DNA Damage Repair Pathways in Cancer Stem Cells

Abstract

The discovery of tumor-initiating cells endowed with stem-like features has added a further level of complexity to the pathobiology of neoplastic diseases. In the attempt of dissecting the functional properties of this uncommon cellular subpopulation, investigators are taking full advantage of a body of knowledge about adult stem cells, as the "cancer stem cell model" implies that tissue-resident stem cells are the target of the oncogenic process. It is emerging that a plethora of molecular mechanisms protect cancer stem cells (CSC) against chemotherapy-and radiotherapy-induced death stimuli. The ability of CSCs to survive stressful conditions is correlated, among others, with a multifaceted protection of genome integrity by a prompt activation of the DNA damage sensor and repair machinery. Nevertheless, many moleculartargeted agents directed against DNA repair effectors are in late preclinical or clinical development while the identification of predictive biomarkers of response coupled with the validation of robust assays for assessing biomarkers is paving the way for biology-driven clinical trials.

Drug Transporter-Mediated Protection of Cancer Stem Cells From Ionophore Antibiotics

“…Eradication of these CSCs, however, has proven difficult, partly because several protection mechanisms are operative in these cells [11,25]. In the face of this challenge, the demonstration that IAs can target various CSC populations (including populations expressing ABCB1 and ABCG2) [3][4][5][6][7][8]12] was particularly remarkable.…”

Adipose mesenchymal stromal cells minimize and repair radiation-induced oral mucositis

“…In a previous study. it has been documented that, breast CSC have much higher ATM, and Chek1 levels compared to differentiated tumor cells [185].…”

Targeting therapy-resistant cancer stem cells by hyperthermia

“…Increased expression of major DNA repair proteins, including BRCA1, ATR and ATM, has been observed in pancreatic, breast and prostate CSCs [156][157][158]. Reduced DNA repair capacity in CSCs has also been reported (reviewed by Wang [159]).…”