Studies by Fukui et al. correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are drawn. Besides these positive effects after therapy, senescence can also have Oxantel Pamoate negative effects displayed post-therapeutically. These unfavorable effects can directly promote malignancy stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing Oxantel Pamoate on deadliest solid (lung, belly, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be Oxantel Pamoate influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed. and studies showed that liver malignancy can originate from adult hepatocytes (29C32) as well as from hepatoblasts and hepatic progenitors (31, 32). Open in a separate window Physique 1 The origin of CSCs at tumor initiation: The two hypotheses of CSC generation. (A) The proliferation and differentiation of adult tissue resident stem cells is usually part of the physiological regeneration program that maintains tissue homeostasis. Adult tissue resident stem cells divide asymmetrically and generate transient amplifying cells, which possess a high proliferative capacity. These cells terminally differentiate; a process during which they will drop their proliferative capacity to finally support organ homeostasis. (B) Tumors can be generated by step-wise accumulation of several mutations (reddish lightening) that transform differentiated cells and cause a de-differentiation. Tissue resident stem cells as well as their progeny can accumulate mutations that lead to uncontrolled and niche independent growth. Heterogeneous tumors are generated. CSCs share phenotypic characteristics and several markers have been explained in solid as CCM2 well as in liquid cancers. Tumor type, prognosis and aggressiveness are also influenced by the origin of the tumor, as analyzed for instance in breast cancers (33C35). Breast tumors originating from luminal progenitors are associated with a good prognosis, except those overexpressing Her2 (34, 36). Tumors originating from basal-like progenitors show a very aggressive phenotype (34). In squamous cell carcinomas the differentiation phenotype seems to be influenced by the cell of origin and the kind of driver mutation, both responsible for the invasiveness and aggressiveness of the tumor (37, 38). Oxantel Pamoate Loss of the phosphatase and tensin homolog (Pten) as well as the liver kinase B1 (Lkb1) in lung epithelia causes tumor formation of highly penetrant tumors. These tumors are rarely metastatic and are characterized by a differentiated phenotype (37). Basal cells located within the trachea and main bronchi have been shown to self-renew and to form heterogeneous spheres (39). These basal stem cells can cause basal cell hyperplasia or epithelial hypoplasia, finally resulting in squamous cell metaplasia or dysplasia, which are discussed as precursors of squamous cell lung carcinomas (SCC) (39, 40). Studies by Fukui et al. suggest that high basal cell signatures correlate to a clinically aggressive phenotype in lung adenocarcinoma (40). Adenocarcinomas are considered to originate from sub-segmental airways of the bronchioalveolar stem cells or Type I and Type II pneumocytes (39). These bronchioalveolar stem cells are quiescent in healthy lungs but can enter proliferation cycles and could be targets of mutations causing transformation (39, 41). In mouse models, data show that small cell lung cancers (SCLC) can also originate from other cell types, i.e., neuroendocrine cells (42). While in solid tumors the origin is usually greatly discussed, in hematological tumors the situation seems to be clearer. In acute myeloid leukemia (AML), the cell of origin is thought to be a hematopoietic stem or progenitor cell (43). However, a subgroup of human AML has been shown to share expression profiles with lymphoid T-cell progenitors. The authors showed that under oncogenic conditions, DN2 (double unfavorable 2) T-cell progenitors process into lymphoid, biphenotypic, and myeloid leukemia cells (43C45). In chronic myeloid leukemia (CML), the cell of origin is characterized by the.