Evidence for Tumour Necrosis Factor/Cachectin Production in Cancer

Balkwill, Frances R.; Burke, Frances; Talbot, D; Tavernier, Jan; Osborne, Richard; Naylor, Stuart; Durbin, Helga; Fiers, Walter

doi:10.1016/s0140-6736(87)91850-2

Cited by 403 publications

(153 citation statements)

References 14 publications

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“…However, some clinical studies failed to correlate TNF␣ levels with the cachectic state. [15][16][17] IL-6 is a powerful cytokine that mediates several cellular events. Strassmann et al 18 reported that IL-6 caused cachexia in an animal model, and recent studies in transgenic mice have demonstrated that IL-6 participates in muscular atrophy.…”

mentioning

confidence: 99%

Elevation of cytokine levels in cachectic patients with prostate carcinoma

Pfitzenmaier

Vessella

Higano

et al. 2003

Cancer

144

100

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BACKGROUNDApproximately 60–70% of patients with advanced prostate carcinoma (CaP) suffer from cachexia, one of the most devastating conditions associated with advanced malignant disease. The pathophysiology of cachexia is multifactorial, and several cytokines, such as tumor necrosis factor α (TNFα) and interleukin 1 (IL‐1), IL‐6, and IL‐8, may be involved. The objective of the current study was to determine whether cachexia associated with advanced CaP is accompanied by increased serum levels of TNFα, IL‐1β, IL‐6, and IL‐8.METHODSThe levels of TNFα, IL‐1β, IL‐6, IL‐8, and prostate specific antigen (PSA) were examined in serum samples from normal donors (n = 10 donors), from patients with organ‐confined CaP (n = 19 patients), from patients with advanced CaP without cachexia (n = 17 patients), and from patients with cachectic CaP (n = 26 patients). DPC Immulite and Abbott IMx Total‐PSA assays were used to determine cytokine and PSA levels, respectively.RESULTSLevels of TNFα, IL‐6, and IL‐8 were elevated significantly in the group of patients with advanced, cachectic CaP compared with patients who were without cachexia. In the cachectic patients, levels of TNFα were correlated positively with IL‐8, and there was no correlation between PSA levels and any of the cytokine levels. IL‐1β levels were below the limit of detection in all samples.CONCLUSIONSThe current results show that levels of TNFα, IL‐6, and IL‐8 were increased in CaP patients with cachexia. Increased levels of these cytokines were not correlated with PSA levels, suggesting that they are regulated by a mechanism that is independent of PSA synthesis. Additional fundamental research is needed to determine the mechanisms involved and to identify potential therapeutic targets in patients with cachexia. Cancer 2003;97:1211–6. © 2003 American Cancer Society.DOI 10.1002/cncr.11178

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confidence: 99%

Elevation of cytokine levels in cachectic patients with prostate carcinoma

Pfitzenmaier

Vessella

Higano

et al. 2003

Cancer

144

100

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“…Implantation into mice of Chinese hamster ovary (CHO) cells transfected with the gene for TNF-a produces a syndrome resembling cancer cachexia with progressive wasting, anorexia and early death (Oliff et al, the requirement for high levels of TNF-a to induce cachexia in experimental models. Even in some cancer patients in whom elevated levels of TNF-a may be present, this does not seem to be correlated with the presence of cachexia (Balkwill et al, 1987;Saarinen et al, 1990). Although CHO cells transfected with the IL-6 gene have been shown to produce a syndrome of cachexia in nude mice (Black et al, 1991), cachexia is not observed in patients with IL-6-producing tumours, at least during the early stage of tumour growth (Ishibashi et al, 1993).…”

mentioning

confidence: 99%

Induction of cachexia in mice by a product isolated from the urine of cachectic cancer patients

Cariuk

Lorite²,

Todorov³

et al. 1997

Br J Cancer

112

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Summary Urine from cancer patients with weight loss showed the presence of an antigen of Mr 24 000 detected with a monoclonal antibody formed by fusion of splenocytes from mice with cancer cachexia. The antigen was not present in the urine of normal subjects, patients with weight loss from conditions other than cancer or from cancer patients who were weight stable or with low weight loss (1 kg month-1). The antigen was present in the urine from subjects with carcinomas of the pancreas, breast, lung and ovary. The antigen was purified from urine using a combination of affinity chromatography with the mouse monoclonal antibody and reversed-phase high-performance liquid chromotography (HPLC). This procedure gave a 200 000-fold purification of the protein over that in the original urine extract and the material isolated was homogeneous, as determined by silver staining of gels. The N-terminal amino acid sequence showed no homology with any of the recognized cytokines. Administration of this material to mice caused a significant (P<0.005) reduction in body weight when compared with a control group receiving material purified in the same way from the urine of a normal subject. Weight loss occurred without a reduction in food and water intake and was prevented by prior administration of the mouse monoclonal antibody. Body composition analysis showed a decrease in both fat and non-fat carcass mass without a change in water content. The effects on body composition were reversed in mice treated with the monoclonal antibody. There was a decrease in protein synthesis and an increase in degradation in skeletal muscle. Protein degradation was associated with an increased prostaglandin E2 (PGE2) release. Both protein degradation and PGE2 release were significantly reduced in mice pretreated with the monoclonal antibody. These results show that the material of Mr 24 000 present in the urine of cachectic cancer patients is capable of producing a syndrome of cachexia in mice.

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“…TNF has been implicated in the induction of cancer cachexia, the acute-phase response and sepsis [8][9][10][11][12]. Impaired lymphocyte function is related to death from Gramnegative sepsis [20,21,33], a phenomenon related to increased TNF activity [7,10,12,16] and in this study was related to endotoxin sensitivity.…”

Section: Discussionmentioning

confidence: 76%

“…Increased sensitivity to endotoxin, and TNF, may therefore be related to impaired lymphocyte function. Increased ratios of TNF/lymphocyte function correlated with clinical disturbances normally attributed to TNF activity [7][8][9][10][11][12], with reduced survival, and with in vitro sensitivity to endotoxin. Improvement of lymphocyte function can prolong survival in animal models of conditions associated with endotoxaemia and increased TNF activity, e.g.…”

Section: Discussionmentioning

confidence: 99%

Metabolic disturbance and sensitivity to endotoxin in patients with advanced cancer: relationship to lymphocyte reactivity, tumour necrosis factor (TNF) production and survival

Gough

Fearon

Carter

1996

Clinical and Experimental Immunology

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SUMMARYIncreased TNF production and impaired lymphocyte function have been individually linked with metabolic disturbance, endotoxaemia and mortality in humans. The inter-relationship between these observations was investigated in humans with cancer. In 13 patients with metastatic colorectal cancer and seven healthy volunteers, observations (n 23) included peripheral blood mononuclear cell (PBMC) TNF production, IL-2 production and phytohaemagglutinin (PHA) response; the acutephase protein response (APPR) (serum C-reactive protein (CRP), albumin, CRP/albumin ratio), and survival. APPR correlated with survival (CRP, r

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Evidence for Tumour Necrosis Factor/Cachectin Production in Cancer

Cited by 403 publications

References 14 publications

Elevation of cytokine levels in cachectic patients with prostate carcinoma

Elevation of cytokine levels in cachectic patients with prostate carcinoma

Induction of cachexia in mice by a product isolated from the urine of cachectic cancer patients

Metabolic disturbance and sensitivity to endotoxin in patients with advanced cancer: relationship to lymphocyte reactivity, tumour necrosis factor (TNF) production and survival

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