Neuropeptide Y receptor Y5 as an inducible pro-survival factor in neuroblastoma: implications for tumor chemoresistance

Czarnecka, Magdalena; Trinh, Emily; Lu, Congyi; Kuan-Celarier, Anna; Galli, Susana; Hong, Sung-Hyeok; Tilan, Jason U.; Talisman, Nicholas; Iżycka-Świeszewska, Ewa; Tsuei, Jessica; Yang, Chao; Martin, Samantha; Horton, Meredith; Christian, David; Everhart, Lindsay; Maheswaran, Induja; Kitlińska, Joanna

doi:10.1038/onc.2014.253

Cited by 26 publications

(69 citation statements)

References 61 publications

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“…Moreover, the high ambient calcium concentration present during bone resorption or stiffness of the bone tissue may change tumor cell properties [36]. In the case of NPY, such an increase in its expression may be driven by brain-derived neurotrophic factor (BDNF), which is abundant in the bone environment and has been shown to induce NPY expression and release [37, 38]. In our model the local bone invasion and interaction of tumor cells with bone components is a secondary event, which provides a plausible explanation for the predominance of bone environment-independent pulmonary metastases in mice bearing TC71 xenografts.…”

Section: Discussionmentioning

confidence: 99%

High neuropeptide Y release associates with Ewing sarcoma bone dissemination -in vivomodel of site-specific metastases

et al. 2015

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Ewing sarcoma (ES) develops in bones or soft tissues of children and adolescents. The presence of bone metastases is one of the most adverse prognostic factors, yet the mechanisms governing their formation remain unclear. As a transcriptional target of EWS-FLI1, the fusion protein driving ES transformation, neuropeptide Y (NPY) is highly expressed and released from ES tumors. Hypoxia up-regulates NPY and activates its pro-metastatic functions. To test the impact of NPY on ES metastatic pattern, ES cell lines, SK-ES1 and TC71, with high and low peptide release, respectively, were used in an orthotopic xenograft model. ES cells were injected into gastrocnemius muscles of SCID/beige mice, the primary tumors excised, and mice monitored for the presence of metastases. SK-ES1 xenografts resulted in thoracic extra-osseous metastases (67%) and dissemination to bone (50%) and brain (25%), while TC71 tumors metastasized to the lungs (70%). Bone dissemination in SK-ES1 xenografts associated with increased NPY expression in bone metastases and its accumulation in bone invasion areas. The genetic silencing of NPY in SK-ES1 cells reduced bone degradation. Our study supports the role for NPY in ES bone invasion and provides new models for identifying pathways driving ES metastases to specific niches and testing anti-metastatic therapeutics.

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Section: Discussionmentioning

confidence: 99%

High neuropeptide Y release associates with Ewing sarcoma bone dissemination -in vivomodel of site-specific metastases

et al. 2015

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“…It involves in a variety of neural and molecular events and plays an important role in both brain development and synaptic plasticity (Hong et al 2011). Recently, BDNF has been reported to be associated with tumor progression in several human malignancies, such as neuroblastoma (Czarnecka et al 2014), lung cancer (Okamura et al 2012), breast cancer, and colon cancer (Yang et al 2012(Yang et al , 2013. BDNF and its receptor, TrkB, are commonly upregulated in a variety of human tumors (Guo et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Brain-derived neurotrophic factor regulates cell motility in human colon cancer

Huang¹,

Lin²,

Lin³

et al. 2015

Endocrine-Related Cancer

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Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that has been shown to affect cancer cell metastasis and migration. In the present study, we investigated the mechanisms of BDNF-induced cell migration in colon cancer cells. The migratory activities of two colon cancer cell lines, HCT116 and SW480, were found to be increased in the presence of human BDNF. Heme oxygenase-1 (HO)-1 is known to be involved in the development and progression of tumors. However, the molecular mechanisms that underlie HO-1 in the regulation of colon cancer cell migration remain unclear. Expression of HO-1 protein and mRNA increased in response to BDNF stimulation. The BDNF-induced increase in cell migration was antagonized by a HO-1 inhibitor and HO-1 siRNA. Furthermore, the expression of vascular endothelial growth factor (VEGF) also increased in response to BDNF stimulation, as did VEGF mRNA expression and transcriptional activity. The increase in BDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Moreover, transfection with HO-1 siRNA effectively reduced the increased VEGF expression induced by BDNF. The BDNF-induced cell migration was regulated by the ERK, p38, and Akt signaling pathways. Furthermore, BDNF-increased HO-1 and VEGF promoter transcriptional activity were inhibited by ERK, p38, and AKT pharmacological inhibitors and dominantnegative mutants in colon cancer cells. These results indicate that BDNF increases the migration of colon cancer cells by regulating VEGF/HO-1 activation through the ERK, p38, and PI3K/Akt signaling pathways. The results of this study may provide a relevant contribution to our understanding of the molecular mechanisms by which BDNF promotes colon cancer cell motility.

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“…under hypoxic conditions (Tab. 1) (Czarnecka et al, 2015; Kitlinska et al, 2005; Lu et al, 2010). Further studies revealed a crucial role for both pathways in different aspects of neuroblastoma biology.…”

Section: Neuroblastoma and Ewing Sarcoma As Models Of Npy-rich Tumorsmentioning

confidence: 99%

“…Moreover, treatment with Y2R antagonist resulted in an induction of apoptosis mediated by BCL-2-interacting mediator of cell death (Bim), the pathway known to be activated in response to growth factor withdrawal (Lu et al, 2010). The proliferative effect of the constitutively active NPY/Y2R axis was further enhanced in the presence of Y5R, which was expressed in some neuroblastoma cell lines in an inducible manner (Czarnecka et al, 2015; Kitlinska et al, 2005). This phenomenon is in line with known interactions between NPY receptors that have been shown to enhance cell sensitivity to the peptide and augment its effects (Gehlert et al, 2007; Movafagh et al, 2006; Pons et al, 2008).…”

Section: Npy In Regulation Of Tumor Cell Proliferationmentioning

confidence: 99%

“…We have found that in addition to its role in augmenting proliferative effects of Y2R, Y5R acts as a survival factor for neuroblastoma cells (Czarnecka et al, 2015). While often not detectable under basal cell culture conditions, Y5R is induced in pro-apoptotic conditions, including serum withdrawal, hypoxia and chemotherapy (Tab 1).…”

Section: Tumor Cell Survival and Chemoresistancementioning

confidence: 99%

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Neuropeptide Y (NPY) in tumor growth and progression: Lessons learned from pediatric oncology

Tilan

Kitlińska

2016

Neuropeptides

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Neuropeptide Y (NPY) is a sympathetic neurotransmitter with pleiotropic actions, many of which are highly relevant to tumor biology. Consequently, the peptide has been implicated as a factor regulating the growth of a variety of tumors. Among them, two pediatric malignancies with high endogenous NPY synthesis and release – neuroblastoma and Ewing sarcoma – became excellent models to investigate the role of NPY in tumor growth and progression. The stimulatory effect on tumor cell proliferation, survival and migration, as well as angiogenesis in these tumors is mediated by two NPY receptors, Y2R and Y5R, which are expressed in either a constitutive or inducible manner. Of particular importance are interactions of the NPY system with the tumor microenvironment, as hypoxic conditions commonly occurring in solid tumors strongly activate the NPY/Y2R/Y5R axis. This activation is triggered by hypoxia-induced up-regulation of Y2R/Y5R expression and stimulation of dipeptidyl peptidase IV (DPPIV), which converts NPY to a selective Y2R/Y5R agonist, NPY3-36. While previous studies focused mainly on the effects of NPY on tumor growth and vascularization, they also provided insight into the potential role of the peptide in tumor progression into a metastatic and chemoresistant phenotype. This review summarizes our current knowledge of the role of NPY in neuroblastoma and Ewing sarcoma and its interactions with the tumor microenvironment in the context of findings in other malignancies, as well as discusses future directions and potential clinical implications of these discoveries.

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Neuropeptide Y receptor Y5 as an inducible pro-survival factor in neuroblastoma: implications for tumor chemoresistance

Cited by 26 publications

References 61 publications

High neuropeptide Y release associates with Ewing sarcoma bone dissemination -in vivomodel of site-specific metastases

High neuropeptide Y release associates with Ewing sarcoma bone dissemination -in vivomodel of site-specific metastases

Brain-derived neurotrophic factor regulates cell motility in human colon cancer

Neuropeptide Y (NPY) in tumor growth and progression: Lessons learned from pediatric oncology

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