Abstract
Human bloodstream monocytes can kill cultured tumour cells (K562), as assessed by specific release of 51Cr from the targets and by inhibition of 3H-thymidine incorporation. Confluent monolayers of monocytes were required for maximal cytotoxicity, and the density of the K562 cells was also an important factor. For example, when K562 cells were seeded at high cell densities, they were killed during incubation with monocytes, but when seeded at low cell densities their growth and survival was enhanced during culture with monocytes. The factor(s) which promoted the survival and division of low density K562 cultures was endogenously secreted from monocytes as it was present in monocyte-conditioned medium, whereas the cytotoxic factor(s) were only expressed during co-culture of monocytes with K562 cells. Conditioned medium from HL 60, U-937, HeLa and K562 could also enhance the growth and survival of low density K562 cultures, and a similar effect was also observed upon the addition of catalase and superoxide dismutase to such cultures. Thus, the monocyte:target ratio is important in determining whether monocytes exhibit cytotoxic or growth-promoting effects and hence tumour-derived or monocyte-derived reactive oxidant species may play a role in tumour cell cycle regulation.
Highlights
Monocytes are capable of producing reactive oxygen intermediates such as 02, H202, 0OH and HOCI via the activities of the NADPH oxidase and myeloperoxidase
We show that freshly-isolated bloodstream monocytes exhibit considerable cytotoxicity towards tumour cells
When 5'Cr loaded K562 cells were incubated in the absence of monocytes, release of this label was undetectable over the first 5 h in culture: after this time 5'Cr release was observed and this progressively increased over the following 17 h (Figure la)
Summary
Monocytes are capable of producing reactive oxygen intermediates such as 02-, H202, 0OH and HOCI via the activities of the NADPH oxidase and myeloperoxidase. These species are damaging to biological molecules and are involved in the killing of certain microorganisms by neutrophils (Edwards et al, 1987; Holmes et al, 1967). There is indirect evidence to suggest that reactive oxygen intermediates are important for the killing of tumour cells by mononuclear phagocytes: (1) myeloperoxidase-deficient individuals have higher incidences of neoplasms compared to normal individuals (Lanza et al, 1987); (2) a cell-free myeloperoxidase-H202-halide system can kill tumour cells in vitro (Klebanoff & Clark, 1978); (3) treatments which increase the tumouricidal competence of murine macrophages (for example, y-interferon) often increase the capacity of the cells to generate reactive oxidants (Reed et al, 1987; Nathan et al, 1984); (4) BCG-elicited peritoneal macrophages have a greater respiratory burst in response to phorbol myristate acetate (PMA) and exert greater tumour cytotoxicity than thioglycollate-elicited macrophages (Drath, 1985); (5) the specificity of mononuclear cytotoxicity to only tumour cells (and not to normal cells) may be explained by the fact that many tumour cell lines have lower than normal levels of enzymes (e.g. superoxide dismutase (SOD), catalase, glutathione peroxidase) associated with combating oxidative stress (Sun et al, 1989)
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