Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)
Part I. Stem Cells
NSCs must possess two qualities to perform their natural function: self-renewal and differentiation. According to the cancer stem cell (CSC) theory, a defined subset of cancer cells has the exclusive properties of stem cells, driving the growth and spread of the tumour. These CSCs can give rise to cancer cell progeny that are more differentiated and are destined to stop proliferating or die, because they have limited or no ability to undergo further mitotic divisions (Lobo et al., 2007). Thus, the CSC theory considers some elements of the cellular hierarchy seen in normal tissues to be retained in many tumours. The concept of CSCs has been demonstrated in several human cancers, including leukaemia, brain and thyroid tumours, breast cancer, prostate cancer, lung cancer, pancreatic cancer and colon cancer (Lin, 2011; Fazilaty et al., 2013; Yi et al., 2013). Although CSCs represent a minority of tumour masses that retain self-renewal capacity, they possess the aggressive characteristics needed for metastatic development, including motility, invasiveness and apoptotic resistance (Pang et al., 2010).
Three key observations classically define the existence of a CSC population. First, only a few cancer cells within each tumour have tumourigenic potential when transplanted into nonobese diabetic severe combined-immunodeficient (NOD/SCID) mice. Second, tumourigenic cancer cells are characterized by a distinctive profile of surface markers and can be differentially and reproducibly isolated from nontumourigenic surface markers by means of flow cytometry or other immunoselection procedures. Third, tumours grown from tumourigenic cells contain mixed populations of tumourigenic and nontumourigenic cancer cells, thus recreating the full phenotypic heterogeneity of the parent tumour (Dalerba et al., 2007).
As discussed in Section 3.2, the fate of stem cells is controlled by a particular microenvironment known as the stem cell niche. It has been reported that CSCs also depend on a similar niche, called the ‘CSC niche’, which controls their differentiation and proliferation (Li and Neaves, 2006; Visvader and Lindeman, 2008). At least two possibilities for generating CSC niches exist: either they are created as nascent domains by tumour cells or they adopt existing tissue-specific stem cell niches (LaBarge, 2010).
The evidence that CSCs are effectively located in a well-defined niche within tumours, close to NSCs, was observed in some brain tumours (Calabrese et al., 2007). NSCs usually reside in perivascular niches located mainly in the hippocampus and SVZ, where rates of cell proliferation are quite low. Starting from these observations on NSCs, several studies have analysed whether the same situation is found in diverse brain tumours. The brain CSCs (Nestin+ /CD133+ ) were found to be strictly associated with perivascular endothelial cells in the tumours, enabling the maintenance of self-renewal and thus affording protection from radiation damage. It was demonstrated that glioblastoma CSCs (CD133+ /CD144) could differentiate into endothelial cells and participate in blood vessel formation. Glioblastoma CSCs differentiated into endothelial progenitors that gave rise to tumour and endothelial cells in vivo (Ricci-Vitiani et al., 2010; Wang et al., 2010). When CD133+ /CD144cells were killed, tumour growth was greatly suppressed, indicating that such CSCs directly contribute to tumour neoangiogenesis, at least in glioblastoma, regulating the generation of cellular elements of the niche.
It must be considered that regulatory factors produced by endothelial cells can control glioma CSC biology. Molecular interaction with the perivascular niche can control glioma CSC maintenance. Notch signalling appears to play a critical role in this process. Glioma CSCs (Nestin+ /CD133+ ) express Notch1 and Notch2 receptors and show elevated levels of activity, as evidenced by upregulated expression of the Notch target gene Hes5. Endothelial cells, on the other hand, express the membrane-bound Notch ligands Delta-like 4 (Dll4) and Jagged-1, and knockdown of these ligands in brain microvascular endothelial cells reduces tumour growth (Zhu et al., 2011). Glioma CSC can stimulate endothelial cells through the production of VEGF (Bao et al., 2006), and the VEGF signalling on endothelial cells can increase Notch and Dll4 gene expression (Bao et al., 2006). Extracellular signals from the niche are crucial for the maintenance of tumour bulk, since the differentiation of CSCs into cancer stromal elements seems to be dependent on niche – CSC interaction.
The interaction of leukaemia stem cells (LSCs) with the marrow niche for their malignant self-renewal and quiescence has been described. Like normal HSCs, LSCs are enriched in CD34+ /CD38 cells (Bonnet and Dick, 1997; Hope et al., 2004). Perturbing the adhesion between LSCs and the marrow niche might therefore ‘mobilize’ LSCs from their protective environment (Lutz et al., 2013). Since LSCs possess prerequisites for interaction with the bone marrow niche, targeting this association might be an effective therapeutic approach to potentially inhibiting their proliferation or stimulating their apoptosis. In vivo blocking of the binding of CD44 to the niche alters LSC fate by transplanting human acute myeloid leukaemia (AML) LSCs into NOD-SCID mice and thus selectively eradicating AML, indicating that LSCs are niche-dependent (Jin et al., 2006). The chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptor, CXCR4, are involved in the interaction of HSCs with the bone marrow niche. Higher expression of CXCR4 in AML LSCs increases the homing of neoplastic cells, defining, in turn, an unfavourable prognosis of AML (Rombouts et al., 2004). The expression of CXCR4 on LSCs, as well as in many CSCs, implies that the CXCL12/CXCR4 axis may play a critical role in directing the migration/metastasis of CXCR4+ tumour cells to organs that express CXCL12, such as lymph nodes, lungs, liver and bones (Teicher and Fricker, 2010). Several CXCR4+ cancer cells metastasize to the bones and lymph nodes in a CXCL12-dependent manner, and the bone marrow in particular can provide a protective environment for tumour cells (Meads et al., 2008). These data suggest that interventions targeting the CXCL12/CXCR4 axis might significantly perturb CSC trafficking, retention and survival, and could be important therapeutic tools in clinical trials.
The CSC hypothesis holds that the CSC niche in tumours is capable of unlimited self-renewal and that eradication of these cells will ultimately halt neoplastic expansion. Consequently, more differentiated cells have limited mitogenic capacity and will not contribute to long-term tumour growth. Niche elements, as discussed in this review, can represent central counterparts for tumour growth, since their interaction with CSCs seems to be essential for proper CSC self-renewal.