Patients with breast cancer can develop metastases in the brain – which means an even worse chance of survival. There may be factors in the blood that can predict this metastasis.
Breast cancer is the most common malignant tumor disease in industrialized nations. It causes the highest tumor-associated mortality rate in women. Whether and how the tumor metastasizes has a decisive influence on the mortality rate and survival time of the patients. Early detection measures and preventive examinations have reduced the mortality rate considerably. However, despite advances in diagnostics and therapy, many patients continue to die. Especially tumor metastasis in the brain leads to a high mortality rate and a massive impairment of the quality of life. Despite intensive research, far too little is known about the links between breast cancer and its metastasis to the brain.
Progress in this field has now been made by a research group from Julius Maximilians University (JMU) and the University Hospital of Würzburg: The team led by Dr. Carolin Curtaz (Women’s Hospital) and PD Dr. Malgorzata Burek (Anesthesiology) has published its new findings in the journal Fluids and Barriers of the CNS.
The important role of the blood-brain barrier
Crucial for breast cancer to metastasize to the brain is for tumor cells to cross the blood-brain barrier. This is a natural barrier in the blood vessels that protects the brain from harmful substances from the bloodstream. It is formed by highly differentiated endothelial cells and maintained in interaction with other cells. Can certain factors in the blood of breast cancer patients influence or even damage this natural protective barrier? And thus promote the passage of tumor cells into the brain? This is what Carolin Curtaz and Malgorzata Burek investigated.
Two cytokines in elevated concentration
The JMU researchers used serum samples from patients whose breast cancer had metastasized to the brain and compared them with samples from patients with primary tumors, bone metastases and visceral metastases. In addition, they examined the serum of control subjects without tumor disease. They found what they were looking for in the area of cytokines: Patients with brain metastases had elevated levels of fractalkine (CX3CL1) and BCA-1 (B cell-attracting chemokine 1, CXCL13). Cytokines are proteins produced by the human body. They act as messengers between cells and play an important role in the immune response. Tumor cells can also produce cytokines and thus influence communication between cells.
Good in vitro model for the blood-brain barrier.
Then the researchers examined how the serum samples affected the blood-brain barrier. For this purpose, they used a cell culture. For a long time, it was not possible to reliably obtain and culture endothelial cells from the human brain. However, advances in stem cell research mean that good in vitro models of the human blood-brain barrier are now available. Curtaz and Burek used a model based on CD34+ cells. It was established in collaboration with French researchers in Würzburg. Treatment of this artificial blood-brain barrier with serum from patients with brain metastases resulted in changes in gene expression and increased permeability of the barrier to test compounds.
This indicates that there are factors in the serum of these patients that can actively alter the properties of the blood-brain barrier. In the future, their detection in the blood could serve as a prognostic marker to predict which patients are likely to develop brain metastases. However, it is not yet clear whether the factors are the two cytokines. Further analysis with a large number of female patients is needed here. Currently, the team of the two scientists is continuing to search for factors that have an influence on the blood-brain barrier.
Original publication:
Curtaz, C.J., Schmitt, C., Herbert, S. … Burek M. Serum-derived factors of breast cancer patients with brain metastases alter permeability of a human blood-brain barrier model. Fluids Barriers CNS 17, 31 (2020). https://doi.org/10.1186/s12987-020-00192-6
