Hanne Verswyvel

Chapter 5 │ Page 161 1. INTRODUCTION Gap junctions (GJs) are protein channels that enable direct intercellular communication (Figure 1) [1], thus allowing cells to exchange signals and molecules directly from the inside of one cell to a neighboring cell. As such, they provide an essential way for the maintenance of physiological functions, e.g., cell growth, di erentiation, homeostasis [2], angiogenesis [3], neural migration [4], and stem cell development [5]. Recently, the importance of GJs for disease induction and progression is becoming more appreciated, especially in the context of oncology, and is therefore seen as a novel target for therapy development. Studies into solid tumor cells revealed a lack of communication through GJs in certain tumor types, resulting in abnormal cell growth [6-8]. Moreover, restoration of gap junction intercellular communication (GJIC) in tumor cell lines reduced tumor growth and proliferation [9-11], suggesting that GJs have anti-tumorigenic properties. However, interestingly, GJIC was also able to facilitate the sharing of cancer cell metabolites with normal (healthy) cells, which in turn led to a gain of malignant properties in normal cells [12,13]. These reports suggest a pro-tumorigenic role of GJs properties. Hence, the current understanding of GJs in cancer cells is paradoxical, as GJs have both tumor-suppressing and promoting properties which depend on gap junction (GJ) type, cancer stage, and tumoral factors [14]. In fact, GJs are often reduced or lost completely in early cancer stages and upregulated in later stages and metastatic lesions, which contribute to tumor aggressiveness [14,15]. Therefore, therapeutic strategies to enhance GJs in early tumor development [16-18] or to inhibit them in advanced stages [19-21] have emerged. Peptides [17,22,23], antibodies [24,25], and chemotherapeutic agents [26,27] have been used to inhibit GJ functions in cancer cells, targeting the pro-tumorigenic properties of GJs. They have been proven useful to restore the sensitivity of cancer cells to cytotoxic drugs [28] and reduce tumor growth [24]. On the other hand, GJs have

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