Molecular Pathogenesis of Radiation-Induced Cell Toxicity in Stem Cells

Abstract

Radiation therapy is an effective cancer therapy, but damage to normal tissues surrounding the tumor due to radiotherapy causes severe complications. The importance of the therapeutic area between tumor suppression and normal tissue injury has long been highlighted in radiation therapy. Recent advances in stem cell biology have shown that stem cell (SC) responses to genotoxic stresses of ionizing radiation can improve the therapeutic effect of radiation by repairing damaged cells. In contrast, cancer stem cells (CSCs), a small subpopulation of cells within tumors, are generally resistant to chemotherapy and radiotherapy and cause tumor recurrence. Although the underlying mechanisms are not clearly understood in detail, efforts are still underway to identify SC treatment or CSC resistant pathogenesis of DNA damage agents such as radiation therapy. In response to radiation, CSCs differ from normal SCs in their biological properties due to severe deregulation of the self-renewal ability in CSCs. Differences of cleavage mode, cell cycle characteristics, replication potential, and activation/inactivation of DNA damage treatment and cancer-specific molecular pathways between normal SCs and CSCs confer a malignant phenotype upon CSCs. However, further studies are needed to identify normal SC and CSC-specific targets. In this review, we summarize the current advances in research regarding how normal SCs and CSCs respond to ionizing radiation, with a special emphasis on cell toxicity, radiosensitivity, signaling networks, DNA damage response (DDR) and DNA repair. In addition, we discuss strategies to develop new diagnostic and therapeutic techniques for predicting responses to cancer treatment and overcoming radiation-related toxicity.

Keywords: cancer stem cell; radiation therapy; radiation-induced toxicity; resistant; stem cell.

Figure 1

Direct and indirect DNA damage by ionizing radiation. Radiation can directly interact with cellular DNA and cause damage. The indirect DNA damage caused by the free radicals is derived from the ionization or excitation of the water component of the cells.

Figure 2

Schematic model for ATM and ATR activation in response to DNA damage. (A) ATM responds to DNA double-strand breaks and phosphorylates histone variant H2AX and nijmegen breakage syndrome 1 (NBS1), which localize to sites of DNA damage, where MRN complexes then form. ATM activation regulates cell-cycle checkpoints through the phosphorylation of Chk2, breast cancer type 1 (BRCA1) and p53, in addition to a wide number of other DDR factors, and the induction of the γH2AX-dependent signaling cascade. (B) ATR is activated in response to single-stranded DNA (ssDNA) by UV light. Activation of ATR requires DNA topoisomerase 2-binding protein 1 (TopBP1). ATR is recruited to replication protein A (RPA)-coated single-stranded DNA by its binding partner ATR Interacting Protein (ATRIP). ATR regulates the cell-cycle through activation of Chk1.

Figure 3

Regulation of self-renewal and DNA-damage response in normal and cancer stem cells. (A) Normal SCs asymmetrically divide, giving rise to stem cells and progenitor cells. Progenitor cells respond to radiation induced damage that induces apoptosis or senescence. SCs lead to the inactivation of apoptotic responses, cell cycle entry and expansion of the SC pool (increasing the rounds of symmetric divisions). Continuous DNA damage and repair suppress apoptosis/senescence, favoring the survival of SCs that harbor DNA mutations. This could have important pathological consequences by generating an actively expanding pool of immortal and genomically unstable SCs, increasing the risk of cancer. (B) In contrast, in cancer stem cells, the self-renewal capability is profoundly deregulated. The CSCs undergo an indefinite number of rounds of cell division, which, ultimately, results in the expansion of the stem cell pool. CSCs are a small but radioresistant cell subpopulation within heterogeneous cancer masses. Under conditions of radiation-induced stress, CSCs survive following IR. However, the majority of non-stem cancer cells are killed via various mechanisms, such as induction of cell apoptosis or mitotic death. A small number of non-stem cancer cells undergo dedifferentiation and transform into CSCs via unknown mechanisms. The newly generated CSCs, together with the intrinsic CSCs, subsequently contribute to the relapse and metastasis of cancer. CSCs, cancer stem cells; IR, irradiation.