Preclinical Models of Brain Metastases

Abstract

Preclinical models are paramount to decipher molecular mechanisms of brain metastases and to develop new therapeutic options. The metastatic process, the movement to and progressive colonization of distant sites by tumor cells, comprises convoluted and dynamic stages: (1) the tumor cells migrate away from the primary tumor; (2) acquire the capacity to intravasate and survive in the vasculature; (3) extravasate at a distant organ to finally survive, potentially through a dormancy phase; (4) and proliferate [1]. At each stage, tumor cells need to circumvent immune surveillance and adapt to each new microenvironment [2]. In parallel, tumor-secreted factors and extracellular vesicles may actively prepare the distant organ, forming the premetastatic niche, to lodge and promote the growth of the arriving tumor cells [3]. Brain metastases evolve in a unique environment, composed of brain-resident cells, such as microglia and astrocytes, and insulated by the blood-brain barrier (BBB), a multicellular dynamic structure regulating exchanges between the blood and the central nervous system [4]. A neuroinflammatory response, consisting of reactive microglia and astrogliosis, is observed around the metastatic lesions [5], as well as infiltrated lymphocytes [6–8]. While parenchymal metastases are the most prevalent, cancer cells can also grow along the meninges, tissues covering the brain and spinal cord, and inside the cerebrospinal fluid, forming leptomeningeal metastases [9, 10]. As the cancer cells co-opt the brain vasculature [11] and proliferate, the BBB develops into the blood-tumor barrier (BTB) [12, 13]. Due to the complexity of the metastatic cascade and the singularity of the brain microenvironment, in vitro models are inadequate and limiting. Progress in understanding the brain metastatic process depends on the development of relevant animal models, mirroring the clinical observations and recapitulating the metastatic cascade in its dynamic milieus.