ASSOCIATION BETWEEN RATIO OF MATRIX METALLOPROTEINASE-1 TO TISSUE INHIBITOR OF METALLOPROTEINASE-1 AND LOCAL RECURRENCE, METASTASIS, AND SURVIVAL IN HUMAN CHONDROSARCOMA

Chondrosarcoma, a malignant cartilage-forming mesenchymal tumor, displ ays a wide range of clinical behavior that can be difficult to predict with histological analysis. Matrix metalloproteinases contribute to t he processes of local invasion and metastasis by controlling the abili ty of a tumor to transverse tissue boundaries. The specificity of matr ix metalloproteinase-1 (interstitial collagenase) for fibrillar collag en may be central to those processes. Matrix metalloproteinase-2 facil itates invasion by degradation of such basement-membrane structures as type-IV collagen. The balance between the activity of tissue inhibito rs of metalloproteinase and the activity of matrix metalloproteinase d etermines the proteolytic activity and may, in part, determine the ove rall invasiveness and potential for metastasis. The measurement of the ratio of matrix metalloproteinase to tissue inhibitor of metalloprote inase may have prognostic value for determining whether individual cho ndrosarcomas are locally invasive or will metastasize. Furthermore, th ere may be a specific pattern of expression of matrix metalloproteinas e and tissue inhibitor of metalloproteinase in chondrosarcomas that is related to local invasion and probability of metastasis. Sixteen para ffin-embedded archival specimens of tumors were examined. Six twenty-m icrometer-thick sections were cut from each tumor, and the amounts of cDNA formed from the mRNA were determined with reverse transcription-p olymerase chain reaction with use of novel primers for matrix metallop roteinase-1, matrix metalloproteinase-2, tissue inhibitor of metallopr oteinase-1, and tissue inhibitor of metalloproteinase-2. The amounts o f cDNA for the matrix metalloproteinases and their inhibitors were det ermined by chemiluminescence and band densitometry. The ratio of the a mount of cDNA for matrix metalloproteinase-1 to that for its tissue in hibitor and the ratio of the amount of cDNA for matrix metalloproteina se-2 to that for its tissue inhibitor were calculated, and the results were compared with use of the Student t test, enabling log-rank analy sis of Kaplan-Meier survival curves. These ratios as well as the age a nd gender of the patient; the grade, size, and location of the tumor; the type of adjuvant therapy; and the operative margins were examined for significance with use of stepwise logistic-regression analysis. Th e patients who had recurrent disease hall a significantly higher (p < 0.003) ratio of matrix metalloproteinase-1 to tissue inhibitor of meta lloproteinase-1 (mean, 0.939; range, 0.647 to 1.101) than the patients who were free of disease (mean, 0.703; range, 0.629 to 0.772). Moreov er, there was a striking difference between the Kaplan-Meier survival curve associated with a high ratio (more than 0.8) and that associated with a low ratio (p = 0.0015). The mean ratio of matrix metalloprotei nase-2 to tissue inhibitor of metalloproteinase-2 was 1.814 (range, 1. 206 to 3.77) in the patients who had recurrent disease compared with 1 .473 (range, 1.073 to 2.390) in those who were free of disease; this d ifference was not found to be significant, with the numbers available. Analysis of the survival curves indicated that a worse prognosis was associated with a high ratio, but again this relationship was not foun d to be significant. Regression analysis revealed that a high ratio of matrix metalloproteinase-1 to its tissue inhibitor was a moderately s ignificant independent predictor of a poor outcome (alpha = 0.07). CLI NICAL RELEVANCE: A high ratio of matrix metalloproteinase-1 to tissue inhibitor of metalloproteinase-1 in human chondrosarcoma may be indica tive of a more invasive and aggressive tumor and a worse prognosis. Th e data presented here suggest that concentrations of matrix metallopro teinase-1, with substrate specificity for fibrillar collagens, may be important in the pathogenesis of local invasiveness and metastasis in human chondrosarcoma. The methods described in the present report may be useful for prognostically stratifying the survival of patients who have chondrosarcoma and for identifying a mechanism for the selection of adjuvant therapy in the future.