Intra-tumor heterogeneity of cancer cells and its implications for cancer treatment

Abstract

Recent studies have revealed extensive genetic and non-genetic variation across different geographical regions of a tumor or throughout different stages of tumor progression, which is referred to as intra-tumor heterogeneity. Several causes contribute to this phenomenon, including genomic instability, epigenetic alteration, plastic gene expression, signal transduction, and microenvironmental differences. These variables may affect key signaling pathways that regulate cancer cell growth, drive phenotypic diversity, and pose challenges to cancer treatment. Understanding the mechanisms underlying this heterogeneity will support the development of effective therapeutic strategies.

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.