Rethinking the chemokine cascade in brain metastasis: Preventive and therapeutic implications

Abstract

Brain metastasis (BrM) is one of the major causes of death in cancer patients and is associated with an estimated 10-40 % of total cancer cases. The survival rate of brain metastatic patients has not improved due to intratumor heterogeneity, the survival adaptations of brain homing metastatic cells, and the lack of understanding of underlying molecular mechanisms that limit the availability of effective therapies. The heterogeneous population of immune cells and tumor-initiating cells or cancer stem cells in the tumor microenvironment (TME) release various factors, such as chemokines that upon binding to their cognate receptors enhance tumor growth at primary sites and help tumor cells metastasize to the brain. Furthermore, brain metastatic sites have unique heterogeneous microenvironment that fuels cancer cells in establishing BrM. This review explores the crosstalk of chemokines with the heterogeneous TME during the progression of BrM and recognizes potential therapeutic approaches. We also discuss and summarize different targeted, immunotherapeutic, chemotherapeutic, and combinatorial strategies (with chemo-/immune- or targeted-therapies) to attenuate chemokines mediated BrM.

Keywords: Brain metastasis; Brain microenvironment; Chemokines; Heterogeneity; Immune cells.

Figure 1:. Incidence of brain metastasis in different cancers.

The red and brown nodes depict cancer progression and metastasis from the primary lung, breast, melanoma, renal and colorectal cancers. Metastatic dissemination to the brain from the primary tumors is regulated through systemic circulatory routes.

Figure 2:. Schematic representation of brain metastasis pathways.

During brain metastasis, cancer cells interact with the tumor microenvironment at the primary site to promote cell motility/invasion via clearance of the extracellular matrix. At this stage, tumor cells disseminated from the primary sites and invade into surrounding areas, blood vessels, and lymph nodes i.e., intravasation. Tumor cells enter into the circulation, following the process of extravasation; these cells adhere to the brain microvasculature and finally reach the brain environment. Cancer cells remain at dormancy for a longer time, and some cancer cells start interacting with the brain microenvironment that allow them to establish neuroinflammatory cascades and neovascularization. In the brain, cancer cells start growing at the junction between grey and white matter and the watershed area between vascular territories.

Figure 3:. Chemokine cascade in brain metastasis.

The multiple roles of chemokines and their receptors in the regulation of immune cells recruitment influence the growth of cancer cells at primary as well as brain metastatic sites. Chemokines regulate immune cell trafficking via their respective receptor at the primary tumor site and promote the growth and proliferation of cancer cells in the presence of stromal cells in the TME. The chemokines released from distant sites direct disseminated cancer cells to establish brain metastasis.