Figure 1.

The origins of intra-tumor heterogeneity. Both cell-intrinsic and cell-extrinsic factors generate intra-tumor heterogeneity. The intrinsic mechanisms include cell-to-cell variability in genotypic alterations (as shown by different colors of cell nucleus), and non-genetic or phenotypic variations (as shown by different colors of cytoplasm), which are due to epigenetic modification, plastic gene expression, and signal transduction. The extrinsic mechanisms originate from unequal microenvironments. Multiple sources of heterogeneity within a tumor may co-exist and interact with each other over time to shape up the heterogeneous cancer.