The Emerging Role of Amino Acids of the Brain Microenvironment in the Process of Metastasis Formation

SIMPLE SUMMARY: Why some cancers choose to form metastases in one organ rather than another is still largely unknown. In this review, we summarized the available information on the possible mechanisms controlling this choice. In particular, we tried to understand how some molecules, especially amino acids, released into the environment outside the cells, participate in selecting the brain as a target organ for the formation of metastases by specific types of aggressive tumors such as melanoma, breast, and lung cancer. ABSTRACT: Brain metastases are the most severe clinical manifestation of aggressive tumors. Melanoma, breast, and lung cancers are the types that prefer the brain as a site of metastasis formation, even if the reasons for this phenomenon still remain to be clarified. One of the main characteristics that makes a cancer cell able to form metastases in the brain is the ability to interact with the endothelial cells of the microvasculature, cross the blood–brain barrier, and metabolically adapt to the nutrients available in the new microenvironment. In this review, we analyzed what makes the brain a suitable site for the development of metastases and how this microenvironment, through the continuous release of neurotransmitters and amino acids in the extracellular milieu, is able to support the metabolic needs of metastasizing cells. We also suggested a possible role for amino acids released by the brain through the endothelial cells of the blood–brain barrier into the bloodstream in triggering the process of extravasation/invasion of the brain parenchyma.