Abstract
The importance of growth factors and nutrition in cancer cachexia was investigated in a group of patients with advanced malignant disease, in mice bearing the Lewis lung tumour, and in cultures of the human hepatoma cell line HEP G2. In addition, the effect of treatment with medroxyprogesterone acetate was also studied. The patients studied show that, in addition to poor appetite and weight loss, cancer cachexia is associated with low levels of serum IGF-I, and high levels of TNF-aand ferritin. Levels of the mean growth hormone and serum cortisol were in the high normal range. Treatment with medroxyprogesterone acetate (MPA) for 4 weeks associated with an improvement in appetite in all patients. This was accompanied by an increase in fasting plasma insulin levels but no change in serum albumin, total proteins or mean levels of IGF-I. A weight gain of more than 3 kg was observed in 28% of patients. This degree of weight gain was associated with a decrease in fasting levels of growth hormone, tumour necrosis factor and cortisol, followed by a significant increase in the levels of IGF-I. Patients who failed to gain or who lost further weight showed an increase in plasma levels of ferritin, cortisol and tumour necrosis factor. While levels of both growth hormone and IGF-I remain low. In the study of tumour-bearing mice, it was found that overall plasma and liver levels of IGF-I were lower in tumour-bearing than normal animals, levels were also lower in muscle but showed evidence of recovery in the later stage of the study. Treatment with MPA had no effect on food intake and no significant effect on non-tumour weight but appear significantly to increase tumour weight. It also prevented the fall in plasma IGF-I levels seen in nontreated animals. Levels of tumour necrosis factor -a (TNF-a) were undetectable in plasma in all animals but were markedly increased in muscle of all tumour-bearing animals, particularly those treated with MPA. This was accompanied by a decrease in muscle glycogen contents and an apparent increase (possibly only relative) in muscle protein content. The low IGF-I and high TNF-a levels in the muscle of tumour-bearing animals may be important factors in the development of muscle wasting in these animals. In studies on the human hepatoma cell line in culture, the addition of insulin and human growth hormone (hGH) together resulted in an increase in the synthesis of IGF-I. While the addition of each separately was without effect. The addition of TNF-a along with insulin and hGH counteracted their ability to increase IGF-I synthesis. Reduction in the glutamine content of the medium resulted in a significant reduction in IGF-I release by the cultured cells. MPA had no direct effect on either cell growth or IGF-I production. In patients with cancer who are losing weight, a reduction in TNF-a levels appears to allow IGF-I levels to rise in response to the prevailing high levels of growth hormone, with restoration of the normal relationship between IGF-I and growth hormone. These changes probably predispose to weight gain. The increase in tumour growth seen in animals treated with MPA suggests that it may be preferable to give such treatment only after removal of the tumour or radiation therapy.