The effects of low shear stress generated in simulated microgravity bioreactors on thyroid cancer cells and endothelial cells, and its role in the multicellular spheroid formation process

Abstract

One in two persons will be diagnosed with cancer in their lifetime, and cancer will soon be the leading cause of death in Europe. New treatment options are needed, which only a deep understanding of the disease can provide. When exposed to microgravity conditions, cancer cells show changes in their malignant properties. However, an explanation for the differences observed is missing. Therefore, a new model explaining microgravity's molecular effects on human cells is necessary. This doctoral thesis discusses that the gravity vector does not directly affect cell physiology. The thesis also investigates the physiological role of ESA Ground-based facilities for microgravity simulation. Multiscale models of tissue mechanobiology are essential for understanding the role of microgravity in biological systems, as it seems that the immediate surroundings of a cell within a 3D environment override external gravitational stimuli. In this work, I investigated the effects of simulated microgravity on different thyroid cancer cell lines, such as epithelial thyroid cells and follicular thyroid cancer cell lines with metastatic origin. Endothelial cells are also important in this thesis, as they possess more mechanosensitive capabilities. Cancer cells exposed to the Random Positioning Machine (RPM) commonly cluster forming spheroids; however, an explanation for the formation process is unclear. In this thesis, a 2-step process is identified: 1) The cell detachment caused by fluid flow dynamics generated as a secondary effect in the RPM. 2) The free-fall obtained in simulated microgravity devices facilitates the aggregation process. Future cancer studies in microgravity conditions should be based on 3D tumor models to provide better insights into the role played by gravity unloading in cancer progression.