Role of cytokines in cancer cachexia in a murine model of intracerebral injection of human tumours

To study the role of cytokines that are relevant in cancer cachexia syndrom e due to intracerebral tumours, mice were injected with human A431 epidermo id carcinoma, OVCAR3 ovarian carcinoma and GBLF glioma cells comparing intr acerebral (i.e.) and systemic (i.p. or s.c.) routes of implantation. Anorex ia and weight loss developed within 7-10 days in mice injected i.e. with A4 31 or OVCAR3 cells well before a large tumour developed, while i.c.-injecte d GBLF cells did not induce cachexia until day 20, when the tumour was larg e. By contrast, mice injected i.p. or s.c. developed tumours without eviden ce of anorexia. Thus, intracerebrally-growing A431 and OVCAR3 resulted in c ancer cachexia independent of tumour mass, and we investigated their cytoki ne pattern. Serum levels of murine and human cytokines are not predictive o f cancer cachexia development. Reverse-transcriptase polymerase chain react ion (RT-PCR) analysis revealed in the brain of i.c.-injected A431 tumour-be aring mice expression of human interleukin(IL-)1 alpha, IL-1 beta and LIF i n all samples and IL-6 in two of four samples while in i.c.-injected OVCAR3 tumour-bearing animals lL-6, and LIF were detected in all samples and tumo ur necrosis factor-alpha (TNF alpha) in two of four samples. Only LIF was e xpressed in brains of mice injected with GBLF cells. Murine IL-6 was increa sed only in the brains of A431-bearing mice. Only mice injected i.e. simult aneously with a monoclonal antibody (mAb) directed against the murine IL-6 receptor and OVCAR3 cells, but not those with mAb and A431 cells, showed a significant increase in survival time with a partial and temporary attenuat ion of cachexia symptoms. These results suggest that IL-6 in OVCAR3 model m ay be important cachectogenic factor when centrally released by even a limi ted number of tumour cells. (C) 2001 Academic Press.