Abstract
In the United States, more than 40% of cancer patients develop brain metastasis. The median survival for untreated patients is 1 to 2 months, which may be extended to 6 months with conventional radiotherapy and chemotherapy. The growth and survival of metastasis depend on the interaction of tumor cells with host factors in the organ microenvironment. Brain metastases are surrounded and infiltrated by activated astrocytes and are highly resistant to chemotherapy. We report here that coculture of human breast cancer cells or lung cancer cells with murine astrocytes (but not murine fibroblasts) led to the up-regulation of survival genes, including GSTA5, BCL2L1, and TWIST1, in the tumor cells. The degree of up-regulation directly correlated with increased resistance to all tested chemotherapeutic agents. We further show that the up-regulation of the survival genes and consequent resistance are dependent on the direct contact between the astrocytes and tumor cells through gap junctions and are therefore transient. Knocking down these genes with specific small interfering RNA rendered the tumor cells sensitive to chemotherapeutic agents. These data clearly demonstrate that host cells in the microenvironment influence the biologic behavior of tumor cells and reinforce the contention that the organ microenvironment must be taken into consideration during the design of therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / genetics
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Adenocarcinoma / pathology
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis
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Astrocytes / metabolism*
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Astrocytes / pathology
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Biomarkers, Tumor / genetics*
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Biomarkers, Tumor / metabolism
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Blotting, Western
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Brain Neoplasms / drug therapy
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Brain Neoplasms / genetics*
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Brain Neoplasms / secondary
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics*
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Breast Neoplasms / pathology
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Cell Proliferation
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Cells, Cultured
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Drug Resistance, Neoplasm / genetics*
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Fibroblasts / drug effects
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Fibroblasts / pathology
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Gene Expression Profiling
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Glutathione Transferase / antagonists & inhibitors
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Glutathione Transferase / genetics
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Glutathione Transferase / metabolism
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Humans
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics*
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Lung Neoplasms / pathology
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Mice
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Mice, Nude
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Oligonucleotide Array Sequence Analysis
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RNA, Messenger / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Twist-Related Protein 1 / antagonists & inhibitors
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Twist-Related Protein 1 / genetics
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Twist-Related Protein 1 / metabolism
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Up-Regulation
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bcl-X Protein / antagonists & inhibitors
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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Antineoplastic Agents
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BCL2L1 protein, human
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Biomarkers, Tumor
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Isoenzymes
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Nuclear Proteins
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RNA, Messenger
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TWIST1 protein, human
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Twist-Related Protein 1
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bcl-X Protein
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Glutathione Transferase
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glutathione S-transferase alpha