THE ROLE OF CYTOKINES IN CANCER CACHEXIA

There is, at present, considerable interest in the possible role for the proinflammatory cytokines, tumor necrosis factor-alpha, interleukin-1, interleukin-gamma, and interferon-gamma in the pathogenesis of cancer cachexia. Indirect evidence for such a role is based on the observation that chronic administration of many of these cytokines, either alone or in combination, can reproduce the myriad of host responses seen in experimental and human cancer cachexia. Elevated plasma levels of tumor necrosis factor-alpha, interleukin-gamma, and inteferon-gamma have rarely been detected in patients or experimental animals with cancer, although interleukin-6 levels appear to correlate with tumor progression in animal models. The strongest evidence for a causal role for cytokines has come from rodent studies in which tumor-bearing animals have been passively immunized with antibodies directed against individual cytokines. Several groups have shown modest but significant improvements in food intake and lean tissue retention with antibodies directed against tumor necrosis factor-alpha, interleukin-1, interleukin-6, and interferon-gamma. However, there has been no consistent finding that one cytokine is universally involved in cancer cachexia in histologically distinct tumor models. One ominous finding in several tumor models has been that the endogenous production of cytokines appears to support tumor growth. Such findings raise the intriguing possibility that these cytokines, although contributors to tissue wasting and anorexia, may also serve the tumor as either direct or indirect cell growth factors. We conclude, however, that because of redundancy in the cytokine network and differential cytokine production in histologically distinct tumors, efforts to block the development of cancer cachexia with anticytokine therapies will require the inhibition of several proinflammatory cytokines simultaneously.