Journal
CANCER JOURNAL
Volume 21, Issue 4, Pages 284-293Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/PPO.0000000000000126
Keywords
Astrocytes; biologic heterogeneity; blood-brain barrier; brain microenvironment; metastasis; seed and soil; selection
Categories
Funding
- Cancer Center Support Core Grant from the National Cancer Institute, National Institutes of Health [CA16672]
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Many patients with lung cancer, breast cancer, and melanoma develop brain metastases that are resistant to conventional therapy. The median survival for untreated patients is 1 to 2 months, which may be extended to 6 months with surgery, radiotherapy, and chemotherapy. The outcome of metastasis depends on multiple interactions of unique metastatic cells with host homeostatic mechanisms which the tumor cells exploit for their survival and proliferation. The blood-brain barrier is leaky in metastases that are larger than 0.5-mm diameter because of production of vascular endothelial growth factor by metastatic cells. Brain metastases are surrounded and infiltrated by microglia and activated astrocytes. The interaction with astrocytes leads to up-regulation of multiple genes in the metastatic cells, including several survival genes that are responsible for the increased resistance of tumor cells to cytotoxic drugs. These findings substantiate the importance of the seed and soil hypothesis and that successful treatment of brain metastases must include targeting of the organ microenvironment.
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