Preclinical Solid Tumor Models to Study Novel Therapeutics in Brain Metastases

Abstract

Metastases are the most common malignancy of the adult central nervous system and are becoming an increasingly troubling problem in oncology largely due to the lack of successful therapeutic options. The limited selection of treatments is a result of the currently poor understanding of the biological mechanisms of metastatic development, which in turn is difficult to achieve because of limited preclinical models that can accurately represent the clinical progression of metastasis. Described in this article are in vitro and in vivo model systems that are used to enhance the understanding of metastasis and to identify new therapies for the treatment of brain metastasis. © 2021 Wiley Periodicals LLC.

Breast Cancer Brain Metastases: Implementation and Characterization of a Mouse Model Relying on Malignant Cells Inoculation in the Carotid Artery

“…Interestingly, the intracarotid injection of the murine mammary carcinoma 4T1 cell line, which is an aggressive, highly tumorigenic and invasive TN tumour model, promotes spontaneous metastases development in a pattern that is analogous to human mammary cancer [ 15 ]. Additionally, as opposed to other models whose growth and progression are not akin to human BC [ 15 , 28 ], 4T1 cells’ intracarotid injection produces a smaller variation of experimental results [ 18 ] and allows for the use of immunocompetent mice, since both the cells and host are from the same species [ 16 ]. Being previously applied in other studies [ 25 , 27 , 29 ], this model requires exceptional microsurgical skills to successfully direct BCCs to the brain, particularly the hippocampus, comprising a suitable strategy to study BCBM development [ 25 , 29 ].…”

“…Ectopic inoculation may rely on different injection routes, such as tail vein, intracardiac or intracarotid [ 11 , 14 ]. The majority of metastatic tumour models rely on intravenous injection to deliver tumour cells [ 16 ]. Even though this injection route presents a very high survival rate and does not require great microsurgical skills, the intravenous injection in the tail vein facilitates the lodging of cells in peripheral organs such as the lungs, as they are the first encountered organ with a considerable capillary bed [ 17 ].…”

“…This may lead to death by large numbers of lung metastases before the BCBM are developed in these models [ 18 ]. Another ectopic model consists of the intracardiac injection, which is useful to determine tumour cell predisposition for specific secondary environments [ 16 ]. However, it presents disadvantages, including the formation of tumours within the heart and the direction of the tumour cell inoculum to sites other than the brain, adding to a decreased reproducibility resulting from the blind nature of the inoculation and a fairly high degree of procedural mortality [ 19 ].…”

“…Although in vivo models have been put into place to effectively deliver cells into the brain [ 23 ] and promote preferential BM formation [ 16 , 20 ], due to the nature of certain procedures, these models may lead to unfortunate outcomes prior to BM development. Therefore, the intracarotid injection represents a preferential highway to the brain, allowing cancer cells’ efficient delivery to this site.…”

Preclinical models to understand the biology and to discover new targets in brain metastases

“…Several methods exist to establish murine models of brain metastases. Indeed, cancer cells can be injected directly into the brain or in the systemic blood flow via notably intracardiac injection [6]. This latter mimics metastatic cells that escape from the primary tumor site to invade another organ via the circulation.…”