Changes in the tumorigenic and metastatic properties of tumor cells treated with quercetin or 5‐azacytidine

Abstract

The effect of quercetin, a flavonoid derivative, on the transplantability (tumorigenicity) and metastatic behavior of mouse tumor cells was studied. BMT-11 c1-9 fibrosarcoma cells were treated in vitro with quercetin, and after cloning by limiting dilution, cell suspensions of each clone were injected subcutaneously (s.c.) into syngeneic C57BL/6 mice at a dose of 2 X 10(5) cells per mouse. Out of 17 clones examined, 8 were nontumorigenic in normal mice ("regressor" clones), whereas these clones were able to grow in immunosuppressed (600-rad-irradiated) mice. Furthermore, 1 out of 9 tumorigenic clones metastasized spontaneously to the lungs despite the very low metastatic potential of the parent BMT-11 c1-9 cells. In contrast, all 15 clones selected from the untreated parental line grew progressively in normal mice with no evidence of metastases. The appearance of both regressor and metastatic clones was also observed after treatment with a DNA hypomethylating agent, 5-azacytidine. These altered phenotypes resulting from treatment with both chemicals, however, were not necessarily stable if maintained in culture for several months. The data suggest that quercetin may be a useful new material for obtaining regressor or metastatic clones from parental tumor lines.

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

“…Xenogenization of tumor cells is the term meaning immunological spontaneous regression of tumor cells which had been infected with xenogeneic viruses, 78 transfected with the genes coding allogeneic antigen, 79 or exposed to mutagenic chemicals, 80 after injected into normal syngeneic host. Another approach to establish the model is to obtain the culture cell lines from a precancerous lesion.…”

“…For further experiments, we obtained regressive clonal QR cells by exposing clonal fibrosarcoma cells, BMT-11 cl-9, to a mutagen, quercetin in vitro. 80 Since QR cells grew progressively in immunosuppressed hosts, their regression was mediated by host immunity. 86 QR cells did not form tumors or metastasis after subcutaneous (2 3 10 5 cells) or intravenous (1 3 10 6 cells) injection into mice.…”

Enhancement of in vitro prostaglandin E2 production by mouse fibrosarcoma cells after co-culture with various anti-tumour effector cells

“…Briefly, after exposure of the tumorigenic mouse fibrosarcoma BMT-11 cl-9 cells to quercetin and cloning by limiting dilution, we were able to obtain QR-32 clone cells which spontaneously regress in normal syngeneic C57BL/6 mice (Ishikawa et al, 1987a).…”

“…We have previously reported that a clone (QR-32 cells) derived from a cultured mouse fibrosarcoma, BMT-l1 cl-9, spontaneously regresses in normal syngeneic C57BL/6 mice (Ishikawa et al, 1987a, Okada et al, 1990. We considered that, because PGE2 suppressed the anti-tumour effector cell induction at the site of tumour implantation in the tumorgenic parental BMT-11 cl-9 cells, the regression of QR-32 cells was likely to be due to a decrease in the production of PGE2 (Okada et al, 1990)_ We have also observed that oxygen radicals produced by host cells reactive to foreign bodies such as gelatin sponge augment the production of PGE2 by QR-32 cells during co-culture in vitro.…”

Transforming growth factor beta 1 (TGF-beta 1) produced in tumour tissue after chemotherapy acts as a lymphokine-activated killer attractant

“…The mice were maintained in the specific pathogen-free animal facility at the Institute for Animal Experiments, Hokkaido University School of Medicine. Tumour BMT-1 1 tumour is a transplantable fibrosarcoma induced by 3-methylcholanthrene in a C57BL/6 mouse (Ishikawa et al, 1987;Okada et al, 1990). The tumour cells were maintained as a monolayer culture in Eagle's minimum essential medium (EMEM) with 10% heat-inactivated fetal bovine serum (FBS).…”