The CSCs niche

Cancer immunology. Bench to bedside immunotherapy of cancersNima Rezaei (Ed.). Springer-Verlag (2015)

Normal stem cells (SCs) are located in a specialized microenvironment called “stem cell niche” that provides SCs with molecular signals necessary to maintain them in a stem-like state and to reach the right balance between self-renewal, activation, and differentiation [154–156].

Emerging evidences suggest that CSCs are also regulated by a similar microenvironment [145]; therefore, tumorigenicity likely depends not only on the biology of tumor cells but also on the cross talk between tumor cells and the neighboring nonmalignant cells [157]. Such an intimate connection between CSCs and the surrounding microenvironment is supported by the observation that CSCs localize to the tumor– stroma interface in different cancers [158, 159].

The CSC niche is composed of several stromal cell populations including mesenchymal, vascular, and immune cells and myofibroblasts, as well as extracellular components [160–162].

Actually, the presence of three different niches in tumor tissue has been hypothesized: a perivascular niche, a hypoxic niche, and a niche at the invasion front.

The perivascular niche has been described as a microanatomical unit composed of proliferating endothelium and other stromal cells (i.e., pericytes and macrophages) and of extracellular components [163–166], closely interacting with cancer cells.

The existence of a hypoxic niche has been suggested since recent studies showed that stem cells are also located in the necrotic areas of the tumor [167] and that they are regulated by local oxygen concentrations [168]. Lastly, the observation that cancer cells undergoing EMT at the invasion front exhibit some of the phenotypic characteristics typical of CSCs (i.e., marker expression or microRNA) [169, 170] has raised the possibility of an invasive niche.


It is now well accepted that niche cells are not malignant per se but that the CSC niche supports cancer growth and has an essential role for tumor survival [171].

As already mentioned, the microenvironment is a crucial component that controls CSC functional features, such as stemness, proliferation, and apoptosis resistance [156, 172, 173]. In fact, it has been observed in several tumors that CSCs rely on niche signals to remain in their stem-like state, while maintaining their self-renewal properties and their capacity to originate differentiated cells [165, 172].

The importance of the interaction between CSCs and their microenvironment is confirmed by the observation that the loss of a niche usually leads to the loss of the CSC pool [156].

Several factors are involved in the cross talk between CSCs and niche microenvironment. For instance, the key role of CD44 [174, 175], CXCR4 (expressed by tumor cells), and CXCL12 (SDF-1, expressed by niche stromal cells) [76, 145] for the homing and engraftment of CSCs to the niche and the importance of CD133 for the CSC selective adhesion to the endothelial cells of perivascular niche [165] have been demonstrated. Moreover, endothelial cells of the vascular niche have been shown to stimulate CSC stemness in part through Notch signaling [109, 165, 176].

However, the observation that CSCs promote blood vessel formation by secreting VEGF has raised the hypothesis that the cross talk between CSCs and tumor vasculature could probably be a bidirectional process [177].

It has also been observed that in colon CSCs, Wnt signaling activity is increased by stromal fibroblasts, through secretion of hepatocyte growth factor (HGF) [89]. Furthermore, the niche microenvironment has been reported to support CSCs in different tumors through the release of Inflammatory molecules, such as interleukin (IL)-6 [178, 179]. Also physiologic conditions existing within niches, such as hypoxia and low pH, are critical determinants in the maintenance of the CSC pool [180, 181]. Indeed, the hypoxiainducible factor 2-a (HIF2a), the main mediator of hypoxia effects, promotes self-renewal and tumorigenicity of glioma CSCs [180]. It has yet to be fully elucidated whether these factors are really essential for the maintenance of CSC homeostasis; however, recent data seem to demonstrate that their loss reduces the clonogenicity of CSCs in vivo [165, 182]. Although a major role of the niche in CSC self-renewal has been suggested, clues from microenvironment may be sometimes negative for CSCs. Indeed, tumor growth can be inhibited by immune-mediated signals [50] or by differentiated tumor cells after xenotransplantation [10]; the latter observation leads to the interesting hypothesis that differentiated tumor cells control CSC spread.

Despite the similarities between normal SC and CSC niche, the microenvironment seems to regulate CSC behavior in a way more favorable to cell proliferation and growth as compared to normal SCs. In fact, while normal SC proliferation and differentiation are usually inhibited by the niche and tissue regeneration can be activated only after a transient proliferating signal, it is believed that internal mutations and niche signals can lead CSCs to proliferate without control [183].

Interestingly, the niche not only plays a pivotal role in the preservation of the CSC population and tumor growth enhancement but also has the ability to induce a CSC phenotype in more differentiated tumor cells [89, 156].

Moreover, the CSC niche is also able to protect CSCs from genotoxic injuries, increasing their resistance to therapeutic treatments [109, 184].

CSC niche as therapeutic target

Given the fundamental role of microenvironment in supporting tumor growth and in affecting CSC response to therapy, the CSC niche, together with the factors involved in niche–CSC interaction, has become an attractive therapeutic target [185]. This proposition is encouraged by the observation that microenvironment deletion leads to tumor’s drug sensitivity restoration [186, 187]. However, even if physiological stem cell niches are known to play important roles in the maintenance of CSC quiescence and resistance to stressinducing treatments [188], the mechanisms by which modulations in the local milieu regulate CSC behavior have yet to be fully clarified [189].