Neuroblastoma is the most common extracranial solid tumor in the pediatric population, accounting for greater than 15% of all cancer-related deaths in infants and children. Despite recent advances in combined modality treatment, the overall mortality for all stages of tumors remains significant at 50%. As a neural crest-derived tumor, neuroblastoma can produce various gastrointestinal (GI) hormones which can affect tumor progression. We have determined that expressions of gastrin-releasing peptide (GRP) and its receptor (GRPR) are increased in aggressive, undifferentiated neuroblastomas and that GRP, acting through GRPR, acts as an autocrine/paracrine growth factor. We have also found that GRPR expression regulates anchorage-independence in neuroblastoma cells in vitro and that GRPR stimulation increases the growth and angiogenesis of neuroblastoma xenografts in vivo. Moreover, we have made exciting innovative progress with in vivo silencing techniques, where we found that GRPR knockdown effectively blocked tumor development and metastasis. Additionally, our studies have identified the phosphatidylinositol 3-kinase (PI3K) pathway as an emergent signaling mechanism for GRPR-mediated tumor progression. Furthermore, PI3K pathway components are regulated by GRPR overexpression and silencing. Based on our preliminary findings, the central hypothesis of this proposal is that GRP/GRPR expression critically regulates neuroblastoma tumorigenesis through the activation of the crucial PI3K signal transduction pathway. To examine this hypothesis, we have planned experiments with the following Specific Aims: 1) to determine the cellular function of GRP/GRPR mechanisms on essential tumorigenic processes in human neuroblastomas, 2) to discern the exact role of PI3K/Akt pathway during GRP/GRPR-mediated cell signaling in human neuroblastomas, 3) to ascertain the effects of targeting GRP/GRPR expression on in vivo tumor growth and metastatic potential of neuroblastomas. A better understanding of the cellular mechanisms and signaling pathways regulating neuroblastoma tumorigenesis could potentially lead to the development of novel therapeutic agents as adjuvant treatment for this devastating disease. This information is clinically significant because GRPR may be an important novel therapeutic target for high-risk neuroblastomas. Furthermore, these studies will also enhance our knowledge of hormone- regulated cancer pathogenesis by elucidation of the complex signaling pathways involved.

Public Health Relevance

In spite of advances in therapy, patients with neuroblastoma still have a staggering mortality rate of 50%. This highly malignant childhood tumor is derived from cells of neural crest origin and as such, its tumor behavior is significantly affected by neuroendocrine peptides. Our project is clinically significant because it will aid in the understanding of the hormonal regulation of neuroblastoma, which could lead to a breakthrough in the treatment of this devastating disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SBIB-E (03))
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Serrano, Jose
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Vanderbilt University Medical Center
Schools of Medicine
United States
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Romain, Carmelle V; Paul, Pritha; Lee, Sora et al. (2014) Targeting aurora kinase A inhibits hypoxia-mediated neuroblastoma cell tumorigenesis. Anticancer Res 34:2269-74
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Qiao, Jingbo; Lee, Sora; Paul, Pritha et al. (2013) Akt2 regulates metastatic potential in neuroblastoma. PLoS One 8:e56382
Lee, Sora; Qiao, Jingbo; Paul, Pritha et al. (2013) Integrin *1 is critical for gastrin-releasing peptide receptor-mediated neuroblastoma cell migration and invasion. Surgery 154:369-75
Kim, Kwang Woon; Paul, Pritha; Qiao, Jingbo et al. (2013) Autophagy mediates paracrine regulation of vascular endothelial cells. Lab Invest 93:639-45
Qiao, Lan; Paul, Pritha; Lee, Sora et al. (2013) Differential regulation of cyclin-dependent kinase inhibitors in neuroblastoma cells. Biochem Biophys Res Commun 435:295-9

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