Cytokine Landscape in Central Nervous System Metastases

Abstract

The central nervous system is the location of metastases in more than 40% of patients with lung cancer, breast cancer and melanoma. These metastases are associated with one of the poorest prognoses in advanced cancer patients, mainly due to the lack of effective treatments. In this review, we explore the involvement of cytokines, including interleukins and chemokines, during the development of brain and leptomeningeal metastases from the epithelial-to-mesenchymal cell transition and blood-brain barrier extravasation to the interaction between cancer cells and cells from the brain microenvironment, including astrocytes and microglia. Furthermore, the role of the gut-brain axis on cytokine release during this process will also be addressed.

Keywords: brain metastases; leptomeningeal metastases; microenvironment; microglia and cytokines; reactive astrocytes.

Figure 1

Illustration of the brain and leptomeningeal metastasis development. During the first steps of the CNS metastasis process, cells dissociate from the systemic tumor site and secrete various factors, such as IL-6, TNFα, TGFβ and VEGF-A [18]. Those cells travel in the bloodstream to the brain parenchyma where they cross the BBB following cytokine release, i.e., IL-6, IL-8, CCL5, CXCL13, CX3CL1 and IL-1β [20,22,23]. Regarding leptomeningeal metastasis, cancer cells pass through the B-CSF barrier via C3 complement secretion [32]. Figure created with Biorender.

Figure 2

Pattern of cytokines which are released during brain metastasis establishment. Cancer cells (red) release several cytokines such as IL-6, IL-1β, TGFα and MIF in the brain leading to the activation of astrocytes (green) and macrophages (violet)/microglia (yellow) that secrete multiple cytokines and chemokines to support tumor growth [43,45,47,48,49,52,53,54]. Figure created with Biorender.