De novo synthesis and deposition of species-specific collagen IV at the epithelial-matrix interface is induced by species-specific diffusible factors and is associated with an invasive phenotype. Neoplastic oral epithelium was reconstructed by growing for 10 days DOK cells on top of human fibroblast-containing matrix (A), simple collagen gel (B, F), mouse fibroblast-containing matrix (C, D, H), or sandwich models with a bottom layer of human fibroblast-containing matrix and an intermediate layer of simple collagen gel (E), or of mouse fibroblast-containing matrix (G). Conditioned medium from human fibroblasts in monolayer (D) or from parallel organotypic co-cultures of DOK on human fibroblast-containing matrices (F, H) were added at day 3 of co-culture. Immunohistochemical staining for human collagen IV is shown. Scale bar, 50 μm.