Extravasation of immune cells or metastasizing cancer cells across the blood brain barrier
The blood brain barrier (BBB) is formed by a uniquely specialized vascular endothelium building up a particularly tight endothelial layer that shields the vulnerable CNS from the constantly changing milieu in the blood stream. Therefore, extravasation of circulating cells from the blood across the tight BBB is difficult to envisage. Nevertheless, in multiple sclerosis (MS) auto-aggressive effector T cells or in secondary brain metastasis disseminated cancer cells successfully breach the BBB. Knowledge on the molecular events is essential for the development of pharmaceuticals specifically designed to target extravasation of auto-aggressive effector T cells or metastasizing cancer cells across the BBB.
In vitro live cell microscopy to image extravasation of immune or cancer cells
We have established an in vitro setup to image the highly dynamic spatiotemporal behavior of immune cells or cancer cells that adhere to and extravasate across the BBB. The tight BBB is modelled in vitro by primary mouse brain microvascular endothelial cells (pMBMECs). A small flow chamber, developed in close collaboration with the TKI’s workshop, ensures physiological blood flow conditions while the dynamic cell-cell interaction is imaged with a computer controlled microscope system.
Studies on the roles of endothelial IgCAMs for T cell extravasation across the BBB
Our in vitro imaging experimental setup allowed us to elucidate the roles of endothelial ICAM-1, ICAM-2 and VCAM-1 on the inflamed BBB for effector T cell shear resistant arrest, crawling against flow and trans- or paracellular diapedesis. We determined that endothelial ICAM-1 supports shear–resistant arrest, polarization and crawling of T cells, whereas endothelial ICAM-2 plays a minor role for T cell arrest but efficiently serves as an alternative endothelial ligand for T cell crawling. Endothelial VCAM-1 acts in parallel to ICAM-1 in shear resistant arrest but does not suffice for sustained shear resistant adhesion or crawling against flow. Finally, high levels of endothelial ICAM-1 promote diapedesis via the transcellular pathway.
Mechanism of cancer cell metastasis into the central nervous system
Brain metastases most commonly arise from cancers of the lung (40 - 50 %), the breast (15 - 25 %) or from malignant melanoma (5 - 20 %). Patients with brain metastasis have a very poor prognosis with a five-year survival rate below 10 %. While treatment success of primary tumors has advanced in the past, therapeutics targeting cancer cell dissemination into the brain are not available. Because the CNS is devoid of lymphatic vessels the obvious route of cancer cell dissemination into the brain is the blood vasculature. Thus metastatic cancer cells invading the CNS parenchyma have to breach the BBB. However, the molecular players in this process are unknown and therefore are subject of our research.