Expression of the human cachexia-associated protein (HCAP) in prostate cancer and in a prostate cancer animal model of cachexia

Prostate cancer (CaP) patients with disseminated disease often suffer from severe cachexia, which contributes to mortality in advanced cancer. Human cachexia-associated protein (HCAP) was recently identified from a breast cancer library based on the available 20-amino acid sequence of proteolysis-inducing factor (PIF), which is a highly active cachectic factor isolated from mouse colon adenocarcinoma MAC16. Herein, we investigated the expression of HCAP in CaP and its potential involvement in CaP-associated cachexia. HCAP mRNA was detected in CaP cell lines, in primary CaP tissues and in its osseous metastases. In situ hybridization showed HCAP mRNA to be localized only in the epithelial cells in CaP tissues, in the metastatic foci in bone, liver and lymph node, but not in the stromal cells or in normal prostate tissues. HCAP protein was detected in 9 of 14 CaP metastases but not in normal prostate tissues from cadaveric donors or patients with organ-confined tumors. Our Western blot analysis revealed that HCAP was present in 9 of 19 urine specimens from cachectic CaP patients but not in 19 urine samples of noncachectic patients. HCAP mRNA and protein were also detected in LuCaP 35 and PC-3M xenografts from our cachectic animal models. Our results demonstrated that human CaP cells express HCAP and the expression of HCAP is associated with the progression of CaP and the development of CaP cachexia.     

Prevention of cancer cachexia by a novel nuclear factor {kappa}B inhibitor in prostate cancer.

PURPOSE: To investigate the association between serum interleukin-6 (IL-6) and cachexia in patients with prostate cancer and the inhibitory effect of a new nuclear factor kappaB (NF-kappaB) inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on IL-6 production and cachexia in an animal model of hormone-refractory prostate cancer. EXPERIMENTAL DESIGN: The association between serum IL-6 levels and variables of cachexia was evaluated in 98 patients with prostate cancer. The inhibitory effects of DHMEQ on IL-6 secretion and cachexia were investigated in in vitro and in vivo studies using JCA-1 cells derived from human prostate cancer. RESULTS: Serum IL-6 levels were significantly elevated and cachexia developed in JCA-1 tumor-bearing mice as well as in prostate cancer patients with progressive disease. IL-6 secretion was significantly inhibited in JCA-1 cells exposed to DHMEQ. Intraperitoneal administration of DHMEQ (8 mg/kg) to tumor-bearing mice produced a significant amelioration of the reduction in body weight, epididymal fat weight, gastrocnemius muscle weight, hematocrit, and serum levels of triglyceride and albumin when compared with administration of DMSO or no treatment. DHMEQ caused a significant decrease of serum IL-6 level in JCA-1 tumor-bearing mice (all P < 0.05). CONCLUSIONS: These results suggested an association between serum IL-6 and cachexia in patients with prostate cancer and in JCA-1 tumor-bearing mice and that a new NF-kappaB inhibitor, DHMEQ, could prevent the development of cachexia in JCA-1 tumor-bearing mice presumably through the inhibition of IL-6 secretion. DHMEQ seems to show promise as a novel and unique anticachectic agent in hormone-refractory prostate cancer.     

Interleukin-6 induces androgen responsiveness in prostate cancer cells through up-regulation of androgen receptor expression.

Interleukin-6 (IL-6) induces prostate cancer (CaP) cell proliferation in vitro. Several lines of evidence suggest that IL-6 may promote CaP progression through induction of an androgen response. In this work, we explored whether IL-6 induces androgen responsiveness through modulation of androgen receptor (AR) expression. We found that in the absence of androgen, IL-6 increased prostate-specific antigen (PSA) mRNA levels and activated several androgen-responsive promoters, but not the non-androgen responsive promoters in LNCaP cells. Bicalutamide, an antiandrogen, abolished the IL-6 effect and IL-6 could not activate the PSA and murine mammary tumor virus reporters in AR-negative DU-145 and PC3 cells. These data indicate the IL-6 induces an androgen response in CaP cells through the AR. Pretreatment of LNCaP cells with SB202190, PD98059, or tyrphostin AG879 [p38 mitogen-activated protein kinase (MAPK), MAP/extracellular signal-regulated protein kinase kinase 1/2, and ErbB2 MAPK inhibitors, respectively) but not wortmannin (PI3-kinase inhibitor) blocked IL-6-mediated induction of the PSA promoter, which demonstrates that IL-6 activity is dependent on a MAPK pathway. Finally, IL-6 activated the AR gene promoter, resulting in increased AR mRNA and protein levels in LNCaP cells. These results demonstrate that IL-6 induces AR expression and are the first report of cytokine-mediated induction of the AR promoter. Taken together, our results suggest that IL-6 induces AR activity through both increasing AR gene expression and activating the AR in the absence of androgen in CaP cells. These results provide a mechanism through which IL-6 may contribute to the development of androgen-independent CaP.     

The usefulness of serum human kallikrein 11 for discriminating between prostate cancer and benign prostatic hyperplasia

Prostate-specific antigen (PSA) is the most useful tumor marker for diagnosis and monitoring of prostate cancer (CaP). Recently, we developed a specific immunoassay for human kallikrein 11 (hK11), one of the kallikrein gene family members, and found that hK11 was highly expressed in prostatic tissue and could be detected in seminal plasma (E. P. Diamandis et al., Cancer Res., 62: 295-300, 2002). The aim of this study was to investigate whether serum hK11 levels could be used to discriminate CaP from benign prostatic hyperplasia (BPH). We analyzed for hK11, total PSA, and percentage of free PSA, 150 serum samples from men with histologically confirmed BPH (n = 64) or CaP (n = 86). Total and free PSA levels were measured by the Immulite PSA assay, and hK11 levels were measured by our previously published immunofluorometric assay. Serum hK11 levels and the hK11:total PSA ratio were both significantly lower in CaP patients than in BPH patients. In the subgroup of patients with percentage of free PSA less than 20, an additional 54% of BPH patients could have avoided biopsies by using the hK11:total PSA ratio. Receiver operating characteristic (ROC) curve analysis demonstrated that the hK11:total PSA ratio [area under the curve (AUC), 0.83] and percentage of free PSA (AUC, 0.83) were much stronger predictors of CaP than total PSA (AUC, 0.69). These preliminary data suggest that the hK11:total PSA ratio could be a useful tumor marker for CaP and could be combined with percentage of PSA to further reduce the number of unnecessary prostatic biopsies.     

Serum osteoprotegerin levels are increased in patients with advanced prostate cancer.

PURPOSE: Osteoprotegerin (OPG) is a soluble osteoclastogenesis inhibitor that regulates bone turnover. We reported recently that OPG protein expression is significantly increased in prostate cancer (CaP) cells present in bone metastases. The aim of this study was to determine serum OPG levels in patients at different stages of CaP and correlate the results with disease status. EXPERIMENTAL DESIGN: OPG levels were examined in patients with benign prostatic hyperplasia, clinically localized CaP, early recurrence of CaP, and advanced CaP and evidence of bone metastases. Serum OPG levels were measured by sandwich ELISA assays. The serum Crosslaps (sCTX) assay was used to quantify bone resorption in the advanced CaP group. RESULTS: Serum OPG levels were increased significantly in the advanced CaP group versus all other groups. There was no significant correlation between serum OPG levels and PSA levels either in the advanced CaP group or within any of three treatment subclasses of this group: no Tx, those not treated; Tx, those treated; and R, those treated with resorption blockers. Levels of OPG were negatively correlated with sCTX levels only in the advanced CaP Tx group. sCTX levels correlated with prostate-specific antigen levels in the advanced CaP Tx and R groups but not in the no-Tx group. CONCLUSIONS: Our data show that serum OPG levels are increased with advanced CaP. We hypothesize that OPG levels are related to CaP progression and suggest that further studies of the biological effects of OPG on CaP metastases are warranted.     

Serum interleukin 6 as a prognostic factor in patients with prostate cancer.

The present study was undertaken to evaluate the prognostic significance of the serum levels of interleukin 6 (IL-6) in patients with prostate cancer. Serum IL-6 levels were measured in 74 patients with prostate cancer. The tumor was stage B in 23 patients, stage C in 14 patients, and stage D in 37 patients. Prognostic significance of tumor histology, performance status (PS), bone metastasis, serum prostate-specific antigen (PSA) level, serum alkaline phosphatase (ALP) level, serum lactate dehydrogenase level, serum IL-6 levels, and hemoglobin on disease-specific survival was assessed using univariate and multivariate Cox's proportional hazards model analyses. Serum IL-6 was significantly correlated with the clinical stage of prostate cancer. Univariate analysis of all patients demonstrated that an extent of disease (EOD) on bone scanning > or = 1, IL-6 > or = 7 pg/ml, PS > or = 1, PSA > 100 ng/ml, and ALP > 620 IU/liter were associated with a significantly lower survival rate than their respective counterparts. In multivariate analysis, however, the only two significant prognostic factors were EOD and IL-6. In 51 patients with stage C and stage D prostate cancer, univariate analysis showed that EOD > or = 1, IL-6 > or = 7 pg/ml, PS > or = 1, PSA > 100 ng/ml, LDH > 200 IU/liter, and ALP > 620 IU/liter were significantly related to survival, whereas multivariate analysis again demonstrated that EOD > or = 1 and IL-6 > or = 7 pg/ml were significant prognostic factors. These results indicate that the serum IL-6 level is a significant prognostic factor for prostate cancer as well as EOD.     

前列腺癌ADC值与血清IL-6、VEGF、PSA的相关性分析

目的:探讨前列腺癌（prostate cancer,PCa）患者表观扩散系数（apparent diffusion coefficient,ADC）与血清血管内皮生长因子（vascular endothelial growth factor,VEGF)、白细胞介素-6（interleukin-6,IL-6）、前列腺特异性抗原（prostate specific antigen,PSA）的相关性。方法:收集2016年1月至2017年12月经临床病理证实且资料齐全的60例PCa患者,将其分成两组,经SPECT/CT全身骨显像诊断为30例骨转移患者及30例未发生全身骨转移患者。采集全部患者的肘静脉血,利用酶联免疫吸附法（ELISA法）及化学发光法测定血清VEGF、IL-6及PSA水平。结果:60例PCa患者ADC值与血清VEGF、IL-6及PSA存在负相关(r=-0.431,P=0.001＜0.005;r=-0.534,P=0.000<0.005;r=-0.593,P=0.000＜0.005),骨转移组血清VEGF、IL-6及PSA水平明显高于无骨转移组（P＜0.05）。结论:血清VEGF、IL-6及PSA与PCa发生、进展及转移关系密切。PCa患者ADC值与血清VEGF、IL-6、PSA的相关性可以作为评估患者病情进展程度的一个指标。     

L-carnitine ameliorates cancer cachexia in mice by regulating the expression and activity of carnitine palmityl transferase

Cancer cachexia is characterized by progressive weight loss with the depletion of adipose tissue and skeletal muscle. Impaired fatty acid oxidation mainly resulting from the decrease of carnitine palmitoyltransferase I and II activities in the liver is an important factor that contributes to cancer cachexia . Although recent studies suggest a potential application of L-carnitine in treatment of cancer cachexia, the underlying mechanisms are unknown. In the present study, we aim to assess the effects of L-carnitine on the activity and expression of CPT I and II in the liver of cachectic cancer mice. Our results show that the inoculation of colon-26 adenocarcinoma cells into mice led to cancer cachexia characterized by notable decreases in food intake, gastrocnemius muscle and epididymus fat weight. In addition, the mRNA level and activity of liver carnitine palmitoyltransferase (CPT) I and II, and serum levels of free carnitine and acetylcarnitine were markedly decreased in cachectic mice, accompanied by marked increases in serum levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). A continuous oral treatment with L-carnitine at 18 mg/kg per day increased dietary uptake, gastrocnemius muscle weight and epididymus fat weight, increased blood glucose and serum albumin levels, and decreased total cholesterol level in cancer cachectic mice, but did not affect tumor growth. These effects of L-carnitine on cancer cachexia mice were accompanied by the upregulation of mRNA level of CPT I and II and increased enzyme activity of CPT I in the liver, as well as the downregulation of serum TNF-α and IL-6 levels. Moreover, free carnitine levels were negatively correlated with serum TNF-α or IL-6 level. These results indicate that L-carnitine ameliorates cancer cachexia by regulating serum TNF-α and IL-6 levels and modulating the expression and activity of CPT in the liver.     

Prostate cancer diagnosis: should patients with prostate specific antigen >10 ng/mL have stratified prostate biopsy protocols?

Background: Trans-rectal ultrasound (TRUS) guided systematic prostate biopsy is a standard tool in prostate cancer (CaP) diagnosis. Extended biopsy techniques using 10-12 cores are the norm. Controversy exists on extended TRUS biopsy in men with PSA >10 ng/mL. We evaluated cancer detection rates on an individual core basis, to stratify prostate biopsy protocols based on PSA levels. Patients and methods: Over a five-year period, 1036 patients underwent TRUS guided prostate biopsy for raised serum PSA (>2.5 ng/mL). 436 patients had PSA >10 ng/mL. Patients with PSA <50 ng/mL underwent a 12-core TRUS guided prostate biopsy including six peripheral biopsies. The six peripheral biopsies were directed laterally towards the base, mid-zone and apices. Remainder were standard para-sagittal sextant biopsies. Patients were stratified into three groups (PSA 10-20 ng/mL, 20-50 ng/mL and >50 ng/mL). Results: Mean age of 436 patients with PSA >10 ng/mL was 70.3years. 270 (62%) men had cancer. Cancer detection rates for different PSA levels were 46% (10-20 ng/mL), 76% (20-50 ng/mL) and 93% (>50 ng/mL). Higher PSA levels and advanced clinical stage were associated with increased cancer detection rates. All patients with clinical T3 and T4 disease had biopsy diagnosed CaP. Conclusion: TRUS guided prostate biopsy in patients with PSA >10 ng/mL did not require 12 cores to diagnose CaP. CaP diagnosis required 8 cores in men with PSA 10-20 ng/mL. These cores were right and left peripheral basal and apical, and right and left para-sagittal basal and apical biopsy. Only 6 cores were necessary to diagnose CaP in men with PSA >20 ng/mL which were right and left peripheral basal and apical, and para-sagittal apical biopsies. We suggest limited TRUS prostate biopsy protocols for men with PSA >10 ng/mL.     

Incidentally Detected Adenocarcinoma Prostate in Transurethral Resection of Prostate Specimens: a Hospital Based Study from India

Background: Awareness about prostate cancer has increased in the community, and prostate cancer screening examinations, including prostate specific antigen (PSA) assays, are now widely available. Prior to the PSA era, up to 27% of prostate cancers were detected incidentally at the time of transurethral resection of prostate (TURP). After PSA testing became widely available, the incidence of incidentally detected carcinoma prostate in TURP specimens without prior diagnosis reduced to 5-13%. However, the incidence of incidentally detected carcinoma prostate has been reported to vary across the globe since various factors can influence the identification of this malignancy in TURP specimens. In this paper, we focus on rates of incidentally detected prostate cancer in TURP specimens in our hospital and correlate it with various parameters. Materials and Methods: This retrospective study of histopathological findings of biopsy specimens was conducted for patients undergoing TURP during a period of 5 years from April 2010. The inclusion criteria were patients diagnosed with benign prostatic hyperplasia (BPH) (digital rectal examination (DRE) not showing any abnormally hard areas and normal age adjusted PSA values). Patients with elevated PSA, abnormal DRE, documented urinary tract infection and proved adenocarcinoma prostate (CaP) were excluded from the study. The total weight of prostatectomy specimen, occurrence of carcinoma prostate in the chips, percentage of total tissue resected showing malignancy and Gleason's scores were recorded. Results: A total of 597 patients belonging to the inclusion criteria were studied. The incidence of occult CaP in the study group was 5.2 % (31/597). Out of these, 8 belonged to T1a and 23 belonged to T1b stages. The age group 70 - 79 years had the maximum incidence of occult CaP. It was observed that the clinical grading of prostate did not have a bearing on the incidence of occult CaP whereas the weight of resected specimen correlated with the incidence of CaP. The incidence of occult CaP was greater with low volume prostates ( < 20 g). (P=0.15). Conclusions: The rate of incidentally detected adenocarcinoma prostate in patients undergoing TURP for clinically diagnosed BPH was found to be only 5.2 % in our study which is low when compared with similar studies done elsewhere. The age of the patient and weight of the resected specimen correlated with incidence of occult prostate cancer. The clinical grading of prostate by DRE however, demonstrated no correlation.     

Hepatic cytochrome P450 3A drug metabolism is reduced in cancer patients who have an acute-phase response

Inflammatory disease states (infection, arthritis) are associated with reduced drug oxidation by the cytochrome P450 3A system. Many chemotherapy agents are metabolised through this pathway, and disease may therefore influence inter-individual differences in drug pharmacokinetics. The purpose of this study was to assess cytochrome P450 3A function in patients with advanced cancer, and its relation to the acute-phase response. We evaluated hepatic cytochrome P450 3A function in 40 patients with advanced cancer using the erythromycin breath test. Both the traditional C(20min) measure and the recently proposed 1/T(MAX) values were estimated. The marker of acute-phase response, C-reactive protein and the pro-inflammatory cytokines IL-6, IL-1beta, TNFalpha and IL-8 were measured in serum or plasma at baseline. Cancer patients with an acute phase response (C-reactive protein >10 mg x l(-1), n=26) had reduced metabolism as measured with the erythromycin breath test 1/T(MAX) (Kruskal-Wallis Anova, P=0.0062) as compared to controls (C-reactive protein < or =10 mg x l(-1), n=14) Indeed, metabolism was significantly associated with C-reactive protein over the whole concentration range of this acute-phase marker (r=-0.64, Spearman Rank Correlation, P<0.00001). C-reactive protein serum levels were significantly correlated with those of IL-6 (Spearman coefficient=0.58, P<0.0003). The reduction in cytochrome P450 3A function with acute-phase reaction was independent of the tumour type and C-reactive protein elevation was associated with poor performance status. This indicates that the sub-group of cancer patients with significant acute-phase response have compromised drug metabolism, which may have implications for the safety of chemotherapy in this population.     

高强度聚焦超声对中晚期前列腺癌患者去势治疗后机体免疫指标的影响

背景与目的：高强度聚焦超声(high intensity focused ultrasound,HIFU)可以有效治疗前列腺癌,但肿瘤是一种全身性的疾病,理想的肿瘤治疗方法是能够在不损伤正常组织的同时进行局部肿瘤切除,还能够激活全身的抗肿瘤免疫反应。本研究旨在探讨HIFU治疗对去势治疗后中晚期前列腺癌患者机体免疫指标的影响。方法：行去势治疗的中晚期前列腺癌患者40例,随机分为2组,HIFU组为去势治疗后2周行HIFU治疗(n=20),对照组为单纯去势治疗(n=20),全部经直肠前列腺穿刺病理检查确诊,均为晚期前列腺癌患者,即前列腺特异性抗原(prostate specific antigen,PSA)>20 ng/mL。患者自愿接受HIFU治疗并签署知情同意书。HIFU组与对照组患者平均年龄(72.56±12.38)岁、(75.23±9.35)岁(P=0.446 3);初始PSA为(105.22±20.55)ng/mL、(100.53±18.38)ng/mL(P=0.451 5)。分别取治疗前和治疗后2周前列腺癌患者外周血6 d,检测T淋巴细胞亚群(CD4⁺、CD8⁺、CD4⁺/CD8⁺)和外周血Th细胞因子(IFN-γ、IL-2、IL-4、IL-10)。结果：HIFU组患者治疗后CD4⁺百分比及CD4⁺/CD8⁺比值明显升高;细胞因子IFN-γ、IL-2水平明显增高,而IL-4、IL-10水平明显降低,与治疗前相比差异有统计学意义(P＜0.05),Th1/Th2平衡向Th1漂移。而对照组患者治疗前、后各项免疫指标差异无统计学意义(P＞0.05)。HIFU组与对照组前、后各项免疫指标差值比较差异有统计学意义(P＜0.05)。结论：HIFU治疗可在近期内改善去势治疗后中晚期前列腺癌患者机体免疫功能。     

Capecitabine improves cancer cachexia and normalizes IL-6 and PTHrP levels in mouse cancer cachexia models

Purpose

To clarify the potential of parathyroid hormone-related protein (PTHrP) and interleukin-6 (IL-6) as cachectic factors in a colon 26 model and the effects of capecitabine on cancer cachexia as determined by plasma levels of IL-6 and PTHrP and body weight loss.

Methods

From two colon 26 sublines-cancer cachectic clone20 and non-cachectic clone5 plasma levels of PTHrP protein and mRNA expression levels in tumor tissues were compared. An IL-6 neutralizing antibody, a PTHrP neutralizing antibody, and capecitabine were administered into mice bearing clone20 and their anticachectic effects evaluated.

Results

The plasma level of PTHrP protein in mice bearing clone20 was higher than that in mice bearing clone5. The expression level of PTHrP mRNA was 49-fold higher in tumor tissues of clone20 than of clone5, according to GeneChip^® analysis. PTHrP antibody as well as IL-6 antibody suppressed wasting of the body and gastrocnemius and adipose tissue weights. PTHrP antibody suppressed the induction of hypercalcemia but not hypoglycemia or elevation of IL-6, whereas IL-6 antibody suppressed the induction of hypoglycemia but not hypercalcemia or elevation of PTHrP. Capecitabine, a fluorinated pyrimidine anticancer agent, improved body wasting of mice bearing clone20 at a low dose with no reduction of tumor volume. Furthermore, capecitabine lowered the levels of PTHrP and IL-6 in plasma and suppressed hypoglycemia and hypercalcemia in this model. Capecitabine also showed anticachectic effects on cachexia in a cancer model induced by human cervical cancer cell line Y (also known as Yumoto).

Conclusions

PTHrP and IL-6 were found to be factors in the development of cachexia in a colon 26 cancer model, and capecitabine improved cancer cachexia by suppressing the plasma levels of IL-6 and PTHrP in colon 26 and Y cachectic models.     

Clinicopathological characteristics of androgen-dependent advanced prostate cancer patients with α2-macroglobulin deficiency

α2-Macroglobulin (α2M) is thought to be involved in cancer metastasis and inflammatory reaction through its functions as a proteinase inhibitor and carrier protein for interleukin-6 (IL-6). We previously reported that advanced prostate cancer (PCa) patients with multiple distant bone metastases had markedly decreased serum α2M levels (<20 mg/dl) and no detection of α2M by immunoelectrophoresis (defined as α2M deficiency). We also showed a relationship between serum α2M levels and acute inflammatory biomarkers in PCa patients with or without α2M deficiency. In this study, we analyzed in detail the clinicopathological characteristics and pathogenesis of α2M deficiency in androgen-dependent advanced PCa patients. In this study, 15 PCa patients were diagnosed at the Kitasato University Hospital. α2M levels were determined by laser-nephelometry and immunoelectrophoresis, and PSA levels were determined by enzyme immunoassay. IL-6 levels were measured by a specific luminescence sandwich-type enzyme-linked immunosorbent assay, and CRP levels were determined by latex nephelometry. Immunohistochemical staining for PSA in PCa specimens was also performed. The binding assay for purified α2M and PSA was analyzed by western blotting. α2M deficiency was specific for advanced PCa patients with multiple distant bone metastases. PSA was markedly detected in sera and prostate specimens of advanced PCa patients with α2M deficiency, and there was a negative correlation between serum α2M and PSA levels during the course of clinical treatment. Acute inflammatory biomarkers such as IL-6 and CRP were within reference range in α2M-deficient patients. The binding assay showed that PSA easily bound to α2M, which was detected as an approximately 800-kDa complex by western blotting. Further, genetic analysis of a α2M-deficient patient showed no mutations in the α2M gene. These results suggested that α2M deficiency develops from catabolism of α2M in androgen-dependent advanced PCa patients, and serum α2M level may be an indicator of PCa disease progression in addition to PSA level.     

Manifestations of cancer cachexia induced by colon 26 adenocarcinoma are not fully ascribable to interleukin-6

In order to further clarify the role of interleukin 6 (IL-6) in the pathogenesis of cachexia, recombinant human IL-6 (hIL-6) was administered s.c. by osmotic pump for 9 days at a dose of 1 or 10 μg/day into CDFI mice inoculated with a non-cachexia-inducing subclone of colon 26 adenocarcinoma (clone 5), or with a cachexia-inducing subclone (clone 20) of this malignancy. The serum level of IL-6 in non-cachectic mice with clone-5 tumors was 35% lower than in cachectic mice bearing clone 20 of colon 26 adenocarcinoma on the 19th day after tumor inoculation. IL-6 administration induced anemia, thrombocytosis and visceral organ hypertrophy not only in mice with clone-5 tumors but also in control mice with no tumor burden. Lipolysis and proteolysis became conspicuous when a large dose (10 μg/day) of IL-6 was infused into mice with clone-5 tumors. However, IL-6 supplementation did not induce loss of body weight, a decline in food intake or lymphocytopenia, which were characteristically observed in cachectic mice with clone-20 tumors. In conclusion, IL-6 appears to be a permissive factor for the development of cachexia but, while it can induce some of the symptoms typical of cachexia, it cannot in itself induce the full cachectic syndrome. © 1995 Wiley-Liss Inc.     

细胞因子在实验性癌症恶病质中的作用

目的 探讨细胞因子TNF-α、IL－1、IL－6与癌症恶病质的关系,观察消炎痛对癌症恶病质的治疗效果。方法 且肺腺癌（LA795)接种T739小鼠建立癌症恶病质实验模型,测定荷瘤前后不同阶段小鼠血清IL－6、IL－1、TNF－α的水平及血糖、甘油三酯和总蛋白的变化及体重变化,并且观察消炎痛对癌症恶病质的治疗效果。结果 癌症恶病质小鼠的体重、血糖、血甘油三酯、血总蛋白显著低于非荷瘤组,而血清IL－6、TNF－α和IL－1水平显著高于非荷瘤组。消炎痛治疗后,恶病质小鼠的体重、摄食量、血糖、血甘油三酯和血总蛋白水平较生理盐水对照组显著提高且生存时间延长,同时IL－6、TNF－α、IL－1的血清水平显著低于生理盐水对照组。结论 IL－6、TNF-α、IL－1参与了本动物模型的癌症恶病质诱导。通过抑制IL-6、TNF-α、IL－1的升高,消炎痛具有改善癌症恶病质的作用。     

A study of thyroid function in cancer cachexia

The mechanisms responsible for cancer cachexia have not yet been clarified. To further investigate the role played by the hypothalamic-pituitary-thyroid axis in cancer cachexia, we evaluated serum levels of T3, FT3, T4, FT4, TSH and TBG in a group of 26 cancer patients, 14 of whom showed cachexia, whereas the other 12 had a body weight within the normal range despite their advanced diseases. As controls, 58 healthy subjects and 11 patients with benign weight loss were included in the study. Low levels of both T3 and FT3 were observed in all patients with benign weight loss and in 9/12 advanced cancer patients who had no cancer cachexia. On the contrary, only 4/14 cachectic cancer patients presented decreased values of T3 and FT3. Moreover, the mean serum levels of T3 and FT3 in cachectic oncologic patients were significantly higher than those seen both in non-cachectic cancer patients and in patients with benign weight loss. Since T3 is the biologically active thyroid hormone, the lack of a decrease in its production might play a role in the pathogenesis of cancer cachexia.