Carcinomas Contain a Matrix Metalloproteinase–Resistant Isoform of Type I Collagen Exerting Selective Support to Invasion

Abstract

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. Cancer Res; 70(11); 4366-74. ©2010 AACR.

Intratumoral oxygen gradients mediate sarcoma cell invasion

“…Growing evidence suggests that ECM remodeling is critical in sarcoma migration and metastasis. In particular, proteolytic degradation and abnormal collagen deposition and modification within hypoxic tumor microenvironments have been implicated as important parameters that enhance tumor invasion and metastasis (19)(20)(21). The gelatin (Gtn)-based HI hydrogels provide matrix adhesion and degradation sites similar to those sites in the tumor microenvironment, yet are collagen-free to prevent confounding results.…”

Screening of diagnostic markers for osteosarcoma

“…Collagen fibers, as well as fibers produced by cancer-associated fibroblasts, may form an invasion barrier (28). However, MMPs are essential for maintaining the invasive phenotype and supporting migration and proliferation of cancer cells (29,30).…”

The Interface between Catalytic and Hemopexin Domains in Matrix Metalloproteinase-1 Conceals a Collagen Binding Exosite

“…We are mindful that in nondiseased adult tissue, the majority of type I collagen exists as ␣1(I) 2 ␣2(I) heterotrimers (50). Indeed, ␣1(I) 3 homotrimers only exist in significant quantities in vivo in fetal tissues (51), carcinomas (50,(52)(53)(54)(55), fibrotic tissues (56 -58), and in genetic disorders in which the ␣2(I) chain is deficient (59 -61). Thus, the homotrimeric THP used in this study is not strictly representative of the homeostatic state.…”