Fig. 1. The aggressiveness potential of hypoxic tumors and the cancer stem cells (CSCs) postulate. The tumour growth generates poorly vascularized areas resulting in the induction of an hypoxic stress. If untreated (middle panel), the hypoxic tumor cells (grey) will develop an adaptive response in three points to overcome this stress: (a) metabolic changes (yellow), (b) phenotypic changes resulting in an increase of the metastatic potential of the tumour (the epithelial mesenchymal transition, EMT, resulting in the migration of the mesenchymal cells, blue) and (c) improvement of cell dedifferentiation and promotion of cancer stem cells (CSCs, red). If treated by conventional anti-cancer agents (bottom panel), hypoxic tumour will always relapse within few months, due to the persistence of the untreated CSCs. In this two cases, the relapsed tumours are heterogeneous cells composed by a mixture of mutated cells; this lead to a poor clinical prognosis. By a marked contrast, the combination of a specific anti-CSCs therapy with conventional anti-cancer drugs or surgery, generally leads to a better outcome (top panel).