Abstract
Abstract Neuroblastoma is a pediatric solid tumor that can be stratified into stroma-rich and stroma-poor histological subgroups. The stromal compartment of neuroblastoma is composed mostly of Schwann cells and they play critical roles in the differentiation, survival and angiogenic responses of tumor cells. In certain neuroblastoma cell lines, the coexistence of neuroblastic N-type and substrate-adherent S-type is frequently observed. One such cell line, SK-N-SH, harbors a F1174L oncogenic mutation in the Anaplastic Lymphoma Kinase (ALK) gene. Treatment of SK-N-SH with an ALK chemical inhibitor, TAE684, resulted in the outgrowth of S-type cells that expressed the Schwann cell marker, S100α6. Nucleotide sequencing analysis of these TAE684-resistant (TR) sublines revealed the presence of the ALK F1174L mutation suggesting their tumor origin, although ALK protein was not detected. Consistent with these findings, TR cells displayed ∼9-fold higher IC50 values than N-type cells. Also, unlike N-type cells, TR cells have readily detectable phosphorylated STAT3 but weaker phosphorylated AKT. Under co-culture conditions, TR cells conferred survival to N-type cells against the apoptotic effect of TAE684. Co-cultivation also greatly enhanced the overall phosphorylation of STAT3 and its transcriptional activity in N-type cells. Finally, conditioned medium from TR clones enhanced cell viability of N-type cells and this effect was Phosphatidylinositol 3-Kinase-dependent. Taken together, these results demonstrate the ability of tumor-derived S-type cells in protecting N-type cells against the apoptotic effect of an ALK kinase inhibitor through upregulating pro-survival signaling. This project was supported by MACC funds, Advancing a Healthier Wisconsin, Wisconsin Breast Cancer Showhouse (O.W.), NIH CA133669 (H.G. and A.M.C.) and the Children's Research Institutes of the Children's Hospital of Wisconsin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1528. doi:1538-7445.AM2012-1528
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