead to cancer. We show how at different stages, various mutational patterns can provide a fitness advantage or even disadvantage depending on their context. We illustrate this with specific examples from acute leukemia in children and adults.

Should tissue structure suppress or amplify selection to minimize cancer risk?

“…For example, during development (growth) cell populations typically expand and favor mutant clones that grow faster, whereas in stationary conditions other phenotypes are selected for [34, 52, 53]. Thus, mutations that are neutral or disadvantageous at first, may become advantageous in later stages of development.…”

“…In isolation, these mutations seem to be harmless because they are less fit than the wild-type cells. But they could interact with other subsequent mutations, leading to altered cell division properties via epistatic effects or environmental changes [28, 33, 34]. Such interactions between mutations have been investigated in experimental evolution in great detail [35–38], but they are usually neglected in the cancer community, partially because they are very difficult to measure.…”

Should tissue structure suppress or amplify selection to minimize cancer risk?

“…In isolation, these mutations seem to be harmless because they are less fit than the wild-type cells. But they could interact with other subsequent mutations, leading to altered cell division properties via epistatic effects or environmental changes [27,32,33]. Such interactions between mutations have been investigated in experimental evolution in great detail [34][35][36][37], but they are usually neglected in the cancer community, partially because they are very difficult to measure.…”

Hierarchical Tissue Organization as a General Mechanism to Limit Somatic Evolution

“…In multicellular organisms such differentiation typically takes place early in development. It is responsible for producing the cells of non-renewing tissues (e.g., primary oocytes in the female germ line [1,5]) and the initial population of stem cells in self-renewing tissues (e.g., hematopoietic stem cells [6][7][8] or the spermatogonia of the male germ line [1,5]). …”