Low-dose aspirin delays an inflammatory tumor progression in vivo in a transgenic mouse model of neuroblastoma

Abstract

Tumor-associated inflammation is a driving force in several adult cancers and intake of low-dose aspirin has proven to reduce cancer incidence. Little is known about tumor-associated inflammation in pediatric neoplasms and no in vivo data exists on the effectiveness of low-dose aspirin on established tumors. The present study employs the transgenic TH-MYCN mouse model for neuroblastoma (NB) to evaluate inflammatory patterns paralleling tumor growth in vivo and low-dose aspirin as a therapeutic option for high-risk NB. Spontaneously arising abdominal tumors were monitored for tumor-associated inflammation ex vivo at various stages of disease and homozygous mice received daily low-dose aspirin (10mg/kg) using oral gavage or no treatment, from 4.5 to 6 weeks of age. Using flow cytometry, a transition from an adaptive immune response predominated by CD8(+) T cell in early neoplastic lesions, towards enrichment in immature cells of the innate immune system, including myeloid-derived suppressor cells, dendritic cells and tumor-associated macrophages, was detected during tumor progression. An M1 to M2 transition of tumor-associated macrophages was demonstrated, paralleled by a deterioration of dendritic cell status. Treatment with low-dose aspirin to mice homozygous for the TH-MYCN transgene significantly reduced the tumor burden (P < 0.01), the presence of tumor-associated cells of the innate immune system (P < 0.01), as well as the intratumoral expression of transforming growth factor-β, thromboxane A2 (P < 0.05) and prostaglandin D2 (P < 0.01). In conclusion, tumor-associated inflammation appears as a potential therapeutic target in NB and low-dose aspirin reduces tumor burden in the TH-MYCN transgenic mouse model of NB, hence warranting further studies on aspirin in high-risk NB.

COX/mPGES-1/PGE 2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

“…This immunosuppressive state has been shown in human tumor samples by the infiltration of M2-polarized macrophages (23) and in neuroblastoma mouse models by the infiltration of MDSCs (26,36). Our data show predominance toward M2-polarization of the tumor-infiltrating macrophages (i.e., tumor-associated macrophages) in both 11q-deleted tumors and MYCN-amplified tumors, with elevated levels of CD206 and CD163, respectively (Fig.…”

“…We previously reported the effect of anti-inflammatory drugs on tumor growth in preclinical in vivo models of neuroblastoma (26)(27)(28). We also have found high expression of the PGE 2 receptors EP1-EP4 in neuroblastoma tumor tissue as well as effects of PGE 2 on neuroblastoma cell growth in vitro (29).…”

“…Approximately 40 mg of human primary tumor tissue from 29 individuals was used in the analysis. Liquid-liquid extraction and analysis by LC-MS/MS was performed essentially as described previously (26). Nude mice were inoculated with SK-N-AS neuroblastoma cells harboring an 11q-deletion and were treated with diclofenac (250 mg/L drinking water) for nine consecutive days.…”

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

“…A transgenic murine model resembling the aggressive growth pattern of high-risk human neuroblastoma has been characterized, where the human MYCN oncogene (TH-MYCN) drives the establishment of spontaneous tumors (6,7). We and others have reported prolonged survival of these animals using novel treatments (8)(9)(10). However, once the tumors are established, it is difficult to achieve tolerable therapeutic effects, due to the known short treatment window and rapid disease progression (7,11,12).…”

Cytotoxic and cytogenetic effects of α-copaene on rat neuron and N2a neuroblastoma cell lines

“…It is the most common solid tumour responsible for 15% of all cancerrelated deaths in childhood. This tumour accounts for more than 7% of malignancies in patients fewer than 15 years of age (Stiller et al 1992;Brodeur 2003;Carlson et al 2013). NBs grow rapidly and often give rise to metastasis (Wassberg et al 1999).…”