Low-dose aspirin delays an inflammatory tumor progression in vivo in a transgenic mouse model of neuroblastoma.
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.
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, S-17176, Sweden. Lena-Maria.Carlson@ki.se
Lena-Maria
LM
Carlson
Agnes
A
Rasmuson
Helena
H
Idborg
Lova
L
Segerström
Per-Johan
PJ
Jakobsson
Baldur
B
Sveinbjörnsson
Per
P
Kogner
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D006720:Homozygote; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D015230:Prostaglandin D2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013928:Thromboxane A2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D016212:Transforming Growth Factor beta; D013928:Thromboxane A2; D001241:Aspirin; D015230:Prostaglandin D2