Tumor microenvironment and exosomes in brain metastasis: Molecular mechanisms and clinical application

Abstract

Metastasis is one of the important biological features of malignant tumors and one of the main factors responsible for poor prognosis. Although the widespread application of newer clinical technologies and their continuous development have significantly improved survival in patients with brain metastases, there is no uniform standard of care. More effective therapeutic measures are therefore needed to improve prognosis. Understanding the mechanisms of tumor cell colonization, growth, and invasion in the central nervous system is of particular importance for the prevention and treatment of brain metastases. This process can be plausibly explained by the "seed and soil" hypothesis, which essentially states that tumor cells can interact with various components of the central nervous system microenvironment to produce adaptive changes; it is this interaction that determines the development of brain metastases. As a novel form of intercellular communication, exosomes play a key role in the brain metastasis microenvironment and carry various bioactive molecules that regulate receptor cell activity. In this paper, we review the roles and prospects of brain metastatic tumor cells, the brain metastatic tumor microenvironment, and exosomes in the development and clinical management of brain metastases.

Keywords: brain tumor; exosomes; metastases; tumor cell; tumor microenvironment.

Figure 1

Sources and formation processes of brain metastases. (A) The most common sources of brain metastases are lung cancer (40%-50%), followed by breast cancer (15%-20%), skin cancer (mainly melanoma) accounting for 5%-10%, and gastrointestinal malignancy (4%-6%). (B) Tumor cells and secreted vesicle contents can disrupt the integrity of BBB, thereby promoting tumor metastasis to intracranial, interacting with surrounding astrocytes, microglia/macrophages, and then influencing the biological behavior of brain metastasis through various pathways such as secreting cytokine networks, direct contact and exosomes, and establishing complex networks. (C) Tumor cells can produce mutual adaptive changes with the components of the central nervous system microenvironment, and it is this interaction that determines the occurrence and development of brain metastatic lesions. (D) Metastatic foci appear in the skull, producing obvious mass and edematic effects, which seriously affects the quality of life of patients.

Figure 2

The role of exosomes in brain metastases. The first mechanism of primary tumor exosomes is that they can promote their own progression and metastasis. The second general mechanism is that exosomes derived from primary tumor cells promote the proliferation of brain metastases, regulated immune mechanism to promote tumor cell proliferation, and regulate the stability of tumor cells, and can be useful diagnostic and/or prognostic biomarkers.