Cancer heterogeneity--a multifaceted view

Abstract

Cancers of various organs have been categorized into distinct subtypes after increasingly sophisticated taxonomies. Additionally, within a seemingly homogeneous subclass, individual cancers contain diverse tumour cell populations that vary in important cancer-specific traits such as clonogenicity and invasive potential. Differences that exist between and within a given tumour type have hampered significantly both the proper selection of patients that might benefit from therapy, as well as the development of new targeted agents. In this review, we discuss the differences associated with organ-specific cancer subtypes and the factors that contribute to intra-tumour heterogeneity. It is of utmost importance to understand the biological causes that distinguish tumours as well as distinct tumour cell populations within malignancies, as these will ultimately point the way to more rational anti-cancer treatments.

Figure 1

Schematic representation of the various factors (diagonal, red boxes) that affect intra- (x-axis, light blue) and inter- (y-axis, light grey) tumour heterogeneity. Several examples are depicted for each factor and for both forms of tumour heterogeneity. CIN, chromosomal instability; CSC, cancer stem cell; MSI, microsatellite instability; SHH, sonic hedgehog signalling.

Figure 2

Cartoon representation of several factors affecting tumour heterogeneity. (A–C) Intra-tumour heterogeneity . (A) From a common ancestor (blue founder cell), different subclones (represented by different colours) emerge due to selection and distinct mutations. (B) In the CSC model, clonal evolution still takes place but only acts on the CSCs. These cells can self-renew and give rise to the various cell lineages present in a tumour (differentiated cells in respective colours). (C) The TME affects intra-tumour heterogeneity by its composition (myofibroblasts in pink and immune cells in grey) as well as their derived factors that can induce the reversion of differentiated cells to CSCs. (D–F) Inter-tumour heterogeneity. (D) The MSI or CIN colon cancer subtypes are distinct subtypes that associate with BRAF or APC and KRAS mutations, respectively. (E) TGF-β pathway activation results in an increase or decrease of CSC phenotype when triggered in the basal or luminal breast cancer subtype, respectively. (F) SDPPs can be used to identify breast cancer patients that differ in their survival probability. APC, Adenomatous polyposis coli; BRAF, v-raf murine sarcoma viral oncogene homologue B1; CIN, chromosomal instability; CSC, cancer stem cell; KRAS, kirsten rat sarcoma viral oncogene homologue; MSI, microsatellite instability; SDPP, stroma-derived prognostic profile; TGF-β, transforming growth factor beta; TME, tumour microenvironment.

Figure 3

Connecting intra- and inter-tumour heterogeneity. (Top) Multiple subclones exist in an individual lung tumour each being represented by a different subtype of lung cancer. (Bottom) Some subtypes of lung cancer are more sensitive to therapy than others. This is reflected in an individual tumour for which a therapy selects the most aggressive subclone, such as the subclone resembling the most aggressive cancer subtype.