24 The Tissue Microenvironment as an Epigenetic Tumor Modifier Meredith Unger and Valerie M. Weaver 1. Introduction The transition from normal to cancerous tissue frequently takes years to occur. Epithelial tumors in particular can exist as premalignant lesions for prolonged periods of time, and even then only a low proportion of benign tumors undergo malignant trans- formation (1,2). Once tumors have formed, their behavior is often erratic, so that deter- mining a treatment strategy based on current clinical criteria can be challenging. For example, some tumors may grow and invade aggressively, while tumors of similar grade can experience extended periods of dormancy (3–5). Tumor metastasis and drug respon- siveness are also just as difficult to predict (6–8). This behavioral variability despite sim- ilarity in tumor phenotype demonstrates that cancer is a complex disease that is likely regulated by multiple pathways. Studies in humans and animals have shown that malignant transformation occurs through a series of increasingly abnormal morphologic stages (9). These tissue mor- phologies have been histologically and behaviorally classified as benign, dysplastic, and premalignant, and they culminate with the transformation of the premalignant lesion into an invasive and often metastatic tumor (10). Extensive molecular and genetic data has shown that the progressively altered precancerous tissues harbor an increasingly per- turbed and unstable genome. This has led to the formulation of the “multihit gene model” of tumor progression. The multihit gene model maintains that tumors arise through a combination of hereditary genetic alterations and the accumulation of incre- mental and sequential somatic changes in the target genome (11–13). Central to this par- adigm is the concept that cumulative mutations, amplifications, and/or deletions occur in critical genes. These mutations release the targeted cells from their normal growth and survival constraints, and permit them to invade into the surrounding tissue and sur- vive, grow, and metastasize (14). Tumor suppressor proteins, by virtue of their critical role in cell-cycle checkpoint control and as regulators of the apoptosis/stress response, play an important role in this process. Accordingly, much effort has been extended to delineate how tumor suppressors influence the pathogenesis of cancer. From: Methods in Molecular Biology, Vol. 223: Tumor Suppressor Genes: Regulation, Function, and Medicinal Applications. Edited by: Wafik S. El-Deiry © Humana Press Inc., Totowa, NJ 315