Chapter 5 │ Page 163 messengers to CD8+ T cell and NK cell, respectively, killing target cells by cytotoxic lymphocytes. (C) Metastatic tumor cell transfers Ca2+ and cGAMP to astrocyte via heterologous GJs, inducing further tumor spreading and therapy resistance. (D) NK cell transfers Ca2+ to tumor cells via Cx43 GJs, for induction of GrzmB-mediated cell death. A rise in the intracellular Ca2+ concentration in the target cell is needed for e icient killing by cytotoxic T lymphocytes or NK cells. GJs have been shown to propagate oxidative stress-induced cell death [38,39], apoptotic cell death [40,41], and radiation-induced cell death [42,43] in cancer cells. This phenomenon is named the “bystander e ect”, and refers to the transmission of responses from cells exposed to certain stimuli, to non-targeted neighboring or more distant cells by means of intercellular communication. Therefore, the development of therapeutic strategies to improve this propagation can contribute to tumor suppression in cancer cells. Furthermore, GJs are also able to transport antigenic peptides between cancer cells and dendritic cells (DCs), which supports activation and tumor-specific killing by cytotoxic lymphocytes [44,45]. Modulation of GJs is therefore also an emerging target in immunotherapeutic research. However, a better understanding of GJ structures and their function are required to elucidate in which conditions GJs act as pro- or anti-tumorigenic agents. Here, computer simulations can be a powerful tool, to investigate the interaction mechanisms at the atomic and molecular level. Moreover, computer simulations can also provide insights into the structural and dynamic properties of GJs, which is sometimes inaccessible with experimental methods. For these simulations to accurately represent the physiological conditions, a detailed understanding of GJ structures is needed. In this way, we can design better GJ promoters or inhibitors for improved cancer treatment. In this review, we provide an overview of the in-depth knowledge on the structure and functions of GJs, and cover the current understanding of their paradoxical pro- and anti-tumoral properties, together with the therapeutic opportunities of GJ function modulation.
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