The Role of EMMPRIN in Tumor Angiogenesis and Metastasis
Abstract
The cell surface glycoprotein, EMMPRIN, enriched on the surface of tumor cells, stimulates production f several MMPs by stromal cells and by the tumor cells themselves, implying that EMMPRIN is an important regulator of MMP production during tumorigenesis in vivo, making it a potentially crucial component of tumor progression. We examined whether increased expression of EMMPRIN in weakly-malignant MDA-MB-436 and MCF-7 mammary carcinoma cells and in non-malignant MCFl0A mammary epithelial cells and MDCK canine kidney epithelial cells induces anchorage independent-growth and invasion, hallmark characteristics of the malignant phenotype. Using a soft agar assay to assess anchorage-independent growth, increased expression of EMMPRIN stimulated 10-fold and 5-fold increases respectively in the number of colonies formed by MDA-MB-436 and MCF-7 cells. When assessed by invasion of reconstituted basement membranes, we found that EMMPRlN enhanced invasiveness 2 to 9-forld in MDA-MB-436, MCF-7, MCFl0A and MDCK cells. Next, we examined changes in MMP production. Increased expression of EMMPRIN in MDA-MB-436, MCF-7 and MCF 10A cells yielded a 2-fold increase in MMP-2 assayed by gelatin zymography. By Western analysis we saw a 2-fold increase in MTl-MMP, an enzyme involved in the activation of MMP-2 and in tumor cell invasion. Hyaluronan (HA), a component of tumor cell pericellular matrix has also been shown to promote tumor progression. Using a competitive ELISA-like method, we found that increase expression of EMMPHN in MDA-M13A36 and MDCK cells gave rise to HA levels 2-fold greater than controls. Using HA oligomers to compete with endogenous HA polymer, we reversed EMMPRIN-enhanced colony formation of MDA-MB436 and MCF- 7 cells to near control levels. These data imply that EMMPRIN promotes tumor progression, most likely through stimulation of HA and MMPs. Therefore,antagonizing EMMPRIN may be a useful therapeutic avenue towards slowing tumor progression.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2002
- Accession Number
- ADA405286
Entities
People
- Bryan Toole
- Erica Marieb
Organizations
- Tufts University