The biology of brain metastases-translation to new therapies

Abstract

Brain metastases are a serious obstacle in the treatment of patients with solid tumors and contribute to the morbidity and mortality of these cancers. It is speculated that the frequency of brain metastasis is increasing for several reasons, including improved systemic therapy and survival, and detection of metastases in asymptomatic patients. The lack of preclinical models that recapitulate the clinical setting and the exclusion of patients with brain metastases from most clinical trials have slowed progress. Molecular factors contributing to brain metastases are being elucidated, such as genes involved in cell adhesion, extravasation, metabolism, and cellular signaling. Furthermore, the role of the unique brain microenvironment is beginning to be explored. Although the presence and function of the blood-brain barrier in metastatic tumors is still poorly understood, it is likely that some tumor cells are protected from therapeutics by the blood-tumor barrier, creating a sanctuary site. This Review discusses what is known about the biology of brain metastases, what preclinical models are available to study the disease, and which novel therapeutic strategies are being studied in patients.

Figure 1

Steps in the formation of hematogenous metastasis to the brain. Once tumor cells shed from primary tumors arrive in brain vasculature, a | they arrest in the capillary bed primarily owing to size restriction, and b | subsequently extravasate across the BBB and enter the brain parenchyma. Three genes mediate cancer cell trans-BBB migration: HBEGF, COX2, and ST6GALNAC5. Also, activation of integrins, such as α_vβ₃^, and β₁, is suggested to control tumor-cell arrest and adhesion to the vasculature. c | Metastasizing tumor cells (seeds) may bring their own host cells (soil) in metastasis. After extravasation, tumor cells either d | grow along pre-existing blood vessels (perivascular growth), or e | recruit new blood vessels (angiogenesis) to obtain sufficient nutrients to support their proliferation. Abbreviation: BBB, blood–brain barrier.

Figure 2

Imaging brain metastases in preclinical models and patients. a | Chronic cranial window (yellow dotted line) for intravital brain imaging (courtesy of Lance Munn). Intravital imaging through cranial window showing b | normal brain (bright field image) and c | metastatic brain tumors (green fluorescent protein-expressing breast cancer cells). d | T2-weighted MRI image of a metastatic brain tumor (arrow) after direct implantation of breast cancer cells (courtesy of Christian Farrar). Scale bar: 1 mm. e | Whole-body bioluminescence imaging of brain metastasis using Gaussia luciferase (Chung, E. et al. unpublished data). Optical frequency domain imaging of murine mammary carcinoma grown in f | breast (primary) and g | brain (metastasis). Scale bars: 0.5 mm. h | T1-weighted post-contrast MRI showing multiple enhancing mass lesions consistent with brain metastases (courtesy of A. F. Eichler). i | 99mTc-folate image of human brain metastasis (arrow) from a primary breast cancer (Courtesy of Phillip S. Low and Endocyte Inc.). Permission for parts f and g obtained from Nature Publishing Group © Vakoc, B. J. et al. Nat. Med. 15, 1219–1223 (2009).

Figure 3

Approaches to enhance drug delivery to the brain. Schematic diagram of the BBB with an enhanced illustration of the brain capillary endothelial cell. The main drug efflux transporters of brain capillary endothelial cells include MRPs, PgP, and ABCG2. All of these transport proteins have been targeted for pharmacological inhibition. a | probenecid, sulfinpyrazone and MK-571; b | verapamil, cyclosporin A, quinidine, valspodar, elacridar, biricodar, zosuquidar, and tariquidar; and c | GF120918, elacridar, and fumitremorgin C. Tight junctions normally restrict penetration of water-soluble compounds across the BBB, but they can be disrupted by mechanical and pharmacological methods, via d | ultrasound and e | bradykinin analogs, respectively. f | Receptor-mediated transcytosis of transferrin or insulin has been used to increase transport of drugs across the BBB, and g | cationization (that is, antibodies) can increase uptake of molecules by absorptive transcytosis. Abbreviations: ABCG2, breast cancer resistant protein; BBB, blood–brain barrier; MRPs, multidrug resistant proteins; PgP, P-glycoprotein.