Matrix Metalloproteinase-8 Functions as a Metastasis Suppressor through Modulation of Tumor Cell Adhesion and Invasion

Abstract

Collagenase-2 (matrix metalloproteinase-8, MMP-8) is an MMP mainly produced by neutrophils and associated with many inflammatory conditions. We have previously described that MMP-8 plays a protective role in cancer through its ability to regulate the inflammatory response induced by carcinogens. Moreover, it has been reported that experimental manipulation of the expression levels of this enzyme alters the metastatic behavior of human breast cancer cells. In this work, we have used mutant mice deficient in MMP-8 and syngenic melanoma and lung carcinoma tumor cells lines overexpressing this enzyme to further explore the putative antimetastatic potential of MMP-8. We report herein that MMP-8 prevents metastasis formation through the modulation of tumor cell adhesion and invasion. Thus, tumor cells overexpressing MMP-8 have an increased adhesion to extracellular matrix proteins, whereas their invasive ability through Matrigel is substantially reduced when compared with control cells. Analysis of MMP-8 in breast cancer patients revealed that the expression of this metalloproteinase by breast tumors correlates with a lower incidence of lymph node metastasis and confers good prognosis to these patients. On this basis, we propose that MMP-8 is a tumor protective factor, which also has the ability to reduce the metastatic potential of malignant cells in both mice and human.

Microarray-based Transcriptional and Epigenetic Profiling of Matrix Metalloproteinases, Collagens, and Related Genes in Cancer

“…According to the results of others (41,42), wildtype MMP-8 is a tumor protective factor. MMP-8 has the ability to inhibit melanoma progression and to reduce the metastatic potential of breast and lung cancer cells in both mice and humans.…”

The Contribution of Matrix Metalloproteinase-8 Promoter Polymorphism to Oral Cancer Susceptibility

“…Thirdly, the rs11225395 C-799T single-nucleotide polymorphism (SNP) at the MMP8 promoter region may affect the expression levels of MMP-8 and associate with early-stage disease (28). Fourthly, higher MMP8 mRNA levels in primary breast cancers are associated with reduced lymph node metastasis and with improved relapse-free and overall survival in nodenegative patients (29).…”

The Association of MMP-8 Genotypes with Pterygium

“…From the viewpoint of a genomic study, some positive epidemiological findings reported that genotypes of promoter region of other MMPs such as MMP-1 and MMP-9, may serve as promising markers for the prediction of lung cancer susceptibility and prognosis (29)(30)(31). From the molecular viewpoint, MMP-8 might increase cell adhesion by rearrangement of cytoskeleton actin, thus decreasing cell invasion (32). However, there were few epidemiological studies investigating the role of MMP-8 polymorphisms in the susceptibility of cancers (33).…”