Neuroblastoma (NB) is a cancer of the sympathetic nervous system that arises from neural crest cells (Walton et. al 2004). NB accounts for approximately 9% of pediatric cancers with about 700 new cases reported each year in the US (Theiele, 1999). NB cell lines express a great deal of heterogeneity and frequently contain three phenotypically and biochemically distinct cell types: neuroblastic (N), substrate-adherent (S) and intermediate (I) (Walton et. al. 2004). I-type cells display the greatest malignancy, followed by N-type, while S-type cells are considered nonmalignant due to their lack of ability of anchorage-independent growth in soft agar (Walton et. al. 2004). It is suggested that the I-type cell is a neural crest stem cell from which the other two cell types may arise based on its ability to express specific enzymatic markers of both N-type and S-type cells, namely neuronal and melanocytic enzyme markers (Walton et. al. 2004). Although the cause of neuroblastoma remains unclear, many attempts toward effective treatments are currently being pursued. Agents that induce apoptosis, which destroy aberrant cells and thereby inhibit tumor progression, and induce cellular differentiation, are current theories behind treatment. One line of cancer treatment involves the administration of retinoids. While the details behind the mechanism of retinoids remain elusive, they have shown to modulate cellular differentiation and apoptosis (Sidell et. al. 1983).
Figure 1-Detection of an alternatively spliced transcript. DCX was expressed in only N-type and I-type of the KCN83n and BE(2)-C respectively. DCX expression was upregulated after RA treatment and down regulated after BUdR treatment in the I-type BE(2)-C cell line.
Figure 2- CASP-1 expression in only BE(2)-C S-type cells. CASP-1 expression was only detected after treatment with BUdR.
Figure 3-IL-18 expression in only the S-type cell of BE(2)-C cell line. IL-18 expression was only detected after BUdR treatment.
We observed that DCX is expressed in only N-type and I-type cells. DCX expression was increased when I-type cells were induced to the neuronal phenotype. DCX expression decreased when I-type were induced toward the S-cell phenotype. These findings suggest that DCX is exclusively expressed in N-type and I-type cells and may be linked to cellular invasiveness in neuroblastoma.
We have also shown that both CASP-1 and IL-18 were only expressed in S-type cells. CASP-1 and IL-18 were also only expressed when I-type cells were induced over to the S-type phenotype by BUdR treatment. These findings demonstrate that CASP-1 and IL-18 are restricted to the non-malignant S-type cell in the cell lines studied.
Altogether, these findings merit further investigation on why CASP-1 and IL-18 are only expressed in the non-invasive S-type cells and on the correlation of DCX expression with the invasiveness and progression of this cancer.
I would like to thank Dr. Robert Ross for generously supplying the cells. I would like to thank Bo Liu for his unyielding patience and guidance throughout this project. Also I would like to give a special thanks to Leleesha Samaraweera for her advice and support.I would like to thank the support and encouragement that my classmates have given me over the course of this project. And finally, I would like to offer a sincere thank you to Dr. Berish Rubin for his guidance and making this project possible.
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