Effects of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) on expression of adhesion molecules and production of cytokines in blood monocytes and ovarian cancer‐associated macrophages

Abstract

The present study was aimed at characterizing the effects of in vitro exposure to GM-CSF on blood monocytes and tumor-associated macrophages (TAM) in human ovarian cancer. Purified populations of TAM from ovarian cancer patients were studied in terms of expression of surface molecules, cytokine production and tumor cytotoxicity after overnight incubation with GM-CSF or IFN gamma and LPS, used as reference activators. GM-CSF augmented the surface expression of ICAM-I and CD18 in TAM and in blood monocytes. Stimulation was more prominent in monocytes than in TAM, which showed higher baseline expression of this adhesion molecule. ICAM-3 was not influenced by GM-CSF or by IFN gamma/LPS. GM-CSF-augmented ICAM-I expression was associated with higher levels of mRNA transcripts. The protein synthesis inhibitor cycloheximide super-induced basal and GM-CSF-induced ICAM-I transcripts, thus excluding a role for secondary polypeptide mediators. In the absence of stimuli, TAM produced higher levels, compared to monocytes, of IL-6 and IL-8 but not of IL-1 and TNF. GM-CSF augmented the production of IL-6 and IL-8 (but not that of IL-1 and TNF) in TAM, whereas it had little effect on blood monocyte. Tumoricidal activity was tested against two ovarian tumor cell lines (OVCAR3 and SW626). GM-CSF more prominently augmented monocyte cytotoxicity, while only 2 of 6 TAM preparations were stimulated by GM-CSF. These results suggest that GM-CSF selectively regulates the function of blood monocytes and TAM, the effect of this cytokine varying with the parameter and cell population examined. These data provide a rational and biological endpoint for further studies with GM-CSF as an activator of mononuclear phagocyte function in ovarian cancer.

The RET receptor tyrosine kinase, but not its specific ligand, GDNF, is preferentially expressed by acute leukaemias of monocytic phenotype and is up-regulated upon differentiation

“…U937 cells induced with a vitamin D 3 /TGF-b combination), in which a more pronounced monocytic differentiation had occurred. Furthermore, as shown here and previously (Gattei et al, 1997a), macrophage activation by GM-CSF, which has been described to upregulate the expression of b2-integrins and ICAM-1/CD54 on circulating monocytes both in vivo and in vitro (Bernasconi et al, 1995;Williams et al, 1995), resulted in a more than 3-fold increase of RET-specific mRNA. Taken together, this data indicated that RET expression in human AML was maturation-associated and probably mirrored the developmental regulation of these genes during physiologic haemopoiesis.…”

Cooperative Autocrine and Paracrine Functions of Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor in the Progression of Skin Carcinoma Cells

“…The role of macrophages for tumor growth and progression is a matter of controversial discussion. Although macrophages can mediate cytotoxicity and have been implicated in antitumor immunity (47,48), tumor cells can develop mechanisms to escape and even benefit from the activities of the tumor-associated macrophages (49 -51). In light of this potentially dual role, the early recruitment of macrophages in the GM-CSF transfectants, which reach the tumor already in week 1 after transplantation, might mediate a cytotoxic antitumor effect in these early stages of tumor growth.…”

Intraperitoneal macrophages and tumor immunity: A review

“…Studies have however noted the tumor growth promoting effects of TAMs [40]. For instance, TAMs isolated from breast, lung, and ovarian carcinomas constitutively secrete less IL-1 and TNF than do circulating monocytes [54,55]. TAMs also produce substantial amounts of transforming growth factor ␤ (TGF-␤), a known suppressor of M function.…”