Biological Adaptations of Tumor Cells to Radiation Therapy

Abstract

Radiation therapy has been used worldwide for many decades as a therapeutic regimen for the treatment of different types of cancer. Just over 50% of cancer patients are treated with radiotherapy alone or with other types of antitumor therapy. Radiation can induce different types of cell damage: directly, it can induce DNA single- and double-strand breaks; indirectly, it can induce the formation of free radicals, which can interact with different components of cells, including the genome, promoting structural alterations. During treatment, radiosensitive tumor cells decrease their rate of cell proliferation through cell cycle arrest stimulated by DNA damage. Then, DNA repair mechanisms are turned on to alleviate the damage, but cell death mechanisms are activated if damage persists and cannot be repaired. Interestingly, some cells can evade apoptosis because genome damage triggers the cellular overactivation of some DNA repair pathways. Additionally, some surviving cells exposed to radiation may have alterations in the expression of tumor suppressor genes and oncogenes, enhancing different hallmarks of cancer, such as migration, invasion, and metastasis. The activation of these genetic pathways and other epigenetic and structural cellular changes in the irradiated cells and extracellular factors, such as the tumor microenvironment, is crucial in developing tumor radioresistance. The tumor microenvironment is largely responsible for the poor efficacy of antitumor therapy, tumor relapse, and poor prognosis observed in some patients. In this review, we describe strategies that tumor cells use to respond to radiation stress, adapt, and proliferate after radiotherapy, promoting the appearance of tumor radioresistance. Also, we discuss the clinical impact of radioresistance in patient outcomes. Knowledge of such cellular strategies could help the development of new clinical interventions, increasing the radiosensitization of tumor cells, improving the effectiveness of these therapies, and increasing the survival of patients.

Keywords: DNA repair pathways; DNA-damage response; cancer; radioresistance; radiotherapy.

Figure 1

DNA repair pathways induced by radiation. During radiotherapy, IR can alter the chemical structure of DNA directly or indirectly. Indirectly, it promotes the formation of molecules, such as the OH- ion and ROS, which bind to nucleotides and modify them structurally. The main modifications induced by radiation are base damage, crosslink, SSB, and DSB. In response, cells regulate the expression of several genes and proteins involved in different DNA repair pathways, such as BER, NHEJ, and HR. The activation of this pathways helps to reduce radiation-induced DNA damage, favoring the survival and proliferation of tumor cells, as well as cellular radioresistance.

Figure 2

Cellular mechanisms associated with radioresistance. Cytoplasmic membrane, reticulum endoplasmic, and mitochondria are the main organelles where tumor cells assemble a response to develop radioresistance. Radiation can damage the endoplasmic reticulum (ER) homeostatic state and cause ER stress that will favor radioresistance. This last is also supported by mitochondrial alterations, metabolic remodeling, and by an increase in plasma membrane interconnections favoring the formation of cytoplasmic bridges. Cetuximab promotes radioresistance involving ERS pathway IRE1α/ATF6-GRP78. Silencing GRP78 inhibits the cooperative effects of radiotherapy and cetuximab inhibiting DSB repair and autophagy in OPCC. IRE1 promotes radioresistance in HPV-negative OPCC through IL-6 activation. Decreased MPC1 expression favors EMT and promotes radioresistance of cancer.