Brain metastasis: Unique challenges and open opportunities

Abstract

The metastasis of cancer to the central nervous system (CNS) remains a devastating clinical reality, carrying an estimated survival time of less than one year in spite of recent therapeutic breakthroughs for other disease contexts. Advances in brain metastasis research are hindered by a number of factors, including its complicated nature and the difficulty of modeling metastatic cancer growth in the unique brain microenvironment. In this review, we will discuss the clinical challenge, and compare the merits and limitations of the available models for brain metastasis research. Additionally, we will specifically address current knowledge on how brain metastases take advantage of the unique brain environment to benefit their own growth. Finally, we will explore the distinctive metabolic and chemical characteristics of the brain and how these paradoxically represent barriers to establishment of brain metastasis, but also provide ample supplies for metastatic cells' growth in the brain. We envision that multi-disciplinary innovative approaches will open opportunities for the field to make breakthroughs in tackling unique challenges of brain metastasis.

Keywords: Brain metastasis; Cancer models; Central nervous system; Metabolism; Tumor-microenvironment interaction.

Figure 1

Methods of studying brain metastasis in vivo. A. Spontaneous brain metastasis assays involve injection of cancer cells into their associated site of primary tumor origin. Left: intradermal injection for study of spontaneous melanoma metastasis. Right: mammary fat pad injection for study of spontaneous breast cancer metastasis. B. Experimental brain metastasis assays by direct inoculation of cancer cells into the circulation. Left: tail vein injection of cancer cells introduces them into the general circulation, but results in inefficient brain metastasis formation as most cells are trapped in the lungs. Right: intracardiac injection of cancer cells distributes them throughout the mouse body, but dispersal can be unpredictable. Mice frequently die of metastasis to other organ sites prior to overt brain metastasis outgrowth. Experimental brain metastasis can be achieved more efficiently by serial in vivo selection of tumors formed in this way, so that cells will home more specifically to the brain in later experiments. C. Experimental brain metastasis by intracarotid arterial injection of cancer cells. This procedure limits the dissemination of cancer cells to the brain vascular bed, resulting in high experimental consistency but is technically challenging. D. Direct, stereotactic intracerebral injection. This method is the most well-controlled and reproducible way to assay cancer cell growth in the brain, as cancer cells are confined to one region of the brain. However, this assay limits the study to tumor cell outgrowth at the site of implantation, not spread and dissemination to secondary locations.

Figure 2

Brain metastatic cancer cells may exploit a number of unique features (illustrated in 1 to 4) of the brain microenvironment. 1. Brain metastatic cancer cells first need to pass the BBB in order to enter the brain. Once they extravasate, they can benefit from the BBB’s exclusion of large molecules (i.e., therapeutic antibodies) and barring the active efflux of compounds. 2. Astrocytes serve homeostatic roles in supporting neuronal function and survival, but preventing brain colonization of cancer cells by expressing FasL. Cancer cells that evade FasL-mediated killing are able to benefit from astrocytes’ pro-survival functions, rendering brain metastases chemo-resistant. 3. Microglia serve as the resident immune cells of the brain. Microglia have the potential to recognize and eliminate brain metastatic cancer cells by TNF-α and inducible nitric oxide synthase (iNOS). Successful brain metastatic cancer cells must be able to avoid microglial detection. 4. The brain environment serves to support the optimal function of neurons, promoting their survival and preventing excitotoxicity. Glutamate, the essential neurotransmitter, cannot freely exist in the brain parenchyma. Following synaptic glutamate (Glu) release, astrocytes scavenge the excess glutamate and convert it into the non-neuroactive glutamine (Gln), which is then released to be taken up by neurons. Cancer cells may use this glutamine, which exists at relatively high concentrations in the brain, as an important biomolecular building block and energy source. Neurons-gray, astrocytes-blue, microglia-green, endothelial cells-red. Figure drawn in collaboration with Chia-Chi Chang.