Carcinomas contain a matrix metalloproteinase-resistant isoform of type I collagen exerting selective support to invasion

TY - JOUR

T1 - Carcinomas contain a matrix metalloproteinase-resistant isoform of type I collagen exerting selective support to invasion

AU - Makareeva, Elena

AU - Han, Sejin

AU - Vera, Juan Carlos

AU - Sackett, Dan L

AU - Holmbeck, Kenn

AU - Phillips, Charlotte L

AU - Visse, Robert

AU - Nagase, Hideaki

AU - Leikin, Sergey

N1 - Copyright 2010 AACR.

PY - 2010/6/1

Y1 - 2010/6/1

N2 - 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 α1(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.

AB - 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 α1(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.

KW - Animals

KW - Cell Growth Processes/physiology

KW - Cell Movement/physiology

KW - Collagen Type I/metabolism

KW - Fibroblasts/metabolism

KW - Fibrosarcoma/enzymology

KW - Humans

KW - Isoenzymes

KW - Matrix Metalloproteinases/metabolism

KW - Mice

KW - Mice, Nude

KW - Neoplasm Invasiveness

U2 - 10.1158/0008-5472.can-09-4057

DO - 10.1158/0008-5472.can-09-4057

M3 - Journal article

C2 - 20460529

SN - 0008-5472

VL - 70

SP - 4366

EP - 4374

JO - Cancer Research

JF - Cancer Research

IS - 11

ER -