Stroma-derived matrix metalloproteinase (MMP)-2 promotes membrane type 1-MMP-dependent tumor growth in mice.
Matrix metalloproteinase-2 (MMP-2) is a stroma-derived MMP belonging to the type IV collagenase family. It is believed to mediate tumor cell behavior by degrading deposits of type IV collagen, a major component of the basement membrane. The membrane type 1-MMP (MT1-MMP) is a highly potent activator of MMP-2 and is expressed in many tumor and stromal cells. However, the roles played by stromal MMP-2 in tumor progression in vivo remain poorly understood. We established a colon epithelial cell line from an Mt1-mmp(-/-) mouse strain and transfected these cells with an inducible expression system for MT1-MMP (MT1rev cells). Following s.c. implantation into Mmp-2(+/+) mice and induction of MT1-MMP expression, MT1rev cells grew rapidly, whereas they grew very slowly in Mmp-2(-/-) mice, even in the presence of MT1-MMP. This MT1-MMP-dependent tumor growth of MT1rev cells was enhanced in Mmp-2(-/-) mice as long as MMP-2 was supplied via transfection or coimplantation of MMP-2-positive fibroblasts. MT1rev cells cultured in vitro in a three-dimensional collagen gel matrix also required the MT1-MMP/MMP-2 axis for rapid proliferation. MT1rev cells deposit type IV collagen primarily at the cell-collagen interface, and these deposits seem scarce at sites of invasion and proliferation. These data suggest that cooperation between stroma-derived MMP-2 and tumor-derived MT1-MMP may play a role in tumor invasion and proliferation via remodeling of the tumor-associated basement membrane. To our knowledge, this is the first study demonstrating that MT1-MMP-dependent tumor growth in vivo requires stromal-derived MMP-2. It also suggests that MMP-2 represents a potential target for tumor therapeutics.
Taniwaki
Kaori
K
Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Fukamachi
Hiroshi
H
Komori
Kiyoshi
K
Ohtake
Yohei
Y
Nonaka
Takahiro
T
Sakamoto
Takeharu
T
Shiomi
Takayuki
T
Okada
Yasunori
Y
Itoh
Takeshi
T
Itohara
Shigeyoshi
S
Seiki
Motoharu
M
Yana
Ikuo
I
D000818:Animals; D048708:Cell Growth Processes; D024042:Collagen Type I / Q000378:metabolism; D024141:Collagen Type IV / Q000096:biosynthesis / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D014161:Transduction, Genetic; D014162:Transfection
D024042:Collagen Type I; D024141:Collagen Type IV; C507096:Mmp14 protein, mouse; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14