A common nerve protein elevated in aggressive neuroblastomas

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WASHINGTON – A protein produced by nerve cells appears to be elevated in the blood of those with an aggressive form of neuroblastoma. The finding, published online October 12 in the American Journal of Pathology, could potentially lead to a prognostic test for the disease or be used to monitor its progress.

Neuroblastoma is a pediatric cancer with varying types, ranging from spontaneously regressing to untreatable fatal tumors. Consequently, treatment strategies vary significantly between patients, encompassing different approaches including observation alone or intensive chemo- and radiotherapy.

"Given the severe late effects of anti-cancer treatment administered to infants and children, proper disease stratification is of utmost importance for neuroblastoma patients," explains Joanna Kitlinska, PhD, associate professor in the department of biochemistry and molecular & cellular biology at Georgetown University Medical Center.

Because of their neuronal origin, neuroblastomas synthesize and release neuropeptide Y (NPY), a small protein normally secreted from mature nerves. In previous research, Kitlinska and her colleagues have shown that NPY, acting via its Y2 and Y5 receptors (Y2R and Y5R), is crucial for maintaining neuroblastoma growth and protecting the tumors from chemotherapy.

"To confirm the clinical relevance of our earlier work and assess NPY and its receptors as potential prognostic factors, we performed clinical study on tissue samples and serum from 87 neuroblastoma patients," Kitlinska explains.

"We have found that NPY is released from aggressive neuroblastoma tumors into the blood, which results in its elevated serum concentrations. These high systemic levels of NPY are associated with several adverse prognostic factors for neuroblastoma and worse survival of neuroblastoma patients. "

She adds that high NPY release is a strong marker of metastatic disease, while the Y5R is present preferentially in invasive neuroblastoma cells. Also, patients with elevated NPY at diagnosis were more likely to have a disease relapse in the future.

"These results support the previously described crucial role for NPY in neuroblastoma biology, and suggest its contribution to the disease dissemination and resistance to therapy. Thus, our study validates the NPY system as a potential therapeutic target and potential prognostic marker for neuroblastoma," she says.

"In contrast to complex genetic analyses currently utilized to assess risk of the disease, the measurement of NPY levels in blood can be converted to a readily available analytical test. Using such easily accessible clinical material may also allow for minimally invasive longitudinal monitoring of the disease progression," Kitlinska explains.

"If confirmed by further prospective studies, this finding may have a significant impact on the clinical management of patients with neuroblastoma," she concludes.

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In addition to Kitlinska, authors include Chris Albanese, Susana Galli, Chao Yang, Jessica Tsuei, Jason Tilan, Emily Trinh, Sung-Hyeok Hong, Olga C. Rodriguez, Hongkun Wang and Yi-Chien Lee of Georgetown; Arlene Naranjo and Collin Van Ryn from the University of Florida Children's Oncology Group; and Ewa Izycka-Swieszewska of Medical University of Gda?sk, Poland.

Kitlinska and her co-authors report having no personal financial interests related to the study.

Samples of neuroblastic tumors were obtained from Children's Oncology Group, which also provided statistical support for the study (Naranjo and Van Ryn). The association of high NPY and Y5R expression with metastatic phenotype of the tumor cells was confirmed in an animal model of neuroblastoma, in collaboration with the Georgetown Lombardi Comprehensive Cancer Center Preclinical Imaging Research Laboratory (Albanese and Rodriguez).

The study was supported by grants from the National Institutes of Health (UL1TR000101 1RO1CA123211, 1R03CA178809, 1R01CA197964, 1R21CA198698, U10CA180899 and P30-CA051008.)

About Georgetown University Medical Center Georgetown University Medical Center (GUMC) is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC's mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis — or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award from the National Institutes of Health. Connect with GUMC on Facebook (Facebook.com/GUMCUpdate), Twitter (@gumedcenter) and Instagram (@gumedcenter).

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Karen Teber
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