Preneoplastic lesion growth driven by the death of adjacent normal stem cells

Abstract

Clonal expansion of premalignant lesions is an important step in the progression to cancer. This process is commonly considered to be a consequence of sustaining a proliferative mutation. Here, we investigate whether the growth trajectory of clones can be better described by a model in which clone growth does not depend on a proliferative advantage. We developed a simple computer model of clonal expansion in an epithelium in which mutant clones can only colonize space left unoccupied by the death of adjacent normal stem cells. In this model, competition for space occurs along the frontier between mutant and normal territories, and both the shapes and the growth rates of lesions are governed by the differences between mutant and normal cells' replication or apoptosis rates. The behavior of this model of clonal expansion along a mutant clone's frontier, when apoptosis of both normal and mutant cells is included, matches the growth of UVB-induced p53-mutant clones in mouse dorsal epidermis better than a standard exponential growth model that does not include tissue architecture. The model predicts precancer cell mutation and death rates that agree with biological observations. These results support the hypothesis that clonal expansion of premalignant lesions can be driven by agents, such as ionizing or nonionizing radiation, that cause cell killing but do not directly stimulate cell replication.clonal expansion ͉ computer simulation ͉ skin cancer ͉ TP53 ͉ UVB

Migration rules: tumours are conglomerates of self-metastases

“…To accommodate the known limitation on cancer cell growth imposed by space constraints (Brú et al, 2003;Drasdo and Höhme, 2005;Galle et al, 2009), if all eight adjacent lattice points are occupied, a cell is considered inhibited and sent into quiescence until neighbouring space becomes available. Similar computational assumptions were made in a recent in silico model of opportunistic preneoplastic lesion growth driven by the death of adjacent normal stem cells (Chao et al, 2008). How these assumptions are consistent with a tumour expanding into normal tissue has been argued based on a principle of compactness (Norton, 2005).…”

“…One population-level factor limiting tumour progression is the space to grow (Brú et al, 2003;Pardal et al, 2003;Drasdo and Höhme, 2005;Chao et al, 2008). The nature of this limitation has been debated, given the observation that tumour cells can push their neighbours under certain circumstances.…”

Stochastic fate ofp53-mutant epidermal progenitor cells is tilted toward proliferation by UV B during preneoplasia

“…In interpreting the PMC size distribution following prolonged UVB exposure, a recent study has placed emphasis on the Frontier model, in which clones expand in response to the loss of adjacent normal cells (18). In this model, the restriction of growth to the boundary of the clone leads to an expansion in the average PMC size that is quadratic with time (i.e., α = 2), leading in turn to an inverse square root dependence of the probability distribution, P n (t), on the clone size, n, i.e., β = 1/2 in Eq.…”

“…If cells within a PMC acquire an increased rate of proliferation and/or a decreased rate of terminal differentiation or apoptosis, the clone will expand exponentially. However, a recent theoretical analysis of PMC growth in mice has proposed an alternative hypothesis (18). Normal cells are more sensitive than mutants to UVB-induced apoptosis because of their wild-type P53.…”

The mysterious steps in carcinogenesis

“…Interactions between cells can protect against their individual defects (Rubin, 2006) and, on a larger scale, the expansion of abnormal clones can be inhibited by their normal neighbours (Chao et al, 2008). Within each individual cell, there is a large set of 'heat-shock proteins' (HSPs) that manages the folding and operation of the products of gene expression, and one of the actions of these HSPs is to sequester or remove the abnormal proteins produced as the result of mutation or chance misfolding.…”