We are interested in the mechanisms of brain tumorigenesis during early childhood. The peak incidence of pediatric brain tumors (3.8 cases/100,000 children) occurs during the first 4 years of life. At this time, tumors arise from virtually every cellular lineage in the growing brain. The rate of brain tumors subsequently declines to a lifetime nadir during adolescence (1.5 cases/100,000) coincident with the emergence of a more adult pattern of brain tumors: one that is primarily restricted to tumors of glial origin. An incidence of 3.8 cases/100,000 is not reached again until the 5th decade of life, but the histological diversity of early brain tumors is not seen again. These observations suggest that the mechanisms of brain tumorigenesis are different early in life as compared to later in life.
The temporal relationship between the peak of pediatric brain tumors and the period of most rapid brain growth strongly suggests that early brain tumorigenesis is a consequence of normal brain development. We hypothesized that factors essential for patterning normal brain development actively stimulate oncogenesis, resulting in a peak of tumor formation that is coincident with the period of most rapid brain growth. These studies identified the chemokine CXCL12 as one candidate brain-derived factor and have supported the conclusion that CXCL12 and its receptor CXCR4 are important regulators of brain tumor growth. They further identified antagonism of CXCR4 signaling as a potent approach to brain tumor treatment. We are currently working to define the molecular basis for CXCR4 dysregulation during tumorigenesis with a focus on how mutational activation of the sonic hedgehog, EGF, PDGF and MAP kinase pathways alters CXCR4 activation and the initiation of downstream signaling. We are especially focused on the dysregulation of CXCR4-induced cAMP suppression in this process.
Among the developmental processes that patterns the brain and impacts on tumorigenesis is sexual differentiation. Brain tumors occur more frequently in males than in females including early in life when there are no differences in circulating sex hormones. We are activley investigating how sexual differentiation and especially sexual dimorphism in the regualtion of growth factor signaling, cellular proliferation and apoptosis, affect the genesis of brain tumors in girls and boys.