Intratumoral heterogeneity is usually a major ongoing challenge in the effective therapeutic targeting of cancer. considerable metabolic plasticity. The molecular mechanisms underlying these Lysionotin different interconnected axes of plasticity has been under considerable investigation and the trans-differentiation process of Epithelial to Mesenchymal transition (EMT) has been identified as a major contributing factor. Besides genetic and epigenetic factors, CSC plasticity is also shaped by non-cell-autonomous effects such as the tumor microenvironment (TME). In this review, we discuss the latest developments in decoding mechanisms and implications of CSC plasticity in tumor progression at Lysionotin biochemical and biophysical levels, and the latest approaches being taken for characterizing malignancy cell plasticity. These efforts can help improve existing therapeutic approaches by taking into consideration the contribution of cellular plasticity/heterogeneity in enabling drug resistance. defined; rather stemness can be thought of as a cell state can that be reversibly gained or lost. In other words, cellular plasticity can allow CSCs and non-CSCs to switch among one another (Chaffer et al., 2011; Marjanovic et al., 2013; Gupta et al., 2019). Moreover, different subsets of CSCs can lie on various Lysionotin points around the epithelial-mesenchymal axis and can possibly interconvert (Liu et al., 2014; Bocci et al., 2018; Bocci et al., 2019). Therefore, clonal development and CSC models are not necessarily mutually exclusive and the plasticity model ushers in more complexity to the manner in which heterogeneous cell populations can possibly arise within a tumor (Cabrera et al., 2015; Physique 1). Open in a Rabbit Polyclonal to MMP-7 separate window Physique 1 Malignancy stem cells (CSCs) constitute a minor sub-population of tumor mass. Phenotypic plasticity can enable CSCs and non-CSCs to interconvert among one another, depending on cell-intrinsic (e.g., epigenetic) and cell-extrinsic (e.g., tumor microenvironment) features. A direct result of interconverting or plastic cellular populations in a tumor is the rise of drug resistant and/or metastatic cells which are ultimately responsible for the mortality associated with malignancy (Biddle et al., 2016; Doherty et al., 2016). The need of the hour is usually hence to understand the molecular underpinnings for CSC plasticity and to decode the impact of bidirectional nature of CSC plasticity around the clinical management of the disease. CSC Heterogeneity and Plasticity in Tumor Progression The concept that CSCs are dynamic populations and can undergo spontaneous state transitions has been strengthened by numerous studies (Chaffer et al., 2011, 2013; Gupta et al., 2011). In the study carried out by Chaffer et al. (2011), using basal-like breast malignancy cells, non-stem cells were shown to spontaneously switch to stem-like cells and and recapitulate the original tumor (Quintana et al., 2010). In breast malignancy, different subsets of CSCs were identified based on ALDH1, CD44, and CD24; and the two subpopulations (epithelial-like ALDH1+, mesenchymal like CD44+/CD24C) were shown to be capable of inter transforming among themselves as well as give rise to non-CSCs (Liu et al., 2014). Moreover, in breast malignancy, CSCs and non-CSCs were shown to exhibit dynamic equilibrium managed by cytokine-mediated crosstalk among Lysionotin these unique populations (Iliopoulos et al., 2011). These results suggest that at least in some cancers, phenotypic plasticity is usually reversible and does not necessarily depend on genetic alterations (Jolly et al., 2018a). Another compelling evidence for CSC plasticity in tumor progression comes from studies on colorectal malignancy. LGR5, a Wnt target gene, is used as a marker for colorectal CSCs. Kobayashi et al. (2012) has established human colon cancer cell lines that express LGR5 and possess CSC properties. However, treatment with an anticancer drug resulted in the conversion of the LGR5+ cells into LGR5C cells; the absence of drug drove the transition back from LGR5C to LGR5+ cells, suggesting the inherent plasticity. Both of these cell types could reconstitute the tumor as the Lgr5C cells could give rise to Lgr5+ cells and sustained the tumor growth. But interestingly, the Lgr5C cells could not form liver metastases (de Sousa e Melo et al., 2017), suggesting that this contribution of CSCs in main tumor formation and that in metastatic settings may be different. However, contrary to.