The microenvironment of an early-stage tumor, in which a small number of cancer cells is surrounded by a normal counterpart milieu, plays a crucial role in determining the fate of initiated cells. Here, we examined cell competition between anaplastic thyroid cancer cells and normal thyroid follicular cells using co-culture method. Cancer cells were grown until they formed small clusters, to which normal cells were added to create high-density co-culture condition. We found that co-culture with normal cells significantly suppressed the growth of cancer cell clusters through the activation of Akt-Skp2 pathway. In turn, cancer cells triggered apoptosis in the neighboring normal cells through local activation of ERK1/2. A bi-directional cell competition provides a suppressive mechanism of anaplastic thyroid cancer progression. Since the competitive effect was negated by terminal growth arrest caused by radiation exposure to normal cells, modulation of reciprocal stress response in vivo could be an intrinsic mechanism associated with tumor initiation, propagation, and metastasis.

DNA double-strand breaks (DSBs) induced by ionizing radiation are the major cause of cell death, leading to tissue/organ injuries, which is a fundamental mechanism underlying the development of tissue reaction. Since unscheduled senescence, predominantly induced among epithelial tissues/organs, is one of the major modes of cell death in response to radiation exposure, its role in tissue reaction has been extensively studied, and it has become clear that senescence-mediated secretion of soluble factors is an indispensable component of the manifestation of tissue reaction. Recently, an unexpected link between cytoplasmic DSBs and innate immunity was discovered. The activation of cyclic GMP-AMP (cGAMP) synthase (cGAS) results in the stimulation of the cGAS–stimulator of interferon genes (STING) pathway, which has been shown to regulate the transactivation of a variety of secretory factors that are the same as those secreted from senescent cells. Furthermore, it has been proven that cGAS–STING pathway also mediates execution of the senescence process by itself. Hence, an autocrine/paracrine feedback loop has been discussed in previous literature in relation to its effect on the tissue microenvironment. As the tissue microenvironment plays a crucial role in cancer development, tissue reaction could be involved in the late health effects caused by radiation exposure. In this paper, the novel findings in radiation biology, which should provide a better understanding of the mechanisms underlying radiation-induced carcinogenesis, are overviewed.