The cancer stem cell hypothesis: in search of definitions, markers, and relevance

Abstract

Cancer is a disease of genes. Inherited or somatic alterations in genes are what make a normal cell ignore growth-controlling signals and form a tumor that eventually leads to the destruction of the organism. Based on accumulated knowledge on the genetic composition of cancer cells, the clonal evolution model of tumorigenesis was established, which explains multiple aspects of human disease and clinical observations. However, the recently popularized cancer stem cell hypothesis questions that all or most tumor cells can participate in tumor evolution and restricts this property to a subset of them defined as 'cancer stem cells' due to their stem cell-like characteristics. Enthusiasm surrounding this area of investigation and its presumed clinical implications led to a spurt of studies in various cancer types and model systems. Rigorous study design and critical data interpretation have to be employed to test the scientific and clinical relevance of the cancer stem cell hypothesis and its relationship to the clonal evolution model.

Figure 1

Hypothetical model of solid tumors cancer stem cells using breast cancer as an example. In the middle is a hypothetical differentiation pathway for normal mammary epithelial cells. Bipotential stem cells give rise to bipotential progenitors that can become committed myoepithelial or luminal progenitors differentiating into mature myoepithelial and luminal epithelial cells, respectively. During the differentiation process the self-renewal capacity of the cells gradually decreases. Cancer stem cells could potentially be derived from bipotential stem cells or from more differentiated cells that acquired self-renewal capabilities. Cancer stem cells, however, have restricted differentiation potential and only produce tumors with features of a particular lineage (eg, luminal or basal like).

Figure 2

Hypothetical model of tumor progression to metastatic disease in breast cancer. Primary luminal breast tumors consist of CD44⁺ stem-like breast cancer cells with high invasive and angiogenic capacity, and more differentiated CD24⁺ breast cancer cells. Distant metastases can be initiated by invasive CD44⁺ breast cancer cells that later can switch to a more differentiated CD24⁺ cell phenotype due to microenvironmental conditions or selection due to therapeutic interventions (left). Alternatively, during tumor progression CD24⁺ can become more invasive and initiate metastases themselves (right), or the two cell types (CD24⁺ and CD44⁺ breast cancer cells) may initiate metastases together (middle). Furthermore, CD24⁺ cells can change to CD44⁺ stem cell-like cells due to acquisition of genetic, epigenetic changes, or environmental factors such as hypoxia.