Effects of physico-chemical cues from the blood-brain barrier microenvironment on tumor cell migration and morphology

Abstract

Cancer metastasis is particularly deadly, leading to 90% of cancer deaths. During metastasis, tumor cells break off from a primary tumor and travel to distant sites. Metastasis to the brain results in a poor patient prognosis. However, several common cancers, such as breast cancer and melanoma, metastasize to the brain. In order to metastasize to the brain, tumor cells have been shown to cross the highly selective blood-brain barrier (BBB), which separates the brain parenchyma from the circulatory system. The BBB is highly impermeable, even for many chemotherapeutics, however, tumor cells are able to cross it by a poorly understood mechanism. The BBB consists of endothelial cells connected by tight junctions, and is supported by cells of the neurovascular unit, such as astrocytes. Furthermore, the composition of the extracellular matrix beyond the BBB is unique and contains hyaluronic acid (HA). In disease, HA organization or biophysical properties may become altered. The goal of this study was to investigate how specific physico-chemical interactions of tumor cells and the BBB microenvironment may impact tumor cell behavior at the BBB, as well as explore cold atmospheric plasma (CAP) as potential cancer treatment. This understanding could lead to better future therapeutics and a better prognosis for patients.

We hypothesized that biophysical and biochemical cues from the BBB microenvironment, as well as the tumor cell phenotype, can influence tumor cells’ migration and morphology. In this dissertation, we investigated the interaction of tumor cells with astrocyte-secreted biochemical cues and the biophysical cues from a HA/gelatin extracellular matrix on tumor cell morphology, migration, and incorporation into an endothelium. Our results showed that tumor cell migration and morphology are significantly altered by astrocyte-secreted factors and the HA/gelatin extracellular matrix; however, the extracellular matrix is less significant during incorporation. We also showed that brain- and bone-seeking tumor cells display varied morphologies on matrices with niche-relevant mechanical properties. Finally, we demonstrated that CAP selectivity for reducing migration of tumor vs. normal cells is highly sensitive to cell culture media formulation. Together, these results provide new insights into tumor cell behavior at the BBB and inform future studies and therapeutic development.