University of Vermont COBRE (P20 RR016435)
"Center for Neuroscience Excellence"
Pilot Project 5: "Role of Transmembrane Protease, Dipeptidyl Peptidase, in Neuroblastomas"
Investigator: Umadevi Wesley, Ph.D.
Neuroblastoma (NB) is a pediatric tumor that originates from precursor cells of the sympathetic nervous system that have discontinued their normal differentiation program. The factors implicated in the differentiation program are therefore of importance in the study of the genesis of NB. About 70% of children with widespread metastatic or aggressive localized tumors have overall poor prognosis. Evidence, such as expression of genes normally expressed only during embryonic and fetal stages, suggests that the tumor is of embryonic origin. Molecular mechanisms involved in NB are not well understood. As a neuroendocrine tumor, NB expresses high levels of growth factors and peptide hormones that exert tumor promoting effects. The differentiation of precursor cells into neurons is influenced by both growth factor and the Notch signaling pathways. The role of Notch and growth factor interaction in NB remains to be determined. The cell surface protease, dipeptidyl peptidase IV (DPPIV) is a differentiating antigen that regulates activity of many neuropeptides and growth factors by proteolytic cleavage, and its expression is lost in many cancers. We have recently shown that DPPIV decreases the levels of basic fibroblast growth factor bFGF, a potent mitogen, an
anti-apoptotic, and an angiogenic inducer. Our previous work provides compelling evidence that
DPPIV functions as a tumor suppressor gene for prostate cancer, lung cancer, and melanoma (a cancer of neuroectodermal origin) by inducing differentiation and apoptosis. Interestingly, DPPIV is expressed in mammalian neurons and its expression is lost in poorly differentiated NBs. Despite these correlative observations, the role of DPPIV in NB is unknown. Our initial studies show that DPPIV is decreased in NB derived cell lines and re-expression of DPPIV leads to induction of the differentiated phenotype. These data imply an important role for DPPIV in regulating the development of NB. The goal of this proposal is to define the roles of DPPIV on malignant phenotype of NB and to identify the link, if any, to bFGF and Notch signaling that play an important role in neuronal development. Taken together, the results from these studies represent an important step towards our long term goal of establishing pathways critical for modulating differentiation program and suppression of cancerous phenotype of NB derived cells by serine proteases including DPPIV.
Hypothesis:
We hypothesize that DPPIV is a negative regulator of NB progression. We predict that loss of DPPIV results in increased bFGF levels and activation of Notch signaling that halts the differentiation program, and provides growth stimulatory signals for proliferation/survival and malignant transformation of NB cells.