Abstract
Breast cancer brain metastasis (BCBM) remains a major clinical problem. Approximately 10–16% of patients with breast cancer develop brain metastases (BCBM). However, no systemic therapy has gained regulatory approval for the specific treatment of BCBM and this remains an area of persistent, unmet medical need. Rapid, predictive and clinically-relevant animal models are critical to study the biology of brain metastases and to identify effective therapeutic approaches for patients with BCBM. Here, we describe a method for efficient establishment of orthotopic mouse models of patient-derived brain metastases via an improved intracarotid injection protocol that permits tumor cell growth in the unique brain microenvironment without compromising the blood-brain barrier (BBB). We demonstrate that our newly improved models of patient-derived brain metastases recapitulate the histologic, molecular, and genetic characteristics of their matched patient tumor specimens and thus represent a potentially powerful tool for pre-clinical and translational research.
Highlights
Very few cancer cells can spread to distant organs because they need to survive a series of highly selective events, termed the “metastatic cascade”[1]
Dish-cultured cancer cells are typically injected into the mouse internal carotid artery, where the cells metastasize into the brain
We found that several mice had obvious ear and/or face inflammation hours after receiving intracarotid injection of primary Breast cancer brain metastasis (BCBM) PDX tumor cells
Summary
Very few cancer cells can spread to distant organs because they need to survive a series of highly selective events, termed the “metastatic cascade”[1] Through this multi-step process, primary tumors cells acquire the ability to invade surrounding tissue, enter the bloodstream, extravasate from the bloodstream, pass through the blood-brain barrier (unique for brain metastasis), and colonize distant organs[2,3,4,5,6,7,8,9]. A number of approaches for generating murine-based breast cancer brain metastasis models currently exist. These models have a number of key technical limitations that hinders their usefulness for application towards preclinical studies. We describe a significantly improved protocol for intracarotid injection for generating orthotopic PDX models of BCBM that overcomes these latest challenges
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