´╗┐Notably, whereas adult SCs self-renew in a highly regulated manner, CSCs do so in a poorly controlled way, and while SCs generate functional mature cells, CSCs often differentiate abnormally

´╗┐Notably, whereas adult SCs self-renew in a highly regulated manner, CSCs do so in a poorly controlled way, and while SCs generate functional mature cells, CSCs often differentiate abnormally. and tumor maintenance. Finally, we provide an update of the main strategies that could be applied to target CSCs and cancer cell plasticity. 1. Introduction Malignancy is usually a heterogeneous group of diseases caused by genetic and epigenetic changes conferring key properties to cancer cells, including chronic proliferation, resistance to cell death, replicative immortality, invasiveness, and metastatic potential. In addition, interactions between tumor cells and the microenvironment are a crucial determinant of malignant growth [1]. Almost all human tumors are characterized by a considerable intratumor heterogeneity, with cancer cells showing different phenotypes, gene expression patterns, and proliferation potentials. Moreover, different patients affected by the same cancer type show a significant intertumor heterogeneity. Intra- and intertumor heterogeneity mostly account for troubles in the development of effective therapies and new targeted brokers [2]. Among the factors that have been proposed to explain intra- and intertumor heterogeneity and therapy resistance, a critical aspect is usually represented by the different potential shown by cancer cells in driving tumorigenesis and cancer progression. Specifically, the uncontrolled growth of many tumors is usually DL-threo-2-methylisocitrate driven by a populace of cancer cells, known as cancer stem cells (CSCs), endowed with self-renewing and differentiation DL-threo-2-methylisocitrate capacity. Unlike bulk malignancy cells, CSCs are able to generate an overt cancer and propagate malignant clones indefinitely [3]. It follows that, at least in the early stages of tumor development, most cancers are characterized by a hierarchical business, similar to that of healthy tissues, in which CSCs stand at the top of the hierarchy and give rise to more differentiated cancer cells. Intratumor heterogeneity can be mainly explained by different grades of differentiation between CSCs and their progeny. It is important to note that this CSC does not necessarily coincide with the cell of origin (CO), namely, the nonneoplastic cell which acquires the first oncogenic hit [4]. Notably, intertumor heterogeneity can be the consequence of two main mechanisms: in one case, a certain CO can be affected by different combinations of genetic and epigenetic aberrations; alternatively, different cell types within the same tissue can serve as CO [4]. In both situations, cell transformation will generate CSCs with different phenotypes, which Rabbit polyclonal to Myocardin will give rise to different tumor subtypes. Increasing evidences indicate that CSCs may originate from transformation of adult stem cells (SCs) as well as from committed progenitor cells. In the case in which cell transformation affects a committed progenitor, such CO has to undergo a dedifferentiation process in which it will lose its identity and will reacquire SC features, in order to evolve in a CSC. As a consequence, the phenotype of the CO will consistently differ from that of the corresponding CSC. It is important to note that these mechanisms not only are unique of the tumor initiation phase but can also take place in differentiated cancer cells in the overt tumor. Specifically, it has been shown that, during tumor progression, nonstem cancer cells undergo cell reprogramming processes and reenter the CSC state [5]. In this regard, it is becoming increasingly evident that not all cancers show a fixed hierarchical business but can be characterized by cell plasticity, a condition in which the pool of CSCs is usually constantly regenerated and changes its features during tumor progression. The aim of this review is at discussing the recent findings around the concepts of CSC and CO and describing how cell DL-threo-2-methylisocitrate reprogramming processes play a critical role both at a pretumoral state and in tumor homeostasis and progression. We will focus on the molecular pathways and epigenetic mechanisms regulating CSC function and self-renewing, whose deregulation in a normal cell, or in a nonstem cancer cell, can drive CSC formation. In this regard, we will provide new insights in the concept of malignancy cell plasticity, describing the reversible epigenetic says which control cell identity and differentiation state. Thereafter, we will elucidate how.

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