Cytokines

Cytokines have a key role as the main humoural factors involved in cancer cachexia (Fig. 1), and a large number of them may be responsible for the metabolic changes associated with cancer wasting. Anorexia may account for malnutrition, invari

Fig. 1. Catabolic mediators in cancer. Both tumour-derived and humoural (cytokines) factors are involved in mediating the anorexia and metabolic changes characteristic of the cachectic state. For abbreviations, see text

ably associated with cancer cachexia; but, are cytokines involved in the induction of anorexia? Cytokines, such as interleukin (IL)-1 and tumour necrosis factor (TNF)-a have been suggested to be involved in cancer-related anorexia, possibly by increasing the levels of corticotropin-releasing hormone (CRH), a central nervous system neuro-transmitter that suppresses food intake, and the firing of glucose-sensitive neurons, which would also decrease food intake. However, many other mediators may be involved in cancer-induced anorexia. Leptin (an adiposity signal to the hypothalamus that it is a member of the cytokine family) does not seem to play a role, at least in experimental models [1, 2], and in human subjects, cancer anorexia does not seem to be due to a dysregu-lation of leptin production [3]. Indeed, leptin concentrations are not elevated in weight-losing cancer patients [4, 5] and are inversely related to the intensity of the inflammatory response [6] and the levels of inflammatory cytokines [7, 8]. Concentrations of the peptide seem to be dependent only on the total amount of adipose tissue present in the patient. Cytokines have been implicated in cancer-induced anorexia since they modulate gastric motility and emptying, either directly in the gastrointestinal system or via the brain, by altering efferent signals that regulate satiety. IL-1, in particular, has been clearly associated with the induction of anorexia [9] in that it blocks neuropeptide Y (NPY)-induced feeding. The levels of this molecule (a feeding-stimulating peptide) are reduced in anorectic tumour-bearing rats [10], and a correlation between food intake and brain-IL-1 has been found in anorectic rats with cancer. The mechanism involved in the attenuation of NPY activity by cytokines may be related to an inhibition of cell firing rates or to an inhibition of NPY synthesis or an attenuation of its postsynaptic effects [11]. Other mediators have been proposed [12], including changes in the circulating levels of free tryptophan; these may induce changes in serotonin brain concentrations and, consequently, cause changes in food intake. Bing et al. [13] suggested that some tumour-derived compounds may mediate anorexia associated with tumour burden.

Different experimental approaches have demonstrated that cytokines are able to induce weight loss. Nevertheless, the results obtained have to be carefully interpreted. Thus, episodic TNF-a administration has proved unsuccessful at inducing cachexia in experimental animals. Indeed, repetitive TNF-a administrations initially induce a cachectic effect, but tolerance to the cytokine soon develops and food intake and body weight return to normal. Other studies have shown that escalating doses of TNF-a are necessary to maintain the cachectic effects.

Strassman et al. [14] have shown that treatment with an anti-mouse IL-6 antibody reversed the key parameters of cachexia in murine colon adenocar-cinoma tumour-bearing mice. These results seem to indicate that, at least in certain types of tumours, IL-6 has a more direct involvement than TNF-a in the cachectic state. Similar results were obtained in a mouse model that reproduced the cachexia associated with multiple myeloma [15, 16] and in a murine model of intracerebral injection of human tumours [17]. Conversely, other studies have shown in a very similar mouse tumour model that IL-6 is not involved in cachex-ia, and studies using incubated rat skeletal muscle have clearly demonstrated that IL-6 had no direct effect on muscle proteolysis.

Another interesting candidate for cachexia is interferon (IFN)-y, which is produced by activated T and NK cells and possesses biological activities that overlap with those of TNF-a. Matthys et al. [18] used a monoclonal antibody against IFN-y to reverse the wasting syndrome associated with growth of the Lewis lung carcinoma in mice, thus indicating that endogenous production of IFN-y occurs in the tumour-bearing mice and is instrumental in bringing about some of the metabolic changes characteristic of cancer cachexia. The same group also demonstrated that severe cachexia develops rapidly in nude mice inoculated with CHO cells constitutively producing IFN-y as a result of the transfection of the corresponding gene.

Other cytokines, such as leukaemia inhibitory factor (LIF), transforming growth factor (TGF)-p, or IL-1 have also been suggested as mediators of cachexia. Thus, mice engrafted with tumours secreting LIF developed severe cachexia. Concerning IL-1, although its anorectic and pyro-genic effects are well-known, administration of IL-

1 receptor antagonist (IL-1ra) to tumour-bearing rats did not result in any improvement in the degree of cachexia, so that the role of this cytokine in cancer cachexia may be secondary to the actions of other mediators. Interestingly, the levels of both IL-6 and LIF are increased in patients with different types of malignancies.

Ciliary neurotrophic factor (CNTF) is a member of the family of cytokines that includes IL-6 and LIF, and is produced predominantly by glial cells of the peripheral nervous system; however, this cytokine also seems to be expressed in skeletal muscle. Henderson et al. [19] demonstrated that CNTF induces potent cachectic effects and the production of acute-phase proteins (independent of the induction of other cytokine family members) in mice implanted with C6 glioma cells, genetically modified to secrete this cytokine. CNTF, however, exerted divergent direct effects dependent on the dose and exposure time of in vitro muscle preparations [20].

If anorexia is not the only factor involved in cancer cachexia, it becomes clear that metabolic abnormalities leading to a hypermetabolic state must have a very important role. Interestingly, injection of low doses of TNF-a, either peripherally or into the brain of laboratory animals, elicits rapid increases in the metabolic rate that are not associated with increased metabolic activity but rather with an increase in blood flow and thermo-genic activity of brown adipose tissue (BAT), associated with uncoupling protein-1 (UCP1). During cachectic states, there is an increase in BAT ther-mogenesis, both in humans and experimental animals. Until recently, UCP1 (present only in BAT) was considered to be the only mitochondrial protein carrier that stimulated heat production, by dissipating the proton gradient generated during respiration across the inner mitochondrial membrane and therefore uncoupling respiration from ATP synthesis. However, two additional proteins sharing the same function, UCP2 and UCP3, have since been described. While UCP2 is expressed ubiquitously, UCP3 is expressed abundantly and specifically in skeletal muscle in humans and in BAT of rodents. Our research group has demonstrated that both UCP2 and UCP3 mRNAs are elevated in skeletal muscle during tumour growth and that the effect of TNF-a mimics the increase in gene expression induced by these proteins [21]. In addition, TNF-a induces uncoupling of mito-chondrial respiration, as recently shown in isolated mitochondria [22].

Several cytokines have been shown to mimic many of the metabolic abnormalities found in the cancer patient during cachexia. Among these metabolic disturbances, changes in lipid metabolism, skeletal muscle proteolysis and apoptosis, and acute-phase protein synthesis have been described [23]. Concerning muscle wasting, it seems that administration of TNF-a to rats results in increased proteolysis of skeletal muscle, associated with an increase in gene expression and higher levels of free and conjugated ubiquitin, both in experimental animals [24] and humans [25]. In addition, the in vivo action of TNF-a during cancer cachexia does not seem to be mediated by IL-1 or glucocorticoids. Other cytokines, such as IL-1 or IFN-y, also activate ubiquitin gene expression. Therefore, TNF-a, alone or in combination with other cytokines [26], seems to mediate most of the changes concerning nitrogen metabolism associated with cachectic states. In addition to the massive muscle protein loss, and similar to that observed in skeletal muscle of patients with chronic heart failure who also suffer from cardiac cachexia [27], muscle DNA is also decreased during cancer cachexia, leading to DNA fragmentation and apoptosis [28, 29]. Moreover, TNF-a can mimic the apoptotic response in muscle of healthy animals [30].

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