Intravascular survival and proliferation determine brain metastasis formation


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W Shawn Carbonel, Olaf Ansorge, Ruth Muschel

University of Oxford, UK

Abstract

Introduction

The “seed and soil” hypothesis is thought to underlie organ-specific metastasis via microenvironmental cues. Brain metastases represent the most common malignancy of the central nervous system (CNS) and are universally fatal. The specific mechanisms of malignant neurotropism remain unresolved. Here we sought to determine the dominant mechanisms for brain-specific metastasis.

Method

Several syngeneic and xenograft experimental murine models of brain metastasis were utilized in this study. Tissues were analyzed with routine histopathology or with ex vivo/in vivo confocal/multiphoton microscopy.

Results

We determined that non-metastatic and even primary tumour cells could colonize the brain when injected directly into the parenchyma. This suggests brain entry is the limiting factor for CNS metastasis formation. Indeed, active extravasation by diapedesis into the brain was not observed after intracardiac injection of tumour cells likely due to the impenetrability of the blood-brain barrier (BBB). Instead, arrested cells which could survive and proliferate entered the CNS passively through mechanical disruption of the vessel wall as a consequence of intravascular colony formation. This mechanism was further verified using the MDA-MB-231 line and its so-called “brain seeking” subclone, MDA231BR.

Conclusion

The BBB exerts positive selection pressure for tumour cells capable of intravascular growth thereby determining brain metastasis formation. Thus, a reexamination of our understanding of the seed and soil concept in the context of metastasis initiation may be warranted. Clinically, the prolonged sequestration of malignant cells in the vessel lumen has immediate implications for treatment of cancer patients at risk for CNS metastasis.

Introduction

The “seed and soil” hypothesis is thought to underlie organ-specific metastasis via microenvironmental cues. Brain metastases represent the most common malignancy of the central nervous system (CNS) and are universally fatal. The specific mechanisms of malignant neurotropism remain unresolved. Here we sought to determine the dominant mechanisms for brain-specific metastasis.

Method

Several syngeneic and xenograft experimental murine models of brain metastasis were utilized in this study. Tissues were analyzed with routine histopathology or with ex vivo/in vivo confocal/multiphoton microscopy.

Results

We determined that non-metastatic and even primary tumour cells could colonize the brain when injected directly into the parenchyma. This suggests brain entry is the limiting factor for CNS metastasis formation. Indeed, active extravasation by diapedesis into the brain was not observed after intracardiac injection of tumour cells likely due to the impenetrability of the blood-brain barrier (BBB). Instead, arrested cells which could survive and proliferate entered the CNS passively through mechanical disruption of the vessel wall as a consequence of intravascular colony formation. This mechanism was further verified using the MDA-MB-231 line and its so-called “brain seeking” subclone, MDA231BR.

Conclusion

The BBB exerts positive selection pressure for tumour cells capable of intravascular growth thereby determining brain metastasis formation. Thus, a reexamination of our understanding of the seed and soil concept in the context of metastasis initiation may be warranted. Clinically, the prolonged sequestration of malignant cells in the vessel lumen has immediate implications for treatment of cancer patients at risk for CNS metastasis.

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