The Tissue Microenvironment as an Epigenetic Tumor Modifier

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 transformation (1 ,2 ). Once tumors have formed, their behavior is often erratic, so that determining 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 responsiveness are also just as difficult to predict (6 –8 ). This behavioral variability despite similarity in tumor phenotype demonstrates that cancer is a complex disease that is likely regulated by multiple pathways.