The concept of dynamic reciprocity in which the cell secretes a matrix and is in turn influenced by that matrix is a thought to be a fundamental principle to neoplastic transformation and metastasis. The current proposal is based on this concept and the following three lines of evidence: (1) we have demonstrated that interstitial collagenase expression is an independent prognostic indicator in human chondrosarcoma; (2) we have also demonstrated that tenascin-C expression, synthesis, and matrix incorporation are distinctly different in chondrosarcoma tissue compared to articular chondrocytes; and (3) other investigators have observed that tenascin-C, particularly the large splice variant, upregulates interstitial collagenase expression in fibrosarcoma cells. This proposal seeks to unify these observations with the hypothesis that: tenascin-C splice variant expression facilitates chondrosarcoma invasion by stimulating integrin-mediated up-regulation of MMP-1. The broad long-term objectives of this proposal are to further understand the metastatic behavior of chondrosarcoma cells and the dynamic roles played by components of the extracellular matrix in inducing the proteolytic environment necessary for tissue invasion and cell egress.
The Specific Aims are: (1) to test the hypothesis that tenascin-C stimulates MMP1 expression and invasive potential in human chondrosarcoma, and (2) to test the hypothesis that the tenascin-C effects on chondrosarcoma invasiveness are mediated via an integrin pathway. 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 through a further understanding of the cellular activities that contribute to the metastatic cascade. 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.
| Galoian, Karine A; Garamszegi, Nandor; Garamszegi, Susanna P et al. (2007) Molecular mechanism of tenascin-C action on matrix metalloproteinase-1 invasive potential. Exp Biol Med (Maywood) 232:515-22 |
| Jiang, Xiaoling; Dutton, Charyl M; Qi, Wen ning et al. (2003) Inhibition of MMP-1 expression by antisense RNA decreases invasiveness of human chondrosarcoma. J Orthop Res 21:1063-70 |
| Lee, Jin Woo; Hee Kim, Yun; Boong Park, Hee et al. (2003) The C-terminal domain of focal adhesion kinase reduces the tumor cell invasiveness in chondrosarcoma cell lines. J Orthop Res 21:1071-80 |
