Electrical signals control the establishment of cell polarity, tumour metastasis and wound healing

Endogenous direct-current electric fields (EFs) play significant roles in biological and pathological processes. In this thesis I will discuss how an applied EF affects cell polarity, tumour metastasis, wound healing and provide some insights to the underlying molecular mechanisms. Directional cell migration requires proper cell polarization. The redistribution of the Golgi apparatus is a critical event in cellular polarisation. Direct current EFs as low as 0.3 V/cm induces Golgi polarization and directed cell migration. The Golgi polarizes at the same time as cells change morphology and migrate directionally in response to an electric field. Golgi polarization in turn significantly reinforces and maintains optimal electrotaxis. PKC/PI3K-GSK-3β signalling is required to promote Golgi polarization and control the direction of cell protrusion. Development of breast cancer is accompanied by electrical depolarization of the tumour epithelial cells. Applied electric fields indeed induce increased speed and directional migration of the highly metastatic cancer cells. EFs enhanced directional migration depends on EGFR/ErbB1 expression levels. Inhibition of ErbB1 activity completely abolished the directional response of tumour cells to an electric field. EFs could be the earliest signal epithelia receive to initiate directional migration and healing. Using a single cell model and a monolayer wound healing model in vitro, we found that a physiological EF overrides other guidance cues. When wound healing required cells to move towards the anode, they failed to do so. By contrast they were repelled and the wound opened up. This suggests that endogenous EFs may play much more important roles in re-epithelialization in wound healing.EThOS - Electronic Theses Online ServiceGBUnited Kingdo