The role of cytokines in cancer cachexia

Immunologic and clinical manifestations of erythema nodosum leprosum (ENL) and their response to thalidomide therapy were evaluated. Circulating tumor necrosis factor-alpha (TNF alpha) levels were assayed in serum obtained from lepromatous leprosy patients at diagnosis, during multidrug therapy, at the onset of ENL episodes, and during treatment with thalidomide. Patients with systemic ENL demonstrated the highest serum TNF alpha levels, which decreased significantly during thalidomide treatment. Serum TNF alpha in nonreactional patients was associated with mild flu-like symptoms and local inflammatory lesions. Serum interferon-gamma (IFN-gamma) was also elevated in patients with high TNF alpha levels. Thalidomide therapy reduced not only serum TNF alpha levels and the clinical symptoms but also the dermal infiltration of polymorphonuclear leukocytes and T cells. The expression of intercellular adhesion molecule 1 and major histocompatibility complex class II antigens on the epidermal keratinocytes was also down-regulated. These results indicate that the thalidomide-induced alleviation of clinical symptoms of ENL was associated with a reduction of TNF alpha levels.

In 1919, glucose intolerance became the earliest recognized metabolic abnormality in cancer patients. Prior to the development of severe malnutrition, colon, gastric, sarcoma, endometrial, prostate, localized head, neck, and lung cancer patients had many of the metabolic abnormalities of type II (noninsulin dependent) diabetes mellitus. These metabolic abnormalities include glucose intolerance, an increase in both hepatic glucose production (HGP) and glucose recycling, and insulin resistance. In a study of over 600 cancer patients, a diabetic pattern of glucose tolerance test was noted in over one-third of the patients. An increased rate of HGP, commonly seen in diabetics, has been noted in almost all types of cancer patients studied to date. Etiology of the increased glucose production in the cancer patient is not known, but abnormalities in the counter regulatory hormones, especially growth hormone, may contribute to the development of abnormal glucose metabolism. A second possible stimulus for the increase in HGP could be the glucose needs of the tumor. Abnormally high glucose utilization rates in small amounts of tumor tissue have recently been described. This suggests that small tumors may have large needs for glucose calories. An increase in anaerobic glycolysis in the tumor tissue can increase lactate production in the tumor-bearing human, thus supplying substrate to the liver to increase glucose production rates. In this paper, the nature of abnormal glucose metabolism in cancer patients is described.

In rats into which a fast-growing ascites hepatoma (Yoshida AH-130) had been transplanted, tumour growth elicited a marked loss of body weight until the animal's death in about 2 weeks. Overall tissue protein metabolism was simultaneously studied in vivo in the gastrocnemius muscle and liver after labelling with [14C]bicarbonate. Early and progressive atrophy developed in the gastrocnemius muscle, the underlying metabolic imbalance being expressed by an elevation in the apparent protein-degradation rate, with no changes in the apparent synthesis rate. A transient hyperplastic response preceded waste in the liver, both states being associated with alterations in protein-degradation rate: an initial decrease during liver growth, then an acceleration as liver regressed. Protein-synthesis rates, virtually unchanged during liver growth, were elevated in the subsequent phase, although not sufficient to balance the enhanced breakdown. Thus, in the tumour host tissues examined, altered states of protein turnover appeared to result mostly from changes in rates of protein breakdown. In sharp contrast with the negative protein balance in the host, the ascites hepatoma cells had the ability to grow or at least, in advanced stages, to maintain a stationary state.