Collagenase specificity in chondrosarcoma metastasis

Abstract

The treatment of some mesenchymal malignancies has made significant gains over the past few decades with the development of effective systemic therapies. In contrast, the treatment of chondrosarcoma has been limited to surgical resection, with the most significant prognostic indicators being surgical margins and histologic grade. We have reported that MMP-1/TIMP-1 gene expression serves to prognosticate for tumor recurrence in this group of patients. This led to the hypothesis that collagenase activity facilitates cell egression from the cartilaginous matrix. In the current study we examine the specificity of collagenase gene expression in archival human chondrosarcoma samples using semi-quantitative PCR. Messenger RNA was affinity extracted and subject to reverse transcription. The subsequent cDNA was amplified using novel primers and quantitated by densitometry. Ratios of gene expression were constructed and compared to diseasefree survival. The data demonstrate that the significance of the MMP-1/TIMP-1 ratio as a predictor of recurrence is confirmed with a larger number of patients. Neutrophil collagenase or MMP-8 was observed in only 5 of 29 samples. Collagenase-3 or MMP-13 was observed in all samples but the level did not correlate with disease-free survival. Since the collagenases have similar activity for fibrillar collagens and cleave the peptide in the same location, post-transcriptional regulatory mechanisms may account for the observed specificity. The determination of the MMP-1/TIMP-1 gene expression ratio not only serves to identify those patients at risk for recurrence but may also serve as a novel therapeutic avenue as an adjunct to surgical resection. Correspondence

IL-6 Increases MMP-13 Expression and Motility in Human Chondrosarcoma Cells

“…In human chondrosarcoma cells, MMPs have been found to correlate with malignancy grade and metastasis (40). MMP-13 expression has been detected in several pathological conditions that are characterized by the destruction of normal collagen tissue architecture (41).…”

Altered Metastatic Behavior of Human Breast Cancer Cells after Experimental Manipulation of Matrix Metalloproteinase 8 Gene Expression

“…Therefore, in addition to the differential expression of MMP-8 in these tumor cell lines, activation of the procollagenase could be an important regulatory step in its inhibitory effect on metastasis. With the exception of two publications reporting the collagenase as a potential tumor marker in patients with head and neck cancer (39,40) and one showing its expression in several melanoma cell lines (14), most of the papers describing MMP expression in different types of cancers failed to observe any correlation between MMP-8 and invasion or metastasis (41)(42)(43)(44)(45)(46). In breast cancer, Duffy et al (47) did not find any relationship, but we have described previously that down-regulation of the enzyme in NM2C5-ASM8 breast cancer cells in vitro by gene transduction experiments significantly increased their ability to invade through Matrigel-coated membranes (3).…”

RNAi mediated MMP-1 silencing inhibits human chondrosarcoma invasion

“…Chondrosarcoma (CS) is the second most common malignancy of bone [2,26,27]. The malignancy demonstrates local invasion, dedifferentiation, and metastasis.…”

“…The malignancy demonstrates local invasion, dedifferentiation, and metastasis. We have shown a marked prognostic significance for recurrence in the patients expressing high levels of matrix metalloproteinases-1 (MMP-1) [2,26] and believe that this enzyme facilitates cellular egress from the tumor matrix [27]. One mechanism by which MMP-1 may promote tumor recurrence is by degrading the extracellular matrix (ECM) [ 181.…”