The CMBS studies the molecular mechanisms required to control growth, induce differentiation and suppress tumorigenicity in pediatric neuroectodermal tumors. Retinoic acid (RA) induced differentiation of Neuroblastoma tumors continues to be our paradigm for studies that define signal transduction pathways that mediate these processes. Delineation of these pathways will not only enable a more efficacious clinical utilization of retinoids and their cogeners but has the possibility to identify novel molecules with therapeutic potential for the treatment of neuroectodermal tumors.

Trk Gene Expression and Function in Neuroblastoma: Trks and their ligands are survival and differentiation factors for neural cells. In NB, Trks serve as tumor markers: Good prognosis tumors express TrkA while most poor prognosis tumors express BDNF and TrkB. We first identified that neuroblastomas expressed TrkB from our finding that although cell lines express little TrkA or TrkB, retinoids induces TrkB in vitro. We have studied the functional consequences of activation of Trk signal transduction paths in a NB cell line from a poor prognosis patient that expresses TrkA or TrkB by gene transfection or selective stimulation. Activation of the BDNF-TrkB path stimulates cell survival, induces neurite extension, alters chemosensitivity and increases cell migration (invasion). In contrast, activation of the NGF-TrkA path decreases cell growth, invasiveness and tumorigenicity. Collaborative studies are in progress to determine intracellular signaling molecules that may account for the different functional consequences of Trk activation in NB cells. Our studies indicate that Trks not only serve as tumor markers but also impact on the biology of the tumor cell. If mechanisms can be identified that increase TrkA and decrease TrkB expression in NB cells then it may be possible to alter the biologic behavior of the tumor cells in vivo and this may have clinical applicability.

Mechanisms of Trk Gene Regulation:To effectively manipulate the level of Trk mRNA and ultimately protein in a cell, molecular mechanisms regulating gene transcription need to be defined. Since there have been no studies delineating Trk gene regulation even in animal models, we have cloned the human TrkB and TrkA promoters and are in the process of cloning the TrkC promoter. The functional and biochemical characterization of the TrkB gene promoter and its regulation by RA identified a novel RA inducible transcription unit involving an INR element and a 3' Hormone responsive element.

RA induced growth control: TGFB-TGBR:The finding that 1nM RA induces TrkB and differentiation of NB cells without altering cell proliferation functionally separated signals stimulating differentiation from those controlling cell growth. Continuing studies exploring the mechanism of RA induced growth arrest have focused on the TGFB signaling path. In NB cell lines that are G1 growth arrested by RA, we find a 40-fold increase in TGFB1 and TGFRI, RII and RIII expression. Cell lines resistant to RA induced growth inhibition constitutively express this signal transduction path and RA decreases expression of ligand and receptors. Current collaborative studies are characterizing TGFBR structure and differences in signal transduction. Most RA resistant cells express IGF2 and the crosstalk between these paths is also under study. Cell cycle gene analysis has demonstrated that RA induces a decrease in cell cycle kinase activity that is mediated by specific upregulation of cell cycle inhibitors.

Last Updated: July 26, 2006

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