Fibroblast-derived MT1-MMP promotes tumor progression in vitro and in vivo.
BACKGROUND
Identification of fibroblast derived factors in tumor progression has the potential to provide novel molecular targets for modulating tumor cell growth and metastasis. Multiple matrix metalloproteases (MMPs) are expressed by both mesenchymal and epithelial cells within head and neck squamous cell carcinomas (HNSCCs), but the relative importance of these enzymes and the cell source is the subject of controversy.


METHODS
The invasive potential of HNSCC tumor cells were assessed in vitro atop type I collagen gels in coculture with wild-type (WT), MMP-2 null, MMP-9 null or MT1-MMP null fibroblasts. A floor of mouth mouse model of HNSCC was used to assess in vivo growth after co-injection of FaDu tumor cells with MMP null fibroblasts.


RESULTS
Here we report changes in tumor phenotype when FaDu HNSCCs cells are cocultured with WT, MMP-2 null, MMP-9 null or MT1-MMP null fibroblasts in vitro and in vivo. WT, MMP-2 null and MMP-9 null fibroblasts, but not MT1-MMP null fibroblasts, spontaneously invaded into type I collagen gels. WT fibroblasts stimulated FaDu tumor cell invasion in coculture. This invasive phenotype was unaffected by combination with MMP-9 null fibroblasts, reduced with MMP-2 null fibroblasts (50%) and abrogated in MT1-MMP null fibroblasts. Co-injection of FaDu tumor cells with fibroblasts in an orthotopic oral cavity SCID mouse model demonstrated a reduction of tumor volume using MMP-9 and MMP-2 null fibroblasts (48% and 49%, respectively) compared to WT fibroblasts. Consistent with in vitro studies, MT1-MMP null fibroblasts when co-injected with FaDu cells resulted in a 90% reduction in tumor volume compared to FaDu cells injected with WT fibroblasts.


CONCLUSIONS
These data suggest a role for fibroblast-derived MMP-2 and MT1-MMP in HNSCC tumor invasion in vitro and tumor growth in vivo.
Zhang
Wenyue
W
Department of Surgery, Division of Otolaryngology - Head and Neck Surgery University of Alabama at Birmingham, Birmingham, AL, USA. Wenyue.Zhang@ccc.uab.edu
Matrisian
Lynn M
LM
Holmbeck
Kenn
K
Vick
Catherine C
CC
Rosenthal
Eben L
EL
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D018920:Coculture Techniques; D018450:Disease Progression; D005347:Fibroblasts / Q000201:enzymology* / Q000502:physiology; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D008297:Male; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000502:physiology*; D053504:Matrix Metalloproteinases, Membrane-Associated; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009361:Neoplasm Invasiveness
C507096:Mmp14 protein, mouse; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14