Carcinomas contain a matrix metalloproteinase-resistant isoform of type I collagen exerting selective support to invasion.
Collagen fibers affect metastasis in two opposing ways, by supporting invasive cells but also by generating a barrier to invasion. We hypothesized that these functions might be performed by different isoforms of type I collagen. Carcinomas are reported to contain alpha1(I)(3) homotrimers, a type I collagen isoform normally not present in healthy tissues, but the role of the homotrimers in cancer pathophysiology is unclear. In this study, we found that these homotrimers were resistant to all collagenolytic matrix metalloproteinases (MMP). MMPs are massively produced and used by cancer cells and cancer-associated fibroblasts for degrading stromal collagen at the leading edge of tumor invasion. The MMP-resistant homotrimers were produced by all invasive cancer cell lines tested, both in culture and in tumor xenografts, but they were not produced by cancer-associated fibroblasts, thereby comprising a specialized fraction of tumor collagen. We observed the homotrimer fibers to be resistant to pericellular degradation, even upon stimulation of the cells with proinflammatory cytokines. Furthermore, we confirmed an enhanced proliferation and migration of invasive cancer cells on the surface of homotrimeric versus normal (heterotrimeric) type I collagen fibers. In summary, our findings suggest that invasive cancer cells may use homotrimers for building MMP-resistant invasion paths, supporting local proliferation and directed migration of the cells whereas surrounding normal stromal collagens are cleaved. Because the homotrimers are universally secreted by cancer cells and deposited as insoluble, MMP-resistant fibers, they offer an appealing target for cancer diagnostics and therapy.
Makareeva
Elena
E
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Building 9, Room1N-111, Bethesda, MD 20892, USA.
Han
Sejin
S
Vera
Juan Carlos
JC
Sackett
Dan L
DL
Holmbeck
Kenn
K
Phillips
Charlotte L
CL
Visse
Robert
R
Nagase
Hideaki
H
Leikin
Sergey
S
D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D024042:Collagen Type I / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005354:Fibrosarcoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007527:Isoenzymes; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness
D024042:Collagen Type I; D007527:Isoenzymes; D020782:Matrix Metalloproteinases
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