Squamous cell carcinoma (SCC) accounts for approximately 96% or all oral cancers. SCC has a tendency to be locally invasive as well as to metastasize widely; the five-year survival rates are less than 50%. Tumor invasion and metastasis is a complex process involving multiple interactions between tumor cells and the extracellular matrix (ECM). Matrix components such as laminin and fibronectin have been studied extensively regarding their roles in tumor progression. However, other ECM components also play a role. In particular, we and others have observed that tenascin-C (TN-C) expression is upregulated in oral cancer. In this project we propose to investigate how the expression of TN-C and its receptor, alpha vbeta6, are regulated during oral SCC progression. TN-C is a large oligomeric glycoprotein that is transiently expressed during development and is involved in morphogenetic movements, tissue patterning, and tissue repair. TN-C contains multiple domains, both adhesive and anti- adhesive, that interact with cells, fibronectin, and other ECM molecules. There are different isoforms of the molecule, which result from alternative mRNA splicing. One receptor for TN-C is alphavbeta6. Several lines of evidence suggest that the alphav integrin subfamily is important for tumor growth, invasion, and metastasis. First, recent work has demonstrated that antagonists to alphavbeta3 inhibit tumor angiogenesis. Second, alphavbeta3 has been shown to be upregulated in vertically invasive melanoma. Third, alphavbeta6 was recently found to be neo-expressed in oral SCC, while absent from normal oral mucosa. We hypothesize that TN-C and alphavbeta6 play a role in the progression of oral cancer by acting as co-stimulatory modulators of tumor cell motility, invasion, or gene expression.
The specific aims of this proposal are; (1) To assess the expression of tenascin-C and its receptor, alphavbeta6, as potential markers for invasive oral SCC. (2) To determine whether alterations in the expression of alphavbeta6 will modify the invasive behavior of oral SCC cells. (3) To evaluate different stages of tumor invasion, using an animal model, for differential expression of TN-C and alphavbeta6. These studies should enrich our understanding of how less- well-characterized matrix proteins like tenascin-C and the alphavbeta6 receptor contribute to oral cancer progression. Being able to identify those oral SCC tumors likely to be most invasive will help in selecting the most appropriate treatment modality and may improve the currently grim prognosis of patients with these tumors.
| Dang, Dongmin; Yang, Yongjian; Li, Xiaowu et al. (2004) Matrix metalloproteinases and TGFbeta1 modulate oral tumor cell matrix. Biochem Biophys Res Commun 316:937-42 |
| Yang, Yongjian; Dang, Dongmin; Atakilit, Amha et al. (2003) Specific alpha v integrin receptors modulate K1735 murine melanoma cell behavior. Biochem Biophys Res Commun 308:814-9 |
| Li, Xiaowu; Yang, Yongjian; Hu, Yongmei et al. (2003) Alphavbeta6-Fyn signaling promotes oral cancer progression. J Biol Chem 278:41646-53 |
| Li, X; Regezi, J; Ross, F P et al. (2001) Integrin alphavbeta3 mediates K1735 murine melanoma cell motility in vivo and in vitro. J Cell Sci 114:2665-72 |
| Xue, H; Atakilit, A; Zhu, W et al. (2001) Role of the alpha(v)beta6 integrin in human oral squamous cell carcinoma growth in vivo and in vitro. Biochem Biophys Res Commun 288:610-8 |
| Bordador, L C; Li, X; Toole, B et al. (2000) Expression of emmprin by oral squamous cell carcinoma. Int J Cancer 85:347-52 |
| Liu, H; Chen, B; Zardi, L et al. (1998) Soluble fibronectin promotes migration of oral squamous-cell carcinoma cells. Int J Cancer 78:261-7 |
| Ramos, D M; Chen, B; Regezi, J et al. (1998) Tenascin-C matrix assembly in oral squamous cell carcinoma. Int J Cancer 75:680-7 |
| Li, X; Chen, B; Blystone, S D et al. (1998) Differential expression of alphav integrins in K1735 melanoma cells. Invasion Metastasis 18:1-14 |
| Ramos, D M; Chen, B L; Boylen, K et al. (1997) Stromal fibroblasts influence oral squamous-cell carcinoma cell interactions with tenascin-C. Int J Cancer 72:369-76 |
