Inflammation and cancer, the mastocytoma P815 tumor model revisited: triggering of macrophage activation in vivo with pro-tumorigenic consequences.
Subcutaneous in vivo injections of cells of the mastocytoma line P815 in syngenic DBA/2 mice induce locally fast growing solid tumors. These have been used extensively as a cancer model to analyze and manipulate the relationship between tumor cells and host's immune defenses. We report that progression of P815 tumors in vivo was accompanied by a burst (Days 5-7) of local inflammatory cells recruitment and angiogenesis observed histologically, corroborated in vivo by MRI with gadolinium, overtranscription of macrophage activation marker genes, secretion of TNF-alpha by regional lymph node cells and concomitant systemic inflammation. No substantial overtranscriptions of either VEGF or IL-10 or TGF-beta genes were observed. Induction of COX-2 gene was a late event. To establish a possible relationship between the tumor-induced local, regional and systemic increase of pro-inflammatory mediators and progression of tumors in vivo, we carried out experiments deliberately modulating the inflammatory status of the recipient animals. Pretreatment of recipient animals by i.p. injection of thioglycolate accelerated P815 tumor growth. At the opposite, treatment of mice with either a COX-1 + COX-2 inhibitor (aspirin, 1 mg/day/mouse) or a specific COX-2 inhibitor (celecoxib, 0.13 mg/day/mouse) for 2 weeks after injection of tumor cells, significantly reduced the size and growth rate of tumors compared to control mice. Experiments carried out in vitro indicated that peritoneal macrophages from untreated animals were strongly activated by live P815 cells and by P815 membrane preparations. The tumor-induced inflammatory reaction could establish a local micro environment favoring tumor progression. The P815 tumor model might be helpful to recognize important factors controlling host/tumor relationship.
Département d'Immunologie, Institut Cochin, INSERM-CNRS-Université Paris V, Hôpital Cochin, Paris, France.
Caroline
C
Kamate
Samia
S
Baloul
Sabine
S
Grootenboer
Eric
E
Pessis
Alain
A
Chevrot
Micheline
M
Tulliez
Carmen
C
Marchiol
Mireille
M
Viguier
Didier
D
Fradelizi
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D007249:Inflammation / Q000097:blood / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D008264:Macrophages / Q000276:immunology*; D008279:Magnetic Resonance Imaging; D012515:Mast-Cell Sarcoma / Q000098:blood supply / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins; D051379:Mice; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D000685:Serum Amyloid A Protein / Q000378:metabolism; D013864:Thioglycolates / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D000685:Serum Amyloid A Protein; D013864:Thioglycolates; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse