Theoretical and Experimental Foundations of the "Cancer Stem Cell" Model

Similar to normal tissues, tumor tissues are frequently composed of a heterogeneous population of cancer cells, containing multiple cellular subtypes. One explanation for the heterogeneity observed within tumors is provided by the "cancer stem cell" (CSC) model. According to this model, tumor tissues can be described as organized three-dimensional structures that mirror, though often aberrantly, the architecture, physiology, and cell composition of the healthy tissues from which they originate. As a result, the CSC model envisions the possibility that malignant tissues, like their normal counterparts, might be organized according to a hierarchical structure akin to a stem cell system, where: a) cancer cells retain the capacity to diversify according to a multi-lineage differentiation process, and b) long-term tissue growth is sustained by a mutated, pathological population of stem-like cells, the "cancer stem cells". The CSC model is supported both by theoretical considerations and by an increasing wealth of experimental evidence. Malignant cells with stem cell properties have now been prospectively identified across many tumor types, both in primary human cancers and in experimental mouse cancer models. Moreover, lineage-tracing experiments have provided formal demonstration of multi-lineage differentiation as a source of epigenetic diversity in cancer tissues. The CSC model has important implications for clinical oncology, as it provides a new conceptual framework for the discovery of prognostic biomarkers and the design of anti-tumor drugs.