Ricerc@Sapienza

The hierarchical organization and heterogeneity that are present within malignancies have been recently attributed to stem cell-like subset of tumor cells. Cancer Stem Cells (CSCs) have gained an exclusive interest as they are identified to push tumor growth and seed metastasis and are responsible for therapy failure and tumor resistance [1]. The molecular mechanism that drives the CSC population
has started to emerge, and the identification and origin of factors that maintain or even induce a CSC phenotype remain an intense area of research. This special issue contains seven articles, four reviews, and three original studies, highlighting the recent advances in CSC-activated pathways, with particular emphasis on the cross-talk between the CSC and the tumor microenvironment (TME). The studies presented here also highlighted compounds (e.g., epi-drugs) that are described to modulate CSCs and TME-activated pathways and thus can be subsequently exploited for therapeutic use. P. Gener et al., in a review article, discussed the overlapping phenotype between CSC and mesenchymal cancer cells, in terms of origin, activated pathways, and the implication for cancer treatment. Indeed, similarly to CSC, a link between epithelial to mesenchymal transition of cancer cells and metastasis as well as resistance to anticancer agents has been proposed [2]. Although other reports suggested that EMT is not necessary for metastasis, but rather it is the tumor microenvironment that regulate epithelial or mesenchymal state, still agent able to target common pathways regulating both CSC and EMT (e.g., TGF-β and NF-κβ signaling) showed antimetastatic potential and improved anticancer treatments. However, the authors also suggested that the strategies to prevent tumor remission by targeting the highlighted pathways should include integrated combining approach that take in account the intrinsic dynamism characterizing, within the tumor, the interconversion capacity of non-CSCs to new CSCs and mesenchymal cells, via EMT activation. As suggested above, several evidences demonstrated a critical role of the microenvironment in regulating CSC and their involvement in tumor progression. In this regard C. Ciardiello et al. reviewed the bidirectional communication mechanisms between the CSC and the microenvironment,
mediated by extracellular vesicles (EVs). EVs are considered as one of the most effective vehicles of information among cells, and recent findings demonstrated that they play an important role in cancer development and progression, by transferring information between cancer cells as well as between cancer cells and tumor microenvironment, at both paracrine and systemic level [3]. EVs are highly heterogeneous;however, they can be classified in two major classes: the shed microvesicles, formed through the direct budding of the plasma membrane, and the exosomes, small size vesicles (30-150 nm) generated through the classical endosome-multivesicular body pathway [3]. The specific role of this latter class of vesicles was reviewed by J. Xu et al. They speculate that exosomes play a role in maintaining homeostasis between non-CSCs and CSCs within the tumor. The authors described how exosomes can regulate both EMT and CSC phenotype activating Hindawi Stem Cells International Volume 2019, Article ID 8549020, 2 pages https://doi.org/10.1155/2019/8549020
stem-related signaling pathways (e.g., Wnt, Notch, or Hedgehog pathways) by docking on cancer cell receptors and/or transferring their cargo inside the cells. Epigenetic alterations play an important role in the initiation
and progression of several cancers. Moreover, since epigenetic alterations are dynamic and generally reversible, epigenetic manipulation has emerged as an attractive novel anticancer treatment. Increasing evidences support the significance of epigenetic regulation in CSC features [4]. DNA methylation and histone acetylation are two epigen