Cancer Biology - Gene Expression and Tumor Development

During normal development, the mechanisms that regulate differentiation of cells from undifferentiated precursors play key roles in tissue/organ development and maintenance.  While dysregulation of expression of critical genes may result in embryonic death or birth defects in the developing embryo, tumor formation may be a dramatic consequence of abnormal gene expression during all stages of life.  The abnormal gene expression may be due to genetic mutation or to epigenetic phenomena.  We are currently focusing on nervous system tumors, with most of the current work being on meningiomas. 

Meningiomas comprise approximately 30% of primary central nervous system tumors in the United States, however their pathobiology is poorly understood. Over 90% of meningiomas are benign while 5% are atypical and 3-5% are malignant. Complete surgical resection is the treatment of choice for benign meningiomas. Surgical resection is often difficult since approximately one-half of benign intracranial meningiomas arise in the skull base. For skull base meningiomas the surgical complication rate can be as high as 30 to 40% even in expert hands. The female to male incidence ratio in adults is 2:1 for intracranial tumors and 10:1 for spinal tumors, while no such sex difference exists for meningiomas in children. Therefore, the female sex steroid hormones progesterone and β-estradiol are suspected factors in meningioma tumorigenesis. However, no mechanisms have been demonstrated for female sex hormones in meningioma formation or progression. We have reported evidence that a steroid responsive gene, deleted in liver cancer-1 (DLC1), may function as a tumor suppressor in meningiomas. Our microarray data indicate that a number of steroid responsive genes are differentially expressed between meningiomas and normal meninges. We also found that steroid hormones and their antagonists can alter the growth of meningioma cells and that histone deacetylase inhibitors induce a decrease of meningioma cell growth in culture. Our long-term goal is to develop strategies to prevent or slow meningioma tumor growth that can serve as alternatives or adjuncts to surgery. The central hypotheses of our current work are that meningioma tumorigenesis is driven in part by actions of female steroid hormones and that the tumorrigenesis may be mediated in part by progesterone and estrogen receptor containing chromatin-modifying complexes.