DNA Repair and Therapeutic Strategies in Cancer Stem Cells

Abstract

First-line cancer treatments successfully eradicate the differentiated tumour mass but are comparatively ineffective against cancer stem cells (CSCs), a self-renewing subpopulation thought to be responsible for tumour initiation, metastasis, heterogeneity, and recurrence. CSCs are thus presented as the principal target for elimination during cancer treatment. However, CSCs are challenging to drug target because of numerous intrinsic and extrinsic mechanisms of drug resistance. One such mechanism that remains relatively understudied is the DNA damage response (DDR). CSCs are presumed to possess properties that enable enhanced DNA repair efficiency relative to their highly proliferative bulk progeny, facilitating improved repair of double-strand breaks induced by radiotherapy and most chemotherapeutics. This can occur through multiple mechanisms, including increased expression and splicing fidelity of DNA repair genes, robust activation of cell cycle checkpoints, and elevated homologous recombination-mediated DNA repair. Herein, we summarise the current knowledge concerning improved genome integrity in non-transformed stem cells and CSCs, discuss therapeutic opportunities within the DDR for re-sensitising CSCs to genotoxic stressors, and consider the challenges posed regarding unbiased identification of novel DDR-directed strategies in CSCs. A better understanding of the DDR mediating chemo/radioresistance mechanisms in CSCs could lead to novel therapeutic approaches, thereby enhancing treatment efficacy in cancer patients.

A Comprehensive Model to Differentiate Spontaneous, Drug-induced, and CSCs-related Drug Resistance

“…We may assume ϵ Z ≪ α Z , Z = C, D. We can also reasonably assume δ Z ≪ γ Z , Z = C, D because sensitive phenotype should be mainly killed due to drug administration or chemotherapy becomes unnecessary. Compared with DCCs, CSCs exhibit enhanced DNA repair capabilities through multiple mechanisms such as efficient engagement of the DNA damage response (DDR) pathway, activation of cell cycle checkpoints, and prolonged residence in the quiescent G0 phase of the cell cycle [27]. Therefore, we assume…”

Tumor microenvironment-induced tumor cell plasticity: relationship with hypoxic stress and impact on tumor resistance

“…Overexpression of Bcl-2 protein in the hematopoietic system results in an increase in hematopoietic stem cell number and chemoresistance ( 177 , 178 ). Furthermore, stem cells possess asynchronous DNA synthesis activity and increased DNA repair activity ( 179 ). During asynchronous DNA synthesis, the parental ‘immortal’ DNA strand consistently segregates with the stem cell rather than the differentiating progeny.…”

“…As a result, stem cells gain an advantage by avoiding the accumulation of mutations related to replication and the detrimental effects of DNA-damaging agents and antiapoptotic proteins. Moreover, there are populations of stem cell-like cells found in many tumors that have been shown to express high levels of multidrug efflux pumps (MDR) or transporter proteins/detoxification proteins, such as MDR1, ABCB1, ABCG2 (BCRP) that play a significant role in expelling cytotoxic drugs from cells leading to high resistance to chemotherapeutic agents ( 179 ). The overexpression of ABC protein is a critical protective mechanism for CSCs in response to chemotherapy ( 152 , 181 ).…”

Exosomes as a Nano-Carrier for Chemotherapeutics: A New Era of Oncology

“…Because they share many characteristics with stem cells, such as the self-renew capability and differential potential conferred by the expression of pluripotency markers (OCT-3/4, Sox2, Nanog, KLF4, and MYC) which are involved in recurrence, metastasis, heterogeneity, and heterogeneity, these cells were named cancer stem cells [79]. In addition, as well as being observed in stem cell populations, CSCs also express high levels of ATPbinding cassette (ABC) transporters [81] and DNA damage response genes [79,82]. The overexpression of these genes increases the efflux of chemotherapeutics and reduces the radiosensitivity, conferring mechanisms of chemo-and radioresistance, thereby explaining the high mortality rate in patients with cancer metastasis [83][84][85][86].…”