Pathogenesis and vascular integrity of breast cancer brain metastasis

Abstract

Dogma dictates that brain metastasis originate from the proliferation of extravasated tumor cells and that the blood-brain barrier (BBB) prevents the delivery of chemotherapeutic drugs to the tumors. The purpose of this study was to clarify the relationship between tumor localization and progression and the involvement of BBB function in a murine model of breast cancer brain metastasis. Green fluorescent protein expressing MDA-MB435 breast cancer cells were injected into the left ventricle of nude mice. At various time points, the entire vasculature was labeled with rhodamine-conjugated albumin. The tumors and vasculature were then imaged by laser-scanning confocal and stereo fluorescence microscopy. About 75% of the cells that reached the brain extravasated and grew perivascularly. Twenty five percent of the cells, however, proliferated within the vasculature and ultimately led to thrombosis-like infarction of the brain parenchyma. The tumorigenic ''embolus'' served as a sustained release source of tumor cells to downstream sites. Continuing intravascular tumor expansion led to disruption of the BBB and to overflow of cells that progressed along the vessels perivascularly to distant sites that regained protection of the BBB. Breast cancer brain metastases involve both extravascular and intravascular growth of tumor cells. These distinct pathways contribute to different pathological phenotypes that generate a heterogeneous BBB that facilitates or inhibits the delivery of chemotherapeutic drugs to the tumor. ' 2006 Wiley-Liss, Inc. Key words: brain metastasis; breast cancerBrain metastases are the most frequently occurring intracranial tumors, outnumbering primary brain tumors by a factor of 10, and represent the major cause of systemic cancer morbidity and mortality.1,2 Their incidence is increasing because of improved cancer therapy for systemic disease.1,3 Most patients die within a few months of diagnosis since systemic therapies are ineffective within the brain. 4 Our knowledge about how brain metastases develop has, for the most part, been extrapolated from observations of tumor growth in other tissues. This has led to the concept that brain metastasis develop after extravasation of metastatic tumor cells into the surrounding tissue 5,6 where they are protected by the blood-brain barrier (BBB) that prevents the delivery of therapeutic agents to the proliferating tumor. 7,8 Because the brain lacks lymphatic drainage, the most common mechanism of brain metastasis is by hematogenous spread through the arterial circulation. By injecting tumor cells into the arterial system to mimic hematogenous spread, we developed a unique breast cancer brain metastasis model that allows us to visualize the development of brain metastasis and monitor BBB function at high resolution. Analysis of breast cancer brain metastases revealed a complex pathogenesis and heterogeneity of BBB integrity. These findings provide a framework for better understanding the clinical presentation of breast cancer and BBB function in brain tumor m...

Pharmacologic Inhibition of MLK3 Kinase Activity Blocks the In Vitro Migratory Capacity of Breast Cancer Cells but Has No Effect on Breast Cancer Brain Metastasis in a Mouse Xenograft Model

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Capturing Changes in the Brain Microenvironment during Initial Steps of Breast Cancer Brain Metastasis

“…4T1 cells exhibited the most rapid growth in their immunocompetent hosts and produced extensive metastatic burden already after 10 days. MDA-MB-435 and brain homing MDA-MB-231/brain cells were previously reported to produce metastatic lesions in the brain when administered into the bloodstream, 28,31 but the early colonization steps have not been previously investigated. MDA-MB-435 cells are aggressively metastatic breast cancer cells that share some characteristics with melanoma, 32,33 another tumor type that frequently causes brain metastasis in patients.…”

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