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.

• Authors: Lena-Maria Carlson, Agnes Rasmuson, Helena Idborg, Lova Segerström, Per-Johan Jakobsson, Baldur Sveinbjörnsson, Per Kogner
• Journal: Carcinogenesis (Carcinogenesis) Vol. 34 Issue 5 Pg. 1081-8 (May 2013) ISSN: 1460-2180 [Electronic] England
• PMID: 23349014 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Transforming Growth Factor beta
• Thromboxane A2
• Aspirin
• Prostaglandin D2

Topics

• Animals
• Aspirin (pharmacology)
• CD4-Positive T-Lymphocytes (drug effects, immunology, metabolism)
• CD8-Positive T-Lymphocytes (drug effects, immunology, metabolism)
• Cytokines (genetics, immunology, metabolism)
• Dendritic Cells (drug effects, immunology)
• Disease Models, Animal
• Disease Progression
• Homozygote
• Immunity, Innate (drug effects, genetics, immunology)
• Inflammation (drug therapy, genetics, immunology, pathology)
• Macrophages (drug effects, immunology, pathology)
• Mice
• Mice, Transgenic
• Neuroblastoma (drug therapy, genetics, immunology, pathology)
• Prostaglandin D2 (genetics, immunology, metabolism)
• Th2 Cells (drug effects, immunology, metabolism)
• Thromboxane A2 (genetics, immunology, metabolism)
• Transforming Growth Factor beta (genetics, immunology, metabolism)