Mutation, clonal fitness and field change in epithelial carcinogenesis

Abstract

Developments in lineage tracing in mouse models have revealed how stem cells maintain normal squamous and glandular epithelia. Here we review recent quantitative studies tracing the fate of individual mutant stem cells which have uncovered how common oncogenic mutations alter cell behaviour, creating clones with a growth advantage that may persist long term. In the intestine this occurs by a mutant clone colonizing an entire crypt, whilst in the squamous oesophagus blocking differentiation creates clones that expand to colonize large areas of epithelium, a phenomenon known as field change. We consider the implications of these findings for early cancer evolution and the cancer stem cell hypothesis, and the prospects of targeted cancer prevention by purging mutant clones from normal-appearing epithelia.

Cell competition: Winning out by losing notch

“…18,19 These may expand to take over large areas from which multiple dysplastic lesions and squamous cell carcinomas arise as additional mutations occur. 20,21 The existence of super competitor mutants may offer an explanation for how such areas of 'field change' arise.…”

“…However, unless probability of cell loss by differentiation and shedding is significantly reduced, most of these clones will not persist for sufficient time to acquire additional mutations. 20,36 If a Notch inhibiting mutation occurs in a cell carrying a preexisting mutation, it might confer a super competitor phenotype, creating a field change within which carcinogenesis can progress (Fig. 4).…”

“…Areas of apparently normal epithelium have been shown to harbor clonal mutations and generate multiple dysplastic lesions and tumors over time. 20,21,71 In squamous epithelium there is no constraint to clone expansion, so a single mutant progenitor whose dynamics are altered in a similar fashion to that produced by DNMaml may colonize a large region. [23][24][25] Over a prolonged period of carcinogen exposure an epithelium may become a patchwork of clonal fields each carrying a super competitor mutation and any preceding oncogenic genomic alterations present in the founder cell.…”

“…However, such resilience results in carcinogen exposed epithelia becoming a patchwork of super-competitor mutations in which cancer evolution will continue unless mutagen exposure ceases. 20 …”

Oesophageal Stem Cells and Cancer

“…Under normal conditions, it is critical that upon division the same number of proliferating and differentiating cells are produced in order to maintain a balanced equilibrium. An imbalance will result in the loss of cell production, compromising tissue integrity, or in an excessive cell proliferation potentially leading to cancer (Doupe et al 2012; Frede et al 2014; Frede et al 2016; Alcolea et al 2014). …”