Niches are complex structures integrating interactions between stem cells and the neighbouring cells (such as stromal, mesenchymal and immune cells) either by direct interactions or by secretion of signalling factors [35, 36]. Both stromal and stem cells also interact with the extracellular matrix, a complex network of macromolecules. The disorganization of the interactions existing within the niche might provide strong signals for normal stem cells to proliferate and/or differentiate, and may favour tumour initiation and progression, in combination with other stimulations such as inflammation and angiogenesis [37]. Like normal stem cells, CSC depend on the microenvironment cues to retain their ability to self-renew or differentiate [36], and the niche contributes to their resistance to therapy by sheltering them from the genotoxic treatments [38, 39]. Aberrant activation of key signalling pathways and/or their mediators (such as Hedgehog, Notch, Wnt/β-catenin, HMGA2, Bcl2, Bmi-1) involved in the control of self-renewal, proliferation and differentiation of normal stem cells may also contribute in the acquisition of new stemness properties by CSC [40]. Moreover, the microenvironment of many ASC is hypoxic (low oxygen tension) and modulates their self-renewal, proliferation and cell-lineage commitment [34, 41]. A synergistic effect of Notch and hypoxia-induced pathways is correlated with increased metastasic tumour potential and poor survival of patients, suggesting that a crosstalk between these pathways is essential to cancer initiation and progression [41].

Standard cancer treatment s by chemotherapy, radiotherapy and surgical ablation have mostly focused on shrinking the tumour size, but CSC might persist after therapy and cause the tumour to relapse. Indeed, CSC may escape treatment due to different sensitivities and specificities to the radiation or chemotherapy used, but also because they have already metastasized in patients newly diagnosed with cancer [42]. In some patients, CSC are in a dormant state, and stress or inflammation reactivate their proliferation and differentiation by release of pro-inflammatory cytokines and chemokines, such IL-6, IL-8, MCP1, CCL5 [43, 44]. Even more worrying, the conventional radiation and chemotherapy may increase CSC numbers in a process analogous to the normal repair-process during tissue damage, by which dying cancer cells might release cytokines that stimulate CSC proliferation and/or differentiation [45, 46]. Thus, to implement efficient treatments targeting specifically CSC and preventing tumour recurrence, new approaches are being developed to destabilize CSC stemness [46]. One strategy is to inhibit the signalling pathways promoting self-renewal and survival of CSC, such as Hedgehog, Notch, Wnt/β-catenin using combinations of specific inhibitors affecting these pathways. A limitation to this approach is the necessity of these pathways for normal stem cells function in patients. Nevertheless, preclinical and clinical studies with Notch signalling inhibitors showed the decrease in the number of breast CSC in animal models, and a promising decline of the disease progression when used in combination with the anti-mitotic compound docetaxel [47]. Moreover, it was recently reported that down-regulation or inhibition by small molecule compounds of BMI-1, a polycomb repressor involved in the maintenance of normal several tissues stem cells or CSC [48–52], diminished CSC proliferation, tumour growth, tumorigenic potential and limited metastasis [53, 54]. CSC may also be resistant to conventional chemotherapy due to overexpression of detoxifying enzymes, membrane transporters or pumps enhancing the elimination of pharmacological agents [55]. Several groups have reported an increase of sensitivity to chemotherapy and radiation by treatment with drugs targeting these transporters in vitro and in vivo in lung cancer cells [56]. The inhibition of aldehyde dehydrogenase activity, a hallmark of human breast carcinoma CSC [57], by inhibitors such as diethylamino-benzaldehyde or all-trans retinoic acid led to a decrease of tumour aggressiveness and increased sensitivity to chemotherapy [58].

Targeting CSC specific surface markers or using these markers to enhance CSC death is also a promising strategy. The blockade of overexpressed CXCR1, a IL-8 receptor, in human breast CSC by specific antibodies or by repertaxin, a small inhibitor of CXCR1, reduced tumour growth, CSC numbers and their metastatic potential in animal models [46]. In human melanoma CSC, down-regulation of the CD133 surface marker by RNA interference reduced their metastatic potential in animal models [59]. The recognition of CD133 by specific monoclonal antibodies also led to a specific cytotoxic effect on melanoma CSC and hepatoma cells [59, 60]. The modulation of miRNA expression in CSC might also provide new means to control CSC fate [61]. Indeed, overexpression of miR-34a in prostate CD44-positive CSC, where it is normally down-regulated, inhibited self-renewal of CSC as well as tumour development [62].

Alternative therapeutic strategies aiming to destabilize the interactions between CSC and their niche, and promoting cell cycle entry of quiescent CSC to enhance their sensitivity to chemotherapy/radiotherapy present a great potential. Hypoxia inducible factors (such as HIF-1 and HIF-2) have often been targeted in cancer therapies because they regulate genes critical for tumour cells survival, metabolic adaptation, angiogenesis and metastasis [63