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Dissertation
Thrombospondin-1 promotes tumor cell invasion by up-regulating matrix metalloproteinase-9 expression
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Jun 1999
DOI:
https://doi.org/10.17918/00010004
Abstract
Significant efforts have been made to understand the molecular and cellular mechanisms involved in tumor cell invasion. Matrix metalloproteinases (MMPs) represent a family of zinc containing enzymes which degrade extracellular matrix components, allowing cells to traverse connective tissue efficiently during tumor cell invasion. Although matrix metalloproteinase-9 (MMP-9) has been shown to play an important role in tumor metastasis, the mechanism of MMP-9 activation is unknown. We hypothesize that thrombospondin-1 (TSP-1), an adhesive glycoprotein found in malignant tumor tissue, up-regulates MMP-9 expression and production in tumor cells thereby permitting tumor cell invasion of collagen. In the following studies, we showed that TSP-1 promotes tumor cell adhesion and invasion. We demonstrate that TSP-1 promotes in vitro tumor cell invasion in three different lines of human breast cancer cells with no effect on benign breast tumor cells. Furthermore, antibodies against TSP-1 and antibodies against a TSP-1 receptor inhibited tumor cell invasion in vitro. In addition, mice inoculated with breast cancer cells in the peritoneal cavity were treated with antibodies against a TSP-1 receptor. No micrometastases developed in the treatment groups. These results suggest that anti-TSP-1 receptor antibody inhibited breast tumor colony development by blocking in vivo adherence, and possibly, invasion. In our final series of experiments, we demonstrated by gelatin zymography and Western blot analysis that TSP-1 up-regulates MMP-9 production. Furthermore, TSP-1 up-regulated MMP-9 expression as demonstrated by mRNA analysis. Antibodies against MMP-9 similarly inhibited TSP-1 stimulated breast cancer cell invasion of collagen in our in vitro model. We conclude that TSP-1, through the up-regulation of MMP-9 expression, production and activation, promotes tumor cell invasion of collagen. We speculate that TSP-1 may play an important role in tumor cell invasion of the basement membrane. Stromal TSP-1, found in higher concentrations adjacent to tumor cells or cancer tissue may stimulate MMP-9 production by the tumor cells or adjacent fibroblasts necessary for tumor cell invasion. Future studies need to be conducted to determine the mechanism of how TSP-1 up-regulates MMP-9 production and the intricate cell-cell and cell-matrix interaction during metastasis.
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Details
- Title
- Thrombospondin-1 promotes tumor cell invasion by up-regulating matrix metalloproteinase-9 expression
- Creators
- Thomas Nien-Tsu Wang
- Contributors
- George P. Tuszynski (Advisor) - Drexel University, Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Awarding Institution
- Medical College of Pennsylvania and Hahnemann University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania and Hahnemann University; Philadelphia, Pennsylvania
- Number of pages
- xii, 87 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Medicine (1993-1996, 1998-2002); Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021888850804721