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Degradation of the extracellular
matrix is part of the pathological process associated with many diseases:
e.g., joint
destruction in arthritis, invasion and metastasis in cancer, bone dissolution
in periodontitis, and plaque rupture in athererosclerosis. Most of this connective tissue
degradation is accomplished by a family of enzymes called the Matrix Metalloproteinases, or MMPs, a
family of enzymes that, collectively, degrade most matrix components. A sub-family of MMPs
is the interstitial collagenases, enzymes that
specifically degrade the stromal collagens, types
I, II and III. Since these collagens
are the most abundant protein in our body, the collagenases
have a major role in connective tissue modeling and remodeling. Of the three interstitial collagenases,
MMP-1 (collagenase-1) is the most ubiquitously expressed. It is produced by a wide variety of normal
cells, e.g., stromal fibroblasts, macrophages,
endothelial cells, and epithelial cells, as well as by numerous tumors,
suggesting a broad-based role for this collagenase
in tumor biology. Normally, expression
of MMP-1 by most cells is low, but is readily induced by phorbol
esters, growth factors and inflammatory cytokines. In contrast, some tumors display
constitutively high levels of MMP-1 expression, even in the absence of
apparent external stimuli. A genetic variation in the MMP-1 promoter can influence
the level of MMP-1 transcription, and hence, the potential of this gene to
mediate connective tissue degradation.
This variation is a single nucleotide polymorphism (SNP) located at
–1607 bp, where an insertion of a guanine
base (G) creates the sequence, 5'-GGAT-3', the core binding site for members
of the Ets family of transcription factors. We have demonstrated that the 2G DNA
displays heightened MMP-1 transcription in both tumor cells and in normal
fibroblasts, and the levels of MMP-1 expression may result from the presence
of the 2G allele and from elevated expression of the transcription factors
that bind to this site. This SNP in the MMP-1 promoter is not a rare mutation or
genetic variation found in a few tumor cells. Genotyping of 100 normal individuals
indicated that the distribution of this SNP in the normal population is
approximately: 30% = 1G homozygous; 30% = 2G homozygous; 40% = 1G/2G
heterozygous. However, in tumor cells
cultured in vitro, the incidence of
the 2G allele rises to 62% (P = < 0.001), supporting the hypothesis that
it correlates with aggressive tumors.
This in vitro correlation
has been confirmed in vivo, where patients with ovarian
cancer had a significantly higher incidence of the 2G allele, compared to
non-cancer controls, and expressed higher levels of MMP-1 protein. The hypothesis is, therefore, that heightened MMP-1
expression results from the presence of (a) the 2G allele and (b) the
appropriate transcription factors that bind to this site. In the absence of these factors, MMP-1
expression from the 2G allele is not necessarily increased compared to the 1G
allele. The precise identity of the Ets family member(s) binding to this site is not known,
and it is possible that several Ets proteins can
function to drive transcription. Once
the identity of these proteins is determined, they may become a target for
therapeutic intervention to reduce MMP-1 expression in certain diseases. Given the strong link between increased MMP-1 expression
and the presence of the 2G allele, it is possible that a simple genetic
analysis of this polymorphism may provide a useful and potentially important
mechanism for predicting prognosis in certain diseases, such as cancer,
arthritis, cardiovascular disease, and periodontitis.
Inhibiting MMP-1 synthesis represents a new therapeutic approach of molecular
medicine for the 21st century. This technology is claimed in
the issued United States Patent No. 7,033,756 and the published United States
Application No. 11/408,202. We are
seeking an industrial partner interested in its commercialization. (Ref: J17) |
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«Technology Transfer Office : Sponsored Projects : Dartmouth College |
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Phone: (603) 646-3027 |
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Fax: (603) 646-3670 |
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