ABSTRACT
The heterogenic nature of tumors has been noted since the earliest pathological examinations. This heterogeneity is traditionally explained by coexisting distinct tumorigenic and mutant clones arising from random genetic and epigenetic events. According to this belief, cells undergoing these changes gain a survival advantage over other inhabitants of the tumor and a greater plasticity in enduring and adapting to environmental perturbations (stochastic or clonal evolution model).1 Accumulating evidence suggests that tumorigenic ability is not a trait that all cancer cells share, but it is confined to an uncommon and phenotypically distinct population possessing two peculiar properties: capacity for self-renewal and ability to differentiate into multiple lineages.2-6 Such properties are characteristics of adult stem cells that enable them to fulfill physiological needs and to thwart conditions requiring an accelerated cellular turnover. Through self-renewal, stem cells divide without depleting the undifferentiated pool, while providing a progeny that lost “stemness” properties to undertake a stepwise differentiation. The existence of a subset of cancer cells resembling normal stem cells, referred to as cancer stem cells (CSCs), allowed to predict a “stem-cell-centric” model of cancer. This model of the origin of cancer helped to envision an adult stem cell as the target of oncogenic hits and to postulate the existence of a stringent cellular hierarchy also in tumors. According to this “hierarchical model,” a tumor possesses a pyramidal organization where the entire tumor population descends from a common ancestor
Introduction ............................................................................................................ 217 Development of CSC-Focused Anticancer Agents ................................................ 218 Alternative Strategies for CSC Targeting ...............................................................225 CSC-Based Animal Models ................................................................................... 227 CSC Concept Applied to Translational Oncology .................................................228 Conclusions and Future Directions ........................................................................ 229 Acknowledgments .................................................................................................. 231 References .............................................................................................................. 231
represented by a CSC residing at the apex of the pyramid.7 In this scenario, the intrinsic plasticity of the founder, which retains the functional properties of its normal counterpart, explains tumor heterogeneity. Although the two models of the origin of cancer are seemingly contradictory, both theories have evolved partially losing their exclusive nature. The convergence of the clonal evolution and hierarchical models derived from a more profound characterization of the actual tumorpropagating population and a better definition of the role of microenvironmental stimuli on tumor cells. While the CSC model originally stated that only stem-like cells can propagate the tumor, recent evidence shows that multiple tumor-initiating clones, represented by both CSCs and their proximal offspring, can coexist and account for the different temporal patterns of tumor formation upon serial transplantation into the murine background.8 Therefore, this type of biological behavior is probably due to the clonal evolution of distinct CSC clones. Secondly, the possibility of reprogramming differentiated cells into pluripotent cells through the forced expression of four embryonic stem cell-specific transcription factors indicated that the “stemness” state is not a static condition and that the differentiation program is not unidirectional.9 Although this groundbreaking evidence was perceived as a major advancement for regenerative medicine, it also triggered the same effect in experimental oncology. For instance, investigations revealed that both paracrine-acting pathways and some adverse conditions existing within the tumor microenvironment, such as hypoxia and low pH, instruct cancer cells to gain stem-like traits.10,11 Even though it is unlikely that exogenous influences generate the whole CSC pool, these stimuli are involved in the process of maintaining and enriching CSCs, highlighting the fact that the retention/acquisition of stem-like features is a dynamic process. The CSC theory has therefore been refined by introducing microenvironmental variables, adding a further feature of the Darwinian evolutionary principles on which the clonal evolution model was shaped (Figure 10.1). The mechanisms driving the CSC-microenvironment interactions also assumed a bidirectional nature with the ability of CSCs to participate in generating blood vessels, a property interpreted as an attempt to render the microenvironment a tumor-promoting site.12,13 In this chapter, we discuss recent advances in CSC biology that translate into innovative therapeutic opportunities, spanning from the development of anti-CSC compounds to generating innovative animal models for optimal preclinical testing of established and investigational anticancer agents. Finally, we discuss the exploitation of CSC-related parameters in the clinical setting.
