In Vivo MRI imaging of single metastatic cells

Basic Sciences

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Abstract

Brain metastasis occurs in 25% of cancer patients, and 50% of brain tumors are of metastatic origin. Molecular mechanisms responsible for the development of brain metastasis are poorly understood, mainly due to the lack of relevant animal models. We have developed one of the first approaches to accurately detect dormant tumor cells and the development of brain metastasis from a single cell. We describe an efficient xenograft model of brain metastasis initiated from hematogenously delivered single cells. The model is based upon DU145 human prostate cancer cells that were originally isolated from a brain metastasis. Although the parental cells are non-metastatic in mouse models, activation of the RasV12G37 effector signaling pathway leads to the formation of highly vascularized brain metastasis. We couple this model with an iron oxide micronparticle-enhanced MRI detection of single cells. This approach allows us to investigate the three possible fates of cancer cells following their arrival in the brain: cell death, the establishment of dormant solitary cells/small pre-angiogenic metastasis, or the development of large vascularized metastasis. Thus, this model enables us to longitudinally monitor the growth of brain metastasis from a single cell in living mice. Experimental and clinical evidence suggest that metastasis is an inefficient process, but the quantification of metastatic efficiency has been for the most part inaccessible. Using the system described above, we have determined that 50-100 tumor cells/105 cells introduced into the arterial blood arrest in the brain, and subsequently, about 5% of these cells develop into brain metastasis. This system is particularly valuable for investigating biological mechanisms that contribute to the initiation of metastases from single cells and the effect of targeted therapies on such processes. We have evaluated the effects of blocking VEGFA activity using the receptor antagonist ADZ2171, generously provided by Astrazeneca. We have observed that daily oral ADZ2171 treatment, administered two weeks after the establishment of tumor cells in the brain, resulted in significantly fewer and smaller metastasis at 5 weeks as determined by MRI-derived volumetric analyses. Ongoing studies are directed at determining the effects of ADZ2171 on metastatic efficiency and tumor dormancy of DU145(RasV12G37) cells, following their arrest in the brain.