TY - JOUR
T1 - Replication stress response in cancer stem cells as a target for chemotherapy
AU - Sistigu, Antonella
AU - De Maria Marchiano, Ruggero
AU - Manic, Gwenola
AU - Corradi, Francesca
AU - Musella, Martina
AU - Vitale, Ilio
PY - 2018
Y1 - 2018
N2 - Cancer stem cells (CSCs) are subpopulations of multipotent stem cells (SCs) responsible for the initiation, longterm
clonal maintenance, growth and spreading of most human neoplasms. Reportedly, CSCs share a very robust
DNA damage response (DDR) with embryonic and adult SCs, which allows them to survive endogenous and
exogenous genotoxins. A range of experimental evidence indicates that CSCs have high but heterogeneous levels
of replication stress (RS), arising from, and being boosted by, endogenous causes, such as specific genetic
backgrounds (e.g., p53 deficiency) and/or aberrant karyotypes (e.g., supernumerary chromosomes). A multipronged
RS response (RSR) is put in place by CSCs to limit and ensure tolerability to RS. The characteristics of
such dedicated cascade have two opposite consequences, both relevant for cancer therapy. On the one hand, RSR
efficiency often increases the reliance of CSCs on specific DDR components. On the other hand, the functional
redundancy of pathways of the RSR can paradoxically promote the acquisition of resistance to RS- and/or DNA
damage-inducing agents. Here, we provide an overview of the molecular mechanisms of the RSR in cancer cells
and CSCs, focusing on the role of CHK1 and some emerging players, such as PARP1 and components of the
homologous recombination repair, whose targeting can represent a long-term effective anti-CSC strategy.
AB - Cancer stem cells (CSCs) are subpopulations of multipotent stem cells (SCs) responsible for the initiation, longterm
clonal maintenance, growth and spreading of most human neoplasms. Reportedly, CSCs share a very robust
DNA damage response (DDR) with embryonic and adult SCs, which allows them to survive endogenous and
exogenous genotoxins. A range of experimental evidence indicates that CSCs have high but heterogeneous levels
of replication stress (RS), arising from, and being boosted by, endogenous causes, such as specific genetic
backgrounds (e.g., p53 deficiency) and/or aberrant karyotypes (e.g., supernumerary chromosomes). A multipronged
RS response (RSR) is put in place by CSCs to limit and ensure tolerability to RS. The characteristics of
such dedicated cascade have two opposite consequences, both relevant for cancer therapy. On the one hand, RSR
efficiency often increases the reliance of CSCs on specific DDR components. On the other hand, the functional
redundancy of pathways of the RSR can paradoxically promote the acquisition of resistance to RS- and/or DNA
damage-inducing agents. Here, we provide an overview of the molecular mechanisms of the RSR in cancer cells
and CSCs, focusing on the role of CHK1 and some emerging players, such as PARP1 and components of the
homologous recombination repair, whose targeting can represent a long-term effective anti-CSC strategy.
KW - Aneuploidy
KW - Chromosomal instability
KW - Fork reversal
KW - Replication catastrophe
KW - Tumor-initiating cells
KW - Aneuploidy
KW - Chromosomal instability
KW - Fork reversal
KW - Replication catastrophe
KW - Tumor-initiating cells
UR - http://hdl.handle.net/10807/125366
U2 - 10.1016/j.semcancer.2018.08.003
DO - 10.1016/j.semcancer.2018.08.003
M3 - Article
SP - N/A-N/A
JO - Seminars in Cancer Biology
JF - Seminars in Cancer Biology
SN - 1044-579X
ER -