Inhibition of Methylcholanthrene-induced Carcinogenesis by an Interferon γ Receptor–dependent Foreign Body Reaction

Abstract

The foreign body reaction is one of the oldest host defense mechanisms against tissue damage which involves inflammation, scarring, and encapsulation. The chemical carcinogen methylcholanthrene (MCA) induces fibrosarcoma and tissue damage in parallel at the injection site. Tumor development induced by MCA but not due to p53-deficiency is increased in interferon-γ receptor (IFN-γR)–deficient mice. In the absence of IFN-γR, MCA diffusion and DNA damage of surrounding cells is increased. Locally produced IFN-γ induces the formation of a fibrotic capsule. Encapsulated MCA can persist virtually life-long in mice without inducing tumors. Together, the foreign body reaction against MCA prevents malignant transformation, probably by reducing DNA damage. This mechanism is more efficient in the presence of IFN-γR. Our results indicates that inflammation and scarring, both suspected to contribute to malignancy, prevent cancer in certain situations.

NK cell heparanase controls tumor invasion and immune surveillance

“…In the Matrigel and tumor model assays we examined, loss of heparanase in NK cells decreased NK cell localization in tumors, but was without an indirect effect on T cell subsets. In the MCAinduced fibrosarcoma model, NK cell-derived IFN-γ is a critical factor responsible for the formation of a fibrotic reaction enclosing the carcinogen and preventing tumor outgrowth (e.g., the foreign body reaction) (36). We hypothesize that the higher incidence of fibrosarcoma observed in the absence of NK cell heparanase is a result of fewer tumor-infiltrating NK cells, a reduced fibrotic reaction, and, consequently, a more frequent tumor initiation and outgrowth.…”

Angiogenesis in a human neuroblastoma xenograft model: mechanisms and inhibition by tumour-derived interferon-γ

“…The demonstration that the ACN/IFN-g cells produced NO strongly supported its role in driving the apoptotic signal to the endothelial cells. In this view, it is conceivable that a non-species-specific mediator, like NO, was responsible for inhibition of angiogenesis observed in other human IFN-transfected tumour cells growing in athymic mice (Hock et al, 1993;Fathallah-Shaykh et al, 2000;Ozawa et al, 2001;Izawa et al, 2002;Qin et al, 2002).…”

Beyond foreign‐body‐induced carcinogenesis: Impact of reactive oxygen species derived from inflammatory cells in tumorigenic conversion and tumor progression

“…Encapsulation is the oldest host adaptive immune system, and all the living things, from invertebrates to vertebrates, are equipped with the system. 48 In man, it is commonly associated with pathological situations and the typically described is fibrous tissue capsule or scar which surrounds foreign bodies. Histological examination shows that fibrous capsule is generally 300-lm thick around the implanted materials; however, no association is observed between the implanted materials and the degree of capsule reaction.…”