Cancer stemness and metastasis: therapeutic consequences and perspectives

The transient and dynamic nature of cancer cells that underlie metastasis cannot only be explained by the progressive accumulation of irreversible genetic changes occurring in the primary tumour. The capacity of cells to switch between different cellular identities, as in epithelial to mesenchymal (EMT) and mesenchymal to epithelial transitions (MET), allows them to respond to different cellular environments, thus efficiently disseminating from the primary mass to eventually colonise distant organs. These more dynamic stem-like cancer cells are earmarked by the ability to self-renew and de-/re-differentiate, and eventually recapitulate the heterogeneous composition of the primary tumour in a distant organ site. This dynamic concept of metastasis has profound consequences and implications for cancer diagnostics, prognostics and therapy. Many of the characteristics that define stem cells, like dormancy, active DNA repair, the expression of several drug transporters, and resistance to apoptosis may underlie the capacity of migrating cancer cells to survive conventional therapeutic protocols based on genotoxic agents targeting active proliferating cells. Accordingly, signal transduction pathways that regulate the balance between self-renewal and differentiation are likely to represent future targets in the development of tailor-made intervention strategies. Also, specific stem cell features, such as the capacity to migrate to diseased areas (pathotropism), open novel avenues towards the development of cell vehicles capable of tracking and delivering anti-cancer compounds to disseminated metastatic lesions.