Phagocytes as Carcinogens: Malignant Transformation Produced by Human Neutrophils

Abstract

In a study of the relation between chronic inflammation and carcinogenesis, C3H mouse fibroblasts of the 10T 1/2 clone 8 line (10T 1/2 cells) were exposed to human neutrophils stimulated to synthesize reactive oxygen intermediates or to a cell-free enzymatic system generating superoxide (xanthine oxidase plus hypoxanthine). After exposure, the 10T 1/2 cells were either placed in tissue culture or immediately injected into athymic nude mice. Both malignant and benign tumors developed in the mice injected with treated cells, but not in those injected with control cells; in one instance cells grown from one of the benign tumors subsequently developed a malignant phenotype. Malignant transformation was also observed in treated cells in the experiments in vitro.

Production of Brominating Intermediates by Myeloperoxidase

“…Chronic inflammation is an important risk factor for cancer, and oxidants generated by phagocytic cells mutate bacteria and transform cultured mammalian cells (57,58). Moreover, recent genetic epidemiological studies have found a relationship between cancer risk and a polymorphism in the promoter region of the myeloperoxidase gene.…”

Stimulated human leukocytes cause activating mutations in the K-ras proto-oncogene

“…Similarly, chronic in¯ammation of the skin, urinary bladder, gall bladder, stomach, esophagus, bone, etc, is associated with an increased incidence of malignancies in these tissues (Weitzman and Gordon, 1990). In addition to this well-known association between in¯ammation and human carcinogenesis, previous studies have also demonstrated that cultured mouse ®broblast cells can be transformed into malignant cells when exposed to in¯ammatory leukocytes (Weitzman et al, 1985;Nassi-Calo et al, 1989;Zimmerman and Cerutti, 1984).…”

Induction of Chromosomal Aberrations and Growth-Transformation of Lymphoblastoid Cell Lines by Inhibition of Reactive Oxygen Species-Induced Apoptosis with Interleukin-6

“…Reactive oxygen species (ROS) released from polymorphonuclear leukocytes and macrophages are the factors causing DNA damage in the foci of inflammation (Cerutti and Trump, 1991). ROS induce DNA strand breaks in mouse epidermal cells (Muehlematter et al, 1988), chromosomal aberrations in Chinese hamster ovary cells (Weitberg et al, 1983), and malignant transformation of cultured mouse fibroblasts (Zimmerman and Cerutti, 1984;Weitzman et al, 1985). Previous studies have shown that ROS can also cause DNA strand breaks (Carson et al, 1986) and chromosomal aberrations (Duell et al, 1995) in resting peripheral blood lymphocytes or phytohemagglutinin-stimulated lymphocytes.…”