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Updated: Jun 26, 2026
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
Increased aggressiveness of human prostate PC-3 tumor cells expressing cell surface localized membrane type-1 matrix
Xing Wang1, Michael J Wilson, Joel W Slaton
1Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.
Abstract:
Membrane type-1 matrix metalloproteinase (MT1-MMP) is a multidomain transmembrane endopeptidase with a major role in physiological and pathological processes through proteolysis of extracellular matrix and other pericellular proteins. We examined cell surface function of MT1-MMP in PC-3 human prostate tumor cells selected for metastasis in nude mice (PC-3-LN4), or transfected with the full-length wild-type (WT) MT1-MMP or with the mutant form lacking the cytoplasmic tail (Delta C-MT1-MMP). Enhanced cell surface MT1-MMP was determined by fluorescence-activated cell sorting analysis and evidenced mechanistically by increased activation of proMMP-2 and invasion into type-I collagen gels. PC-3 cells overexpressing MT1-MMP grew faster than mock-transfected control cells subcutaneously in nude mice. MT1-MMP localized in caveolae, as judged by immunofluorescence microscopy and sucrose-gradient, detergent-resistant cell fractionation. Delta C-MT1-MMP was strongly associated with caveolae, whereas the WT form was present in both caveolae and noncaveolae fractions. The role of plasma membrane MT1-MMP was supported by localization of MT1-MMP by immunofluorescence microscopy at the cell surface of tumor cells in primary prostate cancers. Increased plasma membrane localization of MT1-MMP, either in caveolae or in other lipid raft structures, is a mechanism to localize this proteinase in contact with extracellular matrix and other pericellular proteins, the cleavage of which can facilitate prostate cancer cell invasion and metastasis.
Insights
Membrane type-1 matrix metalloproteinase (MT1-MMP) enhances prostate cancer cell metastasis by increasing its presence on the cell surface. This localization, particularly in caveolae, facilitates extracellular matrix degradation, promoting tumor invasion.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Membrane type-1 matrix metalloproteinase (MT1-MMP) is crucial for extracellular matrix remodeling.
- MT1-MMP's role in prostate cancer metastasis requires further elucidation.
- Understanding MT1-MMP cell surface localization is key to its function.
Purpose of the Study:
- To investigate the cell surface function and localization of MT1-MMP in prostate cancer cells.
- To determine the impact of MT1-MMP expression levels and specific domains on tumor cell behavior.
- To explore the association of MT1-MMP with membrane microdomains like caveolae.
Main Methods:
- Utilized PC-3 human prostate tumor cell lines with varying MT1-MMP expression (metastatic, WT, and cytoplasmic tail deletion mutant).
- Employed fluorescence-activated cell sorting (FACS) to quantify cell surface MT1-MMP.
- Performed in vitro invasion assays using type-I collagen gels and in vivo subcutaneous tumor growth studies in nude mice.
- Investigated MT1-MMP localization using immunofluorescence microscopy and sucrose-gradient, detergent-resistant cell fractionation.
Main Results:
- Enhanced cell surface MT1-MMP correlated with increased proMMP-2 activation and enhanced invasion.
- PC-3 cells overexpressing MT1-MMP exhibited accelerated subcutaneous tumor growth.
- MT1-MMP was found to localize within caveolae, a specific type of cell membrane invagination.
- The cytoplasmic tail deletion mutant (Delta C-MT1-MMP) showed strong caveolae association, while WT MT1-MMP was found in both caveolae and non-caveolae fractions.
- MT1-MMP was observed on the surface of tumor cells in primary prostate cancers.
Conclusions:
- Increased plasma membrane localization of MT1-MMP, especially within caveolae, is a significant mechanism driving prostate cancer cell invasion and metastasis.
- MT1-MMP's interaction with lipid raft structures like caveolae facilitates its access to extracellular matrix substrates.
- Targeting MT1-MMP cell surface function and localization may offer therapeutic strategies for prostate cancer.
