Improved Tumor Models by Functional Genomic Tissue Engineering

Cancer is not a single cell disease: tumors comprise two distinct but interdependent compartments,neoplastic tumor cells and an interposed supporting stroma (e.g. connective tissue, blood vessels). All tumors require stroma for nutritional support and was te product removal and a strong correlative link exists between tumor-stroma function and clinical outcome, emphasized by recent successful therapeutic strategies that target tumor blood vessels. The cellular heterogeneity of tumors is however a confoundi ng element to the development of animal models of human cancer. Standard models either lack the complex tissue architecture of human cancer and do not accurately predict therapeutic efficacy or are not amenable to genetic manipulation limiting the ability to test specific hypotheses. Hence, there is a significant need to develop innovative animal tumor models that are reflective of in situ human tumors yet where individual components can be manipulated. Tissue engineering has evolved to regenerate native human tissue architecture by combining of cells, biomaterials, and biologically active molecules. Tissue engineering techniques employ nanotechnology principles, in particular the use of biocompatible nanophase materials whose surfaces exhibit novel physi cal and chemical properties that allow efficient cell growth. We will apply these principles to develop a novel mouse model of human tumorigenesis, using human carcinoma and microvascular cells grown in three-dimensional biopolymer matrices. The ex vivo o rigin of implant cells provides an opportunity for functional genomic manipulation using retroviral vector transduction systems. In particular, regulatable RNA interference systems allow the in vivo silencing of a specific gene in implanted cells providin g novel insight into physiopathological function. Importantly, this functional genomic manipulation serves to mimic subsequent therapeutic treatments facilitating the validation of novel therapeutic avenues.