Therapy-induced enrichment of cancer stem-like cells in solid human tumors: Where do we stand?

The development of local recurrence and metastatic disease, most probably attributable to the intrinsic or acquired resistance of tumor cells to standard therapy, still constitute the major clinical problem preventing the cure of cancer patients. Despite progress in the research of new therapeutic targets and compounds, resistant cells displaying stem-like properties seem to play a leading role in therapeutic failures and to be the culprit cells responsible for associated tumor recurrence. A whole new plethora of research studies suggest that drug-tolerant cancer stem cells may be induced by conventional cancer chemotherapeutics such as doxorubicin, cisplatinum and ionizing radiation. This phenotypic plasticity and transition from a differentiated to stem-like cell state associates with the activation of diverse stem cell self-renewal (e.g. Notch, Hedgehog, Wnt), drug efflux (e.g. ABC transporters) and survival-related pathways (e.g. TGF-β, ERK, AKT), which may confer resistance and treatment failures in solid tumors. Therefore, combined therapeutic strategies aiming to simultaneously target drug-sensitive tumor cells and their capacity of phenotypic switching may lead to survival benefits and meaningful disease remissions. This knowledge can be applicable to the clinic and contribute to better therapeutic outcomes and prevent tumor recurrence.