Ubiquitin/Proteasome System

This is similar to the results obtained with other anti-CSC drug candidates, including native antibodies, that have been investigated in the clinic

This is similar to the results obtained with other anti-CSC drug candidates, including native antibodies, that have been investigated in the clinic. CSCs themselves, including their heterogeneity, the lack of strictly CSC-specific markers, and the capacity to interconvert between (S)-Willardiine CSCs and non-CSCs; second, inherent limitations of some classes of cytotoxins that have been used for the construction of ADCs; third, the inadequacy of animal models in predicting efficacy in humans. We conclude suggesting some possibilities to address these limitations. efficacy of anti-CSC compounds is to test the number of tumor cells that are required in order to initiate tumor growth in animal models before and after drug treatment (6). Considerable efforts have been devoted to the phenotypic characterization of CSCs, in particular the identification of markers that distinguish CSCs from normal stem cells and the bulk of differentiated tumor cells. Overall, it has been difficult to define CSCs on the basis of their phenotypic profile (5). Thus, a large number of cell surface molecules that are expressed on CSCs have been identified; CD44, CD47, CD33, CD133, CXC chemokine receptor (CXCR) 4, and CD26 are some of these markers. Most of them, however, are not CSC-specific and in some cases are even ubiquitously expressed (e.g., CD44, CD47) (7). Some markers have a more restricted expression and/or are overexpressed on CSCs; these have been used as targets for ADCs, as will be discussed in the following. The plasticity of CSCs is reflected also by the large number of signaling pathways that are involved in the induction and maintenance of CSCs. Given the functional relationship between CSCs and normal stem cells, the role of signaling pathways involved in the physiology of normal stem cells, such as WNT, Notch, and Hedgehog (Hh), has been investigated with particular attention (8). Eventually, also post-transcriptional regulation contributes to the homeostasis and functions of CSCs. These include RNA modifications, RNA-binding proteins, mircoRNAs and long non-coding RNAs (9). As regards the generation of CSCs from differentiated tumor cells, similarly to cells that undergo an EMT, tumor-initiating potential can be acquired when one of three different events occur. First, in (S)-Willardiine response to stressors from the tumor microenvironment like hypoxia, low pH, immune responses, mechanical stress, and antitumor drugs (10, 11). Second, stressor-promoted epigenetic changes that induce heritable effects allowing retention of the mesenchymal state even when the stressors are no longer present (12, 13). Third, stimulus-independent activation of signaling pathways, owing to activating mutations or overexpression of pathway components (14, 15). Intuitively, these events are not mutually exclusive and may (S)-Willardiine differ quantitatively and qualitatively in different tumors and, over time, even within the same tumor. Moreover, some of these events (e.g., stressor-induced responses) can be reversible and, consequently, CSCs can revert back to a differentiated phenotype, as already referred to above. Vice versa, tumor cells that have regained an epithelial (S)-Willardiine and a non-CSC phenotype can undergo a switch toward a more mesenchymal tumor-initiating phenotype, even after drug-induced depletion of CSCs. As such, depletion of CSCs is by no means a conclusive effect but, rather, a transient elimination of tumor cells engaged in the replenishment of a tumor cell population of epithelial phenotype. Antibody-Drug Conjugates (ADC), Tools for the Selective Elimination of Tumor Cells ADCs comprise a monoclonal antibody (mAb) against a tumor-associated antigen, a covalent linker, and a cytotoxic payload (16). Figure 1 gives a schematic view of an ADC and its individual components as will be discussed in the following. In most cases, ADCs are internalized upon binding to the cognate antigen and the cytotoxic payload is released, causing cell death. The targeted delivery of cytotoxins to tumor cells allows for the maximum efficacy and minimal toxicity. Open in a separate window Figure 1 A Schematic View of ADCs and its Individual Components. The mAb targets a tumor-associated antigen, in the present case an antigen that is preferentially expressed on CSCs. The linker may be cleavable (e.g., acid-sensitive or Rabbit Polyclonal to ARSE dipeptide) or non-cleavable (e.g., maleimidocaproyl). The cytotoxin may be an antimitotic drug, active only on proliferating cells or a DNA-binding drug, active also on quiescent cells. Moreover, the cytotoxin may be hydrophilic and act only within the internalizing cell or it may be hydrophobic and act also on nearby cells, whether antigen-positive or Cnegative (so-called bystander effect). ADC, antibody-drug conjugate; CSC, cancer stem-like cell; mAb, monoclonal antibody. The mAb should recognize an antigen expressed on the largest possible fraction of tumor.