Abstract
Migration of cancer cells leads to the invasion of distant organs by primary tumors. Further, endogenous electric fields (EFs) in the tumor microenvironment direct the migration of lung cancer cells by a process referred to as electrotaxis – although the precise mechanism remains unclear. Caveolin-1 (Cav-1) is a multifunctional scaffolding protein that is associated with directional cell migration and lung cancer invasion; however, its precise role in lung cancer electrotaxis is unknown. In the present study, we first detected outward electric currents on the tumor body surface in lung cancer xenografts using a highly-sensitive vibrating probe. Next, we found that highly-metastatic H1650-M3 cells migrated directionally to the cathode. In addition, reversal of the EF polarity reversed the direction of migration. Mechanistically, EFs activated Cav-1 and the downstream signaling molecule STAT3. RNA interference of Cav-1 reduced directional cell migration, which was accompanied by dampened STAT3 activation. Furthermore, pharmacological inhibition of STAT3 significantly reduced the electrotactic response, while rescue of STAT3 activation in Cav-1 knock-down cells restored electrotaxis. Taken together, these results suggest that endogenous EFs in the tumor micro-environment might play an important role in lung cancer metastasis by guiding cell migration through a Cav-1/STAT3-mediated signaling pathway.
Highlights
Cell migration plays a crucial role in many biological processes, including embryonic development, wound healing and immune surveillance, and cancer invasion [1, 2]
At the surface of the tumor, large outward currents were detected, which was statistically greater than that found at the intact epithelium around the tumor (Figure 1B). Such an outward current on the surface of a tumor implies the existence of an established electric fields (EFs) between lung cancer and the surrounding tissues, with the anode being located inside the tumor and the cathode outside the tumor
Given the importance of Cav-1 in cancer invasion [20] and the observation that Cav-1 expression was much higher in H1650-M3 cells than was seen in H1650 cells (Supplementary Figure 2), we investigated whether Cav-1 was involved in electrotaxis of lung cancer cells
Summary
Cell migration plays a crucial role in many biological processes, including embryonic development, wound healing and immune surveillance, and cancer invasion [1, 2]. Migration of cancer cells leads to invasion of distant organs by primary tumors, which is the essence of tumor metastasis, accounting for more than 90 percent of all cancer related deaths [3, 4]. Metastasis is a multistep process where tumor cells disseminate from the primary tumor and colonize distant organs. Directed cancer cell migration is controlled by various environmental factors, including the extracellular matrix (ECM), cytokines and growth factors, and their interacting cognate receptors that transduce chemotactic signals [5]. DcEFs have been suggested to control wound healing, to polarize cells, and to guide directional cell migration - a process termed electro- or galvanotaxis. DcEFs have been suggested to control wound healing, to polarize cells, and to guide directional cell migration - a process termed electro- or galvanotaxis. [7, 10]
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