Delineating the mechanism(s) of BDNF/TrkB mediated proliferation in Neuroblastoma

Delineating the mechanism(s) of BDNF/TrkB mediated proliferation in Neuroblastoma Timothy Christopher Graham, B.S. Supervisory Professor: Patrick Zweidler-McKay, MD/PhD Neuroblastoma is the most common extra-cranial solid tumor in children, arising from neural crest precursor cells. The neurotrophin receptors (TrkA/B/C) have been implicated as important prognostic markers, linking the biology of the tumor to patient outcome. High expression of TrkA and TrkC receptors have been linked to favorable biological features and high patient survival, while TrkB is expressed in unfavorable, aggressive tumors. Several studies suggest that high levels and activation of TrkB by its ligand brain-derived neurotrophic factor (BDNF) stimulates tumor cell survival, proliferation, and chemoresistance. However, little is known about the molecular mechanisms that regulate proliferation. The TrkB signaling pathway in neuroblastoma cells has been difficult to evaluate due to the loss of TrkB expression when the cells are used in vitro. Here we determined the role of proximal signaling pathways downstream of TrkB on neuroblastoma proliferation. By analyzing a panel of neuroblastoma cell lines, we found that the SMS-KCN cells express detectable levels of protein and mRNA levels of TrkB as analyzed by western, RT-PCR, and surface expression by flow cytometry. By the addition of exogenous human recombinant BDNF, we showed that activation of TrkB is important in the proliferation of the cells and can be repressed by inhibiting TrkB kinase function. By BDNF stimulation and use of specific kinase inhibitors, the common pathways involving PLCg, PI3K/AKT, and MAPK were initially investigated in addition to PI3K/MTOR and FYN pathways. We demonstrate for the first time that Fyn plays a critical role in TrkB mediated proliferation in neuroblastoma. Constitutively active and over-expressed Fyn reduced neuroblastoma proliferation, as measured by PCNA expression. Knockdown of Fyn by shRNA was shown to cooperate with activated TrkB for an enhanced proliferative response. Although TrkB activation has been implicated in the proliferation of neuroblastoma cells, little is known about its effects on cell cycle regulation. Protein levels of pRB, CDK2, CDK4, CDC25A, cyclin D1, and cyclin E were analyzed following BDNF stimulation. We found that BDNF mediated activation of TrkB induces multiple common proximal signaling pathways including the anti-proliferative Fyn pathway and drives cell cycle machinery to enhance the proliferation of neuroblastoma cells.

Exploring the Benefits of a Parent Partner Mentoring Program in Child Welfare

Parent partner mentoring programs are an innovative strategy for child welfare agencies to engage families in case planning and service delivery. These programs recruit and train parents who have been involved in the system and have successfully resolved identified child abuse or neglect issues to work with families with current open cases in the child welfare system. Parent partner mentors can provide social and emotional support, advocacy, and practical advice for navigating this challenging system. Insofar as parent partners share similar experiences, and cultural and socioeconomic characteristics of families, they may be more successful in engaging families and building trusting supportive relationships. The current study presents qualitative data from interviews and case studies of families who were matched with a parent partner in a large county in a Midwestern state. Interviews with families, parent partner mentors, child welfare agency staff, and community partners and providers suggest that parent partner programs may be just as beneficial for parent partner mentors as they are for families being mentored. These programs can build professional skills, help improve self-esteem, provide an avenue for social support, and may potentially prevent recidivism. Parent Partner programs also provide a mechanism for amplifying family voice at all levels of the agency.

All Adults Once Were Children

Issue Editor, Robert Block's, point of view and summary of the articles in New Morbidities 2.0