Chondrosarcoma is the most common primary skeletal malignancy occurring at approximately twice the incidence of either Ewing's sarcoma or osteogenic sarcoma. Unlike the latter malignancies that have seen significant increases in long-term survival with effective adjuvant therapies aimed at treating metastatic disease, chondrosarcoma remains resistant to existing adjuvant therapies and survival has not improved over the previous several decades. We have determined that metalloproteinase (MMP) gene expression serves as a highly significant prognostic indicator for recurrence and metastasis in patients with chondrosarcoma. The underlying hypothesis for this proposal is that fibrillar collagenase activity produced by the chondrosarcoma cells facilitates cell dissociation from the primary tumor and initiates invasive and metastatic properties of this neoplasm. We will evaluate this premise through the following hypotheses: (1) chondrosarcoma interstitial collagenase gene expression correlates with clinical recurrence and in vitro invasiveness, both of which can be predicted by the presence of a 2G MMP-1 promoter polymorphism that produces an Ets binding site; (2) cell dissociation from tumor tissue is mediated by interstitial collagenase activity; and (3) MMP-1 in the reactive zone of the tumor is synthesized by chondrosarcoma cells rather than by the surrounding stromal cells. Currently, the treatment of patients with chondrosarcoma is hampered by the absence of an effective adjuvant therapy. The current proposal represents a unique opportunity to improve the care of these patients both in a diagnostic and a therapeutic capacity. These clinical advances can only come through a more comprehensive understanding of the cellular activities that contribute to the metastatic cascade. I have provided preliminary evidence that MMP-1 gene expression correlates with clinical outcome in chondrosarcoma, a malignancy in urgent need of an effective adjuvant therapy. The Mayo Clinic has the volume of patients necessary to support this study (greater than 50/yr), and I have established the techniques to permit the quantitation of MMP in surgical specimens. I have established methods of modulation of MMP translation as a potential adjuvant gene therapy in these patients. The application of this approach to patients will require the proposed studies as a means of verification and extension of previous observations. The results of the proposed studies are likely to have clinical implications for identifying patients at increased risk for metastasis and for the development of novel therapeutic approaches to chondrosarcoma. It is also plausible that lessons learned in the proposed studies of chondrosarcoma can be applicable to a wider spectrum of neoplastic processes.
|Jawad, Muhammad Umar; Garamszegi, Nandor; Garamszegi, Susanna P et al. (2010) Matrix metalloproteinase 1: role in sarcoma biology. PLoS One 5:e14250|
|Garamszegi, Nandor; Garamszegi, Susanna P; Shehadeh, Lina A et al. (2009) Extracellular matrix-induced gene expression in human breast cancer cells. Mol Cancer Res 7:319-29|
|Yuan, Jun; Dutton, Charyl M; Scully, Sean P (2005) RNAi mediated MMP-1 silencing inhibits human chondrosarcoma invasion. J Orthop Res 23:1467-74|
|Fong, Yi-Chin; Dutton, Charyl M; Cha, Stephen S et al. (2004) Absence of a correlation between the presence of a single nucleotide polymorphism in the matrix metalloproteinase 1 promoter and outcome in patients of chondrosarcoma. Clin Cancer Res 10:7329-34|