Tunneling nanotubes for urinary bladder cancer treatments

Urinary bladder cancer is 6th among all cancers worldwide and 1/3 of urinary bladder cancer emerges from the specific epithelium, the urothelium. Treatment usually includes the resection of the tumours during the transurethral resection of the urinary bladder. Despite the progress of surgical and chemotherapeutical approaches, the prognosis is still modest, mostly due to high recurrence rate of these tumours. Multicellular units of organisms rely on intercellular communication; such, cancer cell clustering, organization, synchronization, and coordinated invasion to surrounding tissue are criticalprocesses. Various ways of interactions between the tumour and its microenvironment contribute to its growth. In contrast to the stable interactions of well- differentiated normal epithelial tissues, cancer cells use a more dynamic kind of cell-cell interaction, which in part are small membranous tubes tunnelling nanotubes (TnTs), being in focus of this project. These nanotubes could reach over 100 m in length, connect two or more cells and form highways enabling short and long distance intercellular communication. They were discovered about a decade ago and since then have become an important topic in cell biology and physiology research. Central assumption and goal of the project is, that these TnTs could be used as targets for new innovative treatment of urinary bladder cancer. In earlier projects, the communication between cancer cells could be inhibited by diminishing the nanotube formation as could TnTs be used as a route for anticancer drug distribution. For the delivery system biocompatible composite nanoparticles in which potential anticancer drugs will be integrated will be used. Experts from different disciplines combine key elements, like complementary expertise and experience, proven track record of previous successful collaborations between partners, and all the necessary equipment. The main goals of three work packages within the project contain activities related to the following specific topics 1. Analysis of cell-biological mechanisms of TnT-formation, their molecular and ultrastructure; 2. Analysis of TnT-function and development of systems for tracking drug delivery and targeted inhibition of TnTs; 3. Evaluation of the therapeutic potential of TnTs and biocompatible composite nanoparticles on respective models in vitro and in vivo. Our contributions to the project concern those steps, where number, shape and fine structure of TnTs will be assessed by various microscopical methods. Exact information about the quality of the cellular contact sites will be achieved by electron tomography, a principle where subcellular structures can be visualized 3-dimensionally at high magnifications. At the end, innovative approaches for the treatment of urinary bladder cancer should be developed, being in focus throughout all steps of the project by active participation of clinical partners.