Moscow: In an attempt to establish new approaches for cancer diagnosis and treatment, the international team of scientists, including a researcher at Sechenov University, has reviewed scientific papers on proteins (and genes encoding them) that help cancer cells reach the brain.
Brain tissues are very sensitive to changes in the levels of many substances and to the infiltration of microorganisms and immune cells, which need a significant amount of nutrients and oxygen. Responding to the needs of the brain involves a thick network of thin blood vessels, protected by a special membrane,
which lets in vital substances and blocks all other compounds and cells.
This shell, consisting of adjacent endothelial cells tightly connected to each other by special proteins, forms the blood-brain barrier (BBB), which prevents the free exchange of substances between blood vessels and brain tissues.
BBB works very well (letting fewer than 2% of molecules) but is still not perfect: cancer cells still manage
to get through it and cause metastases; since other drugs can not get into the brain, this greatly complicates
cancer care and worsens the prognosis for patients with metastases.
‘Metastasis formation is controlled by proteins and genes encoding these proteins. The purpose of this work was to systematize experimentally or clinically proven findings of the proteins and microRNAs that allow migration of tumor cells to the brain. It turned out that their production is typical for a number of metastases, while most of the cell molecules described in the literature are unique for a particular type of tumor.
Thus, the possibility of regulating genes that stimulate the migration of tumor cells to the brain may be a challenge faced by doctors in reducing the formation of intracerebral metastases in the future,’ said Ilya Ulasov, one of the authors, a leading researcher at the Institute of Regenerative Medicine, Sechenov University.
It is recognized that tumor cells invade the brain both by thick interactions between the tunica cells
(layers of the blood vessels) and through these cells themselves. In the first example, cancer cells use enzymes and/or microRNAs to break the structure of dense contacts and improve BBB permeability.
One of these enzymes is cathepsin C: it destroys the proteins of the dense contacts, and its inhibitors (substances that slow down its action) can suppress the growth of metastases in breast cancer. Two other enzymes – seprase and urokinase-type plasminogen activator – have shown similar effects in melanoma, and some metalloproteinases may be possible targets for anti-cancer therapy. Another protein, placental growth factor, triggers a chain of reactions to facilitate the development of metastases in lung, gastric or colorectal cancer.
MicroRNAs enable communication between cancer cells and their environment, including BBB cells and proteins. For example, miR-105 affects ZO-1 protein, contributing to the formation of metastases in breast cancer, while miR-143-3p can enhance BBB permeability in lung cancer.
The second way – penetration of cancer cells through BBB cells – is possible due to proteins of the cell wall, integrins, and certain groups of enzymes. In several types of cancer, metastasis cells showed an increased content of integrins avb3 and avb8. It is possible that they are involved in the formation of metastases in the brain and can serve as a biomarker of the disease. Another integrin, VLA-4, is produced in the metastases of most melanoma patients and promotes the binding of cancer cells and BBB cells, which opens the way to the brain.
The authors reviewed 44 proteins in total, identified the mechanism of their effect on metastasis formation, and listed the encoding genes for them. The research will assist scientists in finding new ways to prevent and treat cancer, stroke, and Alzheimer’s disease, which also impacts the reputation of BBB.