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Andrew M. Chan, PhD
Stromal-Derived Trophic Factors in Neuroblastoma
This application will study a novel trophic factor isolated in our laboratory from tumor-derived
stromal cells of neuroblastoma. Neuroblastoma is a childhood cancer with the highest incidence
among infants. High risk neuroblastoma are metastatic and the prognosis for patients greater than
5 year of age is poor with only 40% survival even with aggressive therapies. Development of novel
targeted therapy that can eradicate treatment resistant tumors is an area of great importance.
The existence of Schwann cells in the stromal compartment of neuroblastoma is well established.
However, their roles in neuroblastoma are not clear. Histologically, stroma-rich neuroblastoma are
low grade and well-differentiated. On the contrary, stroma-poor tumors are high-grade and have
poor prognosis. Previous studies have implicated a role for Schwann cells in the survival and
differentiation of neuroblastic tumor cells. However, the origin of these tumor-associated Schwann
cells and their roles in altering the responsiveness towards new generations of kinase inhibitors are
Using a neuroblastoma cell line, SK-N-SH, which has an admixture of both neuroblastic N-type
tumor cells and Schwann-like S-type cells, our laboratory has conclusively determined that
Schwannian stromal cells are derived from a common progenitor as the tumor cells. Also, tumorderived
Schwann cells confers survival advantage to tumor cells against a kinase inhibitor,
TAE684, which specifically blocks the Anaplastic Lymphoma Kinase (ALK) receptor signaling in the
Characterizing the conditioned medium produced by tumor-derived Schwann cells revealed the
presence of heparin-binding trophic factors that can alter the survival and growth properties of
tumor cells. Affinity purification and mass spectrometry analysis have identified secreted frizzledrelated
protein 1 (sFRP1) as a candidate tumor-specific trophic factor. sFRP1 was originally
identified as an antagonist of the Wnt signaling pathway. It acts through binding to Wnt and blocks
its assess to the surface receptors such as Frizzled.
Our major hypothesis is that sFRP1 secreted by tumor-derived Schwann cells regulates
proliferation and survival of neuroblastoma in a dose-dependent fashion. Furthermore, sFRP1
binds and inhibits Wnt ligand on the surface of neuroblastoma cells. Alternatively, sFRP1 binds to
Frizzled receptor and initiates growth or survival promoting signaling leading to tumor progression
This application aims to test (1) the expression profile of sFRP1 and Wnt in a panel of tumorderived
Schwann cells and their corresponding neuroblastoma, (2) the biological effects of sFRP1
on the proliferation and survival towards a panel of ALK inhibitors and chemotherapies, (3) the
alteration in Wnt canonical and non-canonical pathways in response to sFRP1.