The progression of prostate cancer from intraepithelial neoplasia to metastatic disease involves the accumulation of metastasis-promoting genes and inactivation of metastasis-suppressing genes. We have focused on the discovery of such molecules and have discovered a novel collagen, collagen XXIII that is upregulated in highly metastatic tumor cells. We have shown that collagen XXIII can exist as an intact molecule anchored within the cell surface via its transmembrane domain or as a soluble form generated by cleavage of the ectodomain form the cell surface via furin protease activity. At present, no function is known for either the anchored or cleaved forms of the collagen XXIII molecule, yet it is upregulated in many mid and high-grade human prostate cancers. The goal of this proposal is to characterize this new transmembrane collagen in terms of its expression and its function, and to investigate its role in normal development as well as its potential as a biomarker in prostate cancer. We will determine the distribution of collagen XXIII in normal and tumor tissue through the use of tissue microarrays and immunoblotting. Having found a collagen XXIII homolog in zebrafish, we will use this model to investigate the role of collagen XXIII in vertebrate development. Functional characterization will be achieved by manipulating expression levels in prostate cancer cells using transfection and retroviral overexpression of normal and mutant forms of the protein, complemented by RNAi gene silencing of collagen XXIII in prostate cancer cells. We will analyze the effects of altered collagen XXIII expression on cell adhesion and migration. In vivo studies will assess the role of collagen XXIII in tumor progression and metastasis. The effect of the cleaved purified collagen XXIII protein on both prostate cancer and endothelial cell adhesion and migration will also be determined. Preliminary data indicates collagen XXIII expression is upregulated in human prostate cancer tissue, suggesting a potential role as a biomarker. We will further investigate this possibility by immunostaining of prostate cancer tissue sections and prostate cancer tissue microarrays. Correlation with patient data will enable us to determine whether collagen XXIII has use as a diagnostic or predictive marker in prostate cancer.
|Banyard, Jacqueline; Bao, Lere; Hofer, Matthias D et al. (2007) Collagen XXIII expression is associated with prostate cancer recurrence and distant metastases. Clin Cancer Res 13:2634-42|