Progression Of Cancer Cachexia Research Articles

IL‐6‐induced Cachexia and Muscle IGF‐1 Signaling

Inflammatory cytokine IL‐6 is necessary for the development and progression of cancer cachexia in the ApcMin/+ mouse, a model of colorectal cancer and cachexia. The purpose of this study is to determine if circulating IL‐6 over‐expression (OE) regulates muscle protein synthesis and associated IGF‐1 signaling in wild type (Wt) and ApcMin/+ mice. Twelve week, weight stable, male ApcMin/+ and Wt mice were randomly assigned to IL‐6 OE or control groups. Circulating IL‐6 OE was induced by electroporation of an IL‐6 expressing vector into the quadriceps muscle while an empty vector served as the control. At the end of the 2 week OE period, mice were given an IP injection of deuterium‐labeled phenylalanine to measure myofibrillar protein synthesis rates. IL‐6 OE reduced ApcMin/+ mice body weight 14% over the 2 week time period. ApcMin/+ mice over‐expressing IL‐6 had a 16% decrease in gastrocnemius mass when compared to controls. Body and muscle weights in Wt mice were not affected by IL‐6 OE. ApcMin/+ mice had a 90% reduction in muscle IGF‐1 mRNA expression and an 80% reduction in the phosphorylation of eIF 4EBP‐1 protein. Myofibrillar protein synthesis was reduced 53% in the ApcMin/+ mouse over‐expressing IL‐6. There was no difference in protein synthesis in the Wt mice. IL‐6 OE can accelerate cachexia in the ApcMin/+ mouse, in part, through the repression of muscle IGF‐1 signaling and muscle protein synthesis. R01CA121249‐01A2

Expression of NF-κB and IκB proteins in skeletal muscle of gastric cancer patients

The mechanisms eliciting cancer cachexia are not well understood. Wasting of skeletal muscle is problematic because it is responsible for the clinical deterioration in cancer patients and for the ability to tolerate cancer treatment. Studies done on animals suggest that nuclear factor of kappa B (NF-κB) signalling is important in the progression of muscle wasting due to several types of tumours. However, there are no published studies in humans on the role of NF-κB in cancer cachexia. In this project, we studied the rectus abdominis muscle in patients with gastric tumours ( n = 14) and in age-matched control subjects ( n = 10) for markers of NF-κB activation. Nuclear levels of p65, p50 and Bcl-3 were the same in both groups of subjects. However, phospho-p65 was elevated by 25% in the muscles of cancer patients. In addition, expression of the inhibitor of kappa B alpha (IκBα) was decreased by 25% in cancer patients. Decreased expression of IκBα reflects its degradation by one of the IκBα kinases and is a marker of NF-κB activation. Interestingly, there was no correlation between the stage of cancer and the extent of IκBα decrease, nor was there a correlation between the degree of cachexia and decreased IκBα levels. This suggests that the activation of NF-κB is an early and sustained event in gastric cancer. The work implicates the NF-κB signalling in the initiation and progression of cancer cachexia in humans and demonstrates the need for additional study of this pathway; it also recommends NF-κB signalling as a therapeutic target for the amelioration of cachexia as has been suggested from studies done on rodents.

A viscerally driven cachexia syndrome in patients with advanced colorectal cancer: contributions of organ and tumor mass to whole-body energy demands

Background: Cancer cachexia–associated weight loss is poorly understood; energetically demanding tissues (eg, organ and tumor mass) and resting energy expenditure (REE) are reported to increase with advanced cancer.Objective: The objective was to quantify the potential contribution of increasing masses of energetically demanding tissues to REE with colorectal cancer cachexia progression.Design: A longitudinal computed tomography (CT) image review was performed to quantify organ size (liver, including metastases, and spleen) and peripheral tissues (skeletal muscle and adipose tissue) during colorectal cancer cachexia progression (n = 34). Body composition was prospectively evaluated by CT and dual-energy X-ray absorptiometry, and REE was determined by indirect calorimetry in advanced colorectal cancer patients (n = 18).Results: Eleven months from death, the liver (2.3 ± 0.7 kg) and spleen (0.32 ± 0.2 kg) were larger than reference values. One month from death, liver weight increased to 3.0 ± 1.5 kg (P = 0.010), spleen showed a trend to increase (P = 0.077), and concurrent losses of muscle (4.2 kg) and fat (3.5 kg) (P < 0.05) were observed. The estimated percentage of fat-free mass (FFM) occupied by the liver increased from 4.5% to 7.0% (P < 0.001). The most rapid loss of peripheral tissues and liver and metastases gain occurred within 3 mo of death. A positive linear relation existed between liver mass and measured whole-body REE (r2 = 0.35, P = 0.010); because liver accounted for a larger percentage of FFM, measured REE · kg FFM−1 · d−1 increased (r2 = 0.35, P = 0.010).Conclusions: Increases in mass and in the proportion of high metabolic rate tissues, including liver and tumor, represented a cumulative incremental REE of ≈17,700 kcal during the last 3 mo of life and may contribute substantially to cachexia-associated weight loss.

Insulin Treatment in Cancer Cachexia: Effects on Survival, Metabolism, and Physical Functioning

The present study was designed to evaluate whether daily insulin treatment for weight-losing cancer patients attenuates the progression of cancer cachexia and improves metabolism and physical functioning in palliative care. One hundred and thirty-eight unselected patients with mainly advanced gastrointestinal malignancy were randomized to receive insulin (0.11 +/- 0.05 units/kg/d) plus best available palliative support [anti-inflammatory treatment (indomethacin), prevention of anemia (recombinant erythropoietin), and specialized nutritional care (oral supplements + home parenteral nutrition)] according to individual needs. Control patients received the best available palliative support according to the same principles. Health-related quality of life, food intake, resting energy expenditure, body composition, exercise capacity, metabolic efficiency during exercise, and spontaneous daily physical activity as well as blood tests were evaluated during follow-up (30-824 days) according to intention to treat. Patient characteristics at randomizations were almost identical in study and control groups. Insulin treatment for 193 +/- 139 days (mean +/- SD) significantly stimulated carbohydrate intake, decreased serum-free fatty acids, increased whole body fat, particularly in trunk and leg compartments, whereas fat-free lean tissue mass was unaffected. Insulin treatment improved metabolic efficiency during exercise, but did not increase maximum exercise capacity and spontaneous physical activity. Tumor markers in blood (CEA, CA-125, CA 19-9) did not indicate the stimulation of tumor growth by insulin; a conclusion also supported by improved survival of insulin-treated patients (P<0.03). Insulin is a significant metabolic treatment in multimodal palliation of weight-losing cancer patients.