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      1. Author :
        Acuff, H. B.; Carter, K. J.; Fingleton, B.; Gorden, D. L.; Matrisian, L. M.
      2. Title :
        MMP9 from bone marrow-derived cells contributes to survival but not growth of tumor cells in the lung microenvironment
      3. Type :
        Journal Article
      4. Year :
      5. Publication :
        Cancer Research
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      11. Keywords :
        IVIS, Xenogen
      12. Abstract :
        The role of specific stromal-derived MMPs was analyzed in experimental metastasis assays in wildtype and either MMP9, MMP7, or MMP2 null mice. MMP9 null mice showed an 81% reduction in Lewis Lung Carcinoma tumor number, while MMP7 null mice showed a 42% increase in tumor number and there was no difference in tumor number in MMP2 null mice compared to wildtype controls. Similarly, in an orthotopic model of lung cancer, 50% fewer MMP9 null mice were able to establish tumors in the lung compared to control mice, although the size of the tumors was not different. The effect of MMP9 on lung tumor colonization was dependent on the expression of MMP9 from bone marrow-derived cells and is most likely contributed by neutrophils. To examine temporal effects of stromal MMP9, bioluminescence imaging from luciferase expressing human lung cancer-derived A549 cells revealed that there were fewer tumor cells in the lungs of MMP9 null mice as early as 19 hours after injection compared to control mice, with no difference in subsequent growth rates. Six hours after injection of tumor cells, MMP9 null mice showed a four-fold increase in the percent of tumor cells undergoing apoptosis compared to control mice. We conclude that MMP9 from the bone marrow contributes to the early survival and establishment of tumors in the lung and has no effect on subsequent growth. These results provide insights into the failure of MMP inhibitors in clinical trials in patients with late stage lung cancer.
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