Tumour Cell Heterogeneity

Abstract

The population of cells that make up a cancer are manifestly heterogeneous at the genetic, epigenetic, and phenotypic levels. In this mini-review, we summarise the extent of intra-tumour heterogeneity (ITH) across human malignancies, review the mechanisms that are responsible for generating and maintaining ITH, and discuss the ramifications and opportunities that ITH presents for cancer prognostication and treatment.

Keywords: Cancer evolution; evolutionary biomarkers; intra-tumour heterogeneity; personalised medicine.

Figure 1.. Intra-tumour heterogeneity and prognostication.

( A) Intra-tumour heterogeneity means a targeted biopsy may miss a lesion with a poor prognostic signature (“red” phenotype) within the tumour (majority of tumour has a “blue” phenotype that is associated with a good prognosis). ( B) Differences between tumours (inter-tumour heterogeneity) mean that a single prognostic biomarker may be unsuitable for use in some tumours that have evolved along a different carcinogenic pathway; this yellow tumour does contain either the previously identified good (blue) or bad (red) phenotypes. ( C) Epistasis between genes (or other intra- or inter-cellular interactions) can alter the prognostic value of any individual feature; here, the presence of the “green” mutation may alter the bad prognosis of the “red” mutation assayed in ( A). ( D) Inter-cancer heterogeneity means that a feature-based prognostic marker developed for one cancer type is unlikely to work in another cancer type.

Figure 2.. Intra-tumour diversity as a universal prognostic marker.

A homogeneous tumour ( A) will be eradicated in response to a selective pressure such as chemotherapy, whereas a heterogeneous tumour ( B) is more likely to contain a pre-existing resistant clone that survives the selective pressure and seeds the repopulation of the tumour.