Am. Delany et E. Canalis, The metastasis-associated metalloproteinase stromelysin-3 is induced by transforming growth factor-ss in osteoblasts and fibroblasts, ENDOCRINOL, 142(4), 2001, pp. 1561-1566
Bone matrix serves as a reservoir of growth factors important in growth and
tissue remodeling, and transforming growth factor-beta (TGF-beta) is abund
ant in bone matrix. Normal processes, such as remodeling, and pathological
processes. such as osteolytic metastasis, cause the release of growth facto
rs from the matrix, allowing them to influence the behavior of cells within
their microenvironment. Breast cancer metastases frequently establish them
selves in the bone compartment, often causing localized osteolysis. Stromel
ysin-3 is a matrix metalloproteinase associated with tumor metastases. Its
expression in host tissues favors the homing and survival of malignant epit
helial cells in early tumorigenesis by releasing and/or activating growth f
actors sequestered in the extracellular matrix. Osteoblasts express stromel
ysin-3, and Northern and Western blot analysis show that its messenger RNA
and protein levels are increased by TGF-beta. Nuclear run-off assays demons
trate activation of gene transcription, and experiments using transcription
inhibitors demonstrate stabilization of stromelysin-3 messenger RNA by TGF
-beta. Importantly. TGF beta induces stromelysin-3 in fibroblasts by simila
r mechanisms, indicating that it is likely to stimulate stromelysin-3 expre
ssion in breast stroma. Stimulation of stromelysin-3 expression by TGF-beta
in fibroblasts and osteoblasts could play a role in the metastasis of brea
st cancer cells and their homing and survival in bone.