Pretreatment serum levels of cytokines and cytokine receptors in patients with non-small cell lung cancer, and correlations with clinicopathological features and prognosis. M-CSF - an independent prognostic factor

OBJECTIVES: Cytokines are potential new serum markers, especially desirable for malignancies with poor prognosis like non-small cell lung cancer (NSCLC). METHODS: Cytokines, tumor necrosis factor alpha (TNFalpha), interleukin (IL)-6 and IL-8, soluble TNF (sTNF) RI, sTNF RII, soluble IL-2 receptor-alpha, IL-1 receptor antagonist (IL-1ra), IL-10, vascular endothelial growth factor, basic fibroblast growth factor, and macrophage (M-CSF) and granulocyte colony-stimulating factor, as well as tumor markers - carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and CYFRA 21.1 - were assessed in the sera of 103 untreated NSCLC patients, and these cytokines and tumor markers were referred to clinical parameters of the disease and to the overall survival of patients evaluated during a 6-year follow-up. RESULTS: Most of the factors analyzed were found to be elevated in the sera of NSCLC patients, and increases in IL-6, IL-8 and sTNF RI were noted in the greatest proportion of stage I patients. Most cytokine/cytokine receptor levels revealed higher sensitivity than the standard tumor markers; IL-6 and IL-1ra levels were significantly different in patients with squamous cell versus adenocarcinoma; IL-6 and IL-10 were related to the tumor size, while IL-6 and M-CSF levels significantly increased with disease progression. A significant prognostic value of pretreatment serum M-CSF and CEA levels in NSCLC patients has been shown, but only M-CSF proved to be an independent prognostic factor. CONCLUSIONS: Increased pretreatment serum M-CSF level is a significant independent predictor of poor survival in patients with NSCLC.     

A survey of prognostic value of serum factors in multiple myeloma patients before treatment: macrophage-colony stimulating factor (M-CSF) is a powerful predictor of survival

Cytokines are involved in the pathogenesis of multiple myeloma (MM) and other cancers. The aim of this study was to evaluate a range of cytokines of diverse activity in patients with multiple myeloma for a possible prognostic value. Concentrations of the following cytokines and cytokine receptors were measured by ELISA in the sera of 64 untreated MM patients: IL-6, IL-8, IL-10, TNFα, sTNF R I and II, sIL-2Rα, IL-1ra, M-CSF, G-CSF, VEGF, and bFGF. Serum levels of sTNF RI, IL-6, and bFGF were elevated in over 50% of patients. There was an inverse relationship between sTNF RII, TNFα, IL-1ra, and albumin levels. There was no significant relationship between cytokines/cytokine receptors and other serum correlates of myeloma. In a univariate survival analysis, β2-microglobulin, LDH, sIL-2Rα, sTNF RI, and M-CSF were significant variables. In a multivariate analysis, only M-CSF and β2-microglobulin retained a significant influence on survival. Serum M-CSF may be considered another independent and clinically useful prognostic factor in multiple myeloma.     

Cytokine and cytokine receptor serum levels in adult bone sarcoma patients: correlations with local tumor extent and prognosis

BACKGROUND AND OBJECTIVES: We analyzed the correlations between pretreatment serum levels of 11 cytokines and soluble cytokine receptors (interleukin 6 (IL-6); interleukin 8 (IL-8); interleukin 10 (IL-10); vascular endothelial growth factor (VEGF); basic fibroblast growth factor (bFGF); macrophage colony-stimulating factor (M-CSF); granulocyte colony-stimulating factor (G-CSF); interleukin 1 receptor antagonist (IL-1ra); sIL-2Ralpha; tumor necrosis factor receptor I (TNF RI), and TNF RII) with clinico-pathological features and survival of patients with bone sarcomas. METHODS: Altogether, 72 patients with bone sarcomas without distant metastases before treatment (26 osteosarcomas-36%, 23 chondrosarcomas-32%, 13 Ewing's sarcomas/PNET-18%, 10 giant-cell tumors-14%), 22 patients with benign non-inflammatory bone tumors and 50 age-matched healthy controls were included into this prospective study. RESULTS: Median serum levels of 9/11 cytokines, with the exception of sIL-2Ralpha and G-CSF, were significantly higher in sarcoma patients than in controls. Median serum levels of IL-6, IL-8, IL-1ra, TNF RI, and M-CSF were significantly higher in patients with bone sarcoma as compared to patients with benign bone tumors. In 45.9% of sarcoma patients, six or more cytokines and cytokine receptors, including those that are involved in bone destruction (e.g., IL-6 and IL-8) and bone formation (e.g., IL-1ra and TNFRI and TNFRII), were elevated in parallel. Serum levels of IL-6, IL-8, TNF RI, TNF RII, and VEGF correlated significantly with tumor size (<10 cm vs. >or=10 cm in diameter) and serum levels of IL-6, IL-8, TNF RI, and IL-1ra correlated significantly with local tumor extent (E2/4 vs. E5/6 according to the classification proposed by Spanier et al. 46). Moreover, serum levels of IL-1ra and IL-6 were significantly higher in patients with small tumors (<5 cm in diameter) infiltrating structures adjacent to the periosteum (E5/6) than in large tumors (>10 cm in diameter) but confined to the bone and periosteum (E < 4). The lowest median serum levels of 8/11 cytokines/cytokine receptors were found in patients with giant-cell tumors. In an univariate analysis, increased serum levels of IL-1ra, IL-6, IL-8, IL-10, sIL-2Ralpha, M-CSF, TNF RI, and TNF RII, the number of cytokines elevated, higher tumor grade, larger tumor size, greater local extent (E) and patients' age >35 years correlated with poor overall survival (OS) (P < 0.05). Similarly, high serum levels of IL-1ra, IL-6, TNF RI and TNF RII, tumor grade, tumor size, and tumor local extent (E) (P < 0.05) affected disease free survival (DFS) in univariate analysis. Multivariate analysis using Cox's proportional hazards model showed that high serum levels of IL-1ra (P = 0.039) and TNF RI (P = 0.048), the number of serum cytokines above normal cut-off values (0-1 vs. 2-5 vs. >or=6; P = 0.029), greater tumor local extent E (E2/4 vs. E5/6; P = 0.02) correlated significantly with shorter OS. Only E was found as an independent prognostic factor for DFS (P = 0.04). CONCLUSIONS: These findings indicate that cytokines and soluble cytokine receptors, both physiologically involved in bone destruction and bone formation, have an essential role in the progression of malignant bone tumors.     

Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer

Cancer-related indoleamine (2,3)-dioxygenase up-regulation by interferon-gamma might influence quality of life by depleting serum tryptophan. We correlated serum tryptophan levels with immune activation and quality of life in patients with colorectal liver metastases. Venous blood was sampled from patients with primary colorectal cancer and from patients with metachronous colorectal liver metastases who completed quality of life and psychological questionnaires. Serum tryptophan, kynurenine, neopterin, interleukin 2 soluble receptor alpha (IL-2 sRalpha), soluble tumour necrosis factor receptor I (sTNF RI), interleukin 6, and C-reactive protein were measured. Liver metastasis volume was estimated by computerised tomography, and survival from blood sampling was noted. Sixty-six patients with colorectal cancer were studied (39 males; median age 66 years) of whom 25 had colorectal liver metastases only (17 males; median age 62 years; median liver metastasis volume 208 ml; median survival 234 days). Reduced serum tryptophan was significantly associated with Rotterdam Symptom Checklist physical symptom (r=-0.51, P=0.01) and Sickness Impact Profile (r=-0.42, P=0.04) scores, and correlated with increased serum neopterin (r=-0.36, P=0.003), IL-2 sRalpha (r=-0.51, P=0.01) and sTNF RI (r=-0.45, P=0.02) levels. Stepwise regression analyses suggested that serum tryptophan was an independent predictor of Rotterdam Symptom Checklist physical symptom (regression coefficient -20.78, P=0.01) and Sickness Impact Profile (regression coefficient -109.09, P=0.04) scores. The results supported a role for interferon-gamma-mediated serum tryptophan decrease in cancer-induced quality of life deterioration.     

Cytokine serum levels in soft tissue sarcoma patients: correlations with clinico-pathological features and prognosis

We investigated the correlations between serum levels of selected proinflammatory, hematopoietic and angiogenic cytokines and soluble cytokine receptors with the clinico-pathological features and prognosis in soft tissue sarcoma patients. Serum levels of 9 cytokines (TNFalpha, IL-1ra, IL-6, IL-8, IL-10, M-CSF, G-CSF, VEGF, bFGF) and 4 free cytokine receptors (sIL-2R alpha, sIL-6R, TNFRI, TNFRII) were measured by means of an enzyme-linked immunoadsorbent assay kit in 156 soft tissue sarcoma patients before the treatment and in 50 healthy controls. Serum levels of 10 cytokines and cytokine receptors were also assayed during patients' follow-up after the treatment. Significantly elevated pretreatment serum levels of 11/13 cytokines and cytokine receptors were found in sarcoma patients, as compared to healthy controls. In 40.4% of patients 6 or more cytokines and cytokine receptors (most frequently: TNF RI, IL-6, IL-8) were elevated in parallel. Serum levels of IL-6, sIL-2R, VEGF, M-CSF and TNF RI correlated significantly with tumor size and serum levels of IL-8 and IL-6 were significantly higher in patients with Grade 2/3 vs. Grade 1 tumors. We did not observe any significant differences in cytokine serum levels between patients with primary and recurrent tumors and patients with and without distant metastases. Using univariate analysis, overall survival (OS) in all patients was affected by tumor size (<5 cm vs. 5-10 cm vs. >10 cm), tumor grade (G1 vs. G2/3), presence of metastases, pretreatment serum levels of 8 cytokines (IL-6, IL-8, IL-10, sIL-2R, TNF RI, TNF RII, M-CSF, VEGF) and the number of cytokines increased (0-1 vs. 2-5 vs. < or = 6). Elevated serum levels of IL-6, IL-8, IL-10 and sIL-2R alpha, high tumor grade and larger tumor size strongly correlated with shorter disease-free survival (DFS). Multivariate analysis identified G2/3 tumor grade (p = 0.001), the presence of metastases (p = 0.004), elevated IL-6 serum level (p = 0.02), elevated IL-8 serum level (p = 0.048) and the number of cytokine serum levels above upper cut-off values (p = 0.01) as the independent prognostic factors related to OS, and G2/3 tumor grade (p = 0.005) and increased IL-6 serum level (p = 0.035) as independent prognostic factors related to DFS. In a group of patients without metastases (M0) higher tumor grade, elevated serum level of IL-6 and TNF RII, and the number of elevated cytokine serum levels correlated independently with poor survival. We found a significant decrease of several cytokine serum levels in patients after treatment (IL-1ra, IL-6, IL-8, IL-10, TNF RII, M-CSF) [p < 0.05]. Persistently elevated serum level of IL-6 after the treatment has also shown negative prognostic significance for OS (univariate analysis). Serum levels of some proinflammatory, hematopoietic and angiogenic cytokines and cytokine receptors are elevated, frequently in parallel, in a large percentage of soft tissue sarcoma patients. Significant correlations of serum cytokine levels with tumor size and grade suggest that some of these cytokines may be directly or indirectly involved in the progression of soft tissue sarcomas. Serum assays of IL-6, IL-8 and TNF RII before or after the treatment may be useful in establishing soft tissue sarcoma patients prognosis.     

大肠癌血清肿瘤坏死因子α、白细胞介素8和可溶性白细胞介素2受体水平的检测及其临床意义

目的探讨血清肿瘤坏死因子（TNFα）、白细胞介素8（IL-8）和可溶性白细胞介素2受体（sIL-2R）水平在结直肠癌中的意义。方法用酶联免疫吸附试验（ELISA）法测定93例结直肠癌患者和33例健康对照组外周静脉血清TNFα、IL-8和sIL-2R含量。结果结直肠癌患者血清TNFα、IL-8和sIL-2R含量明显高于正常对照组（P〈0．001）,Dukes分期C＋D期结肠癌患者血清TNFα,IL-8和sIL-2R含量明显高于DukesA＋B期（P〈0．001）,手术后3年复发者血清TNFα、IL-8和sIL-2R的含量均高于未复发组（P〈0．001）。结论TNFα、IL-8、sIL-2R是与结肠癌病情变化和预后相关的细胞因子,可作为结肠癌病情监测和预后判断的指标。     

Stage-dependent alterations of the serum cytokine pattern in colorectal carcinoma

Background:

Inflammation contributes to the pathogenesis of colorectal cancer (CRC), and cytokine levels are altered during colorectal carcinogenesis.

Methods:

The serum levels of 13 cytokines and their relation to clinical and pathological parameters, and systemic inflammatory response (mGPS, CRP and neutrophil–lymphocyte ratio), were analysed from a prospective series of 148 CRC patients and 86 healthy age- and sex-matched controls.

Results:

CRC patients had higher serum platelet-derived growth factor, interleukin (IL)-6, IL-7, and IL-8 levels and lower monocyte chemotactic protein-1 (MCP-1) levels than the controls. A logistic regression model for discriminating the patients from the controls – including the five most predictive cytokines (high IL-8, high IL-6, low MCP-1, low IL-1ra, and low IP-10) – yielded an area under curve value of 0.890 in receiver operating characteristics analysis. Serum cytokines showed distinct correlation with other markers of systemic inflammatory response, and advanced CRCs were associated with higher levels of IL-8, IL-1ra, and IL-6. A metastasised disease was accompanied by an orientation towards Th2 cytokine milieu.

Conclusion:

CRC is associated with extensive alterations in serum cytokine environment, highlighting the importance of studying relative cytokine level alterations. Serum cytokine profile shows promise in separating CRC patients from healthy controls but its clinical value is yet to be confirmed.     

Cytokine responses to intraventricular injection of interleukin 2 into patients with leptomeningeal carcinomatosis: rapid induction of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, gamma-interferon, and soluble interleukin 2 receptor (Mr 55,000 protein).

Interleukin 2 (IL-2) is a potent immunostimulant that causes the release of secondary cytokines and the production of lymphokine-activated killer cells. We investigated the cellular and cytokine responses to injection of recombinant human IL-2 into the human cerebrospinal fluid of 11 patients with metastatic tumors involving the spinal or cerebral leptomeninges. After initial intraventricular IL-2 administration (1.25 x 10(5) to 2 x 10(6) Cetus units/injection), cerebrospinal fluid samples were collected at intervals from 0 to 24 h. Enzyme-linked immunosorbent assay results indicated that IL-2 levels gradually decreased during the first 24 h, with an average t1/2 between 4 and 8 h. Induction of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, gamma-interferon, and interleukin 2 receptor (p55) was also assessed by enzyme-linked immunosorbent assay. Tumor necrosis factor alpha and interleukin 6 levels peaked at 2 to 4 h and 4 to 6 h, with concentrations between 71 to 1,714 pg/ml and 942 to 10,500 pg/ml, respectively. Interleukin 1 beta, gamma-interferon, and soluble IL-2 receptor peaked later, during 6 to 12 h; the levels achieved were 234 pg/ml, 25 NIH units/ml, and 207 units/ml, respectively. All cytokine concentrations returned to near baseline between 12 and 24 h; however, the soluble IL-2 receptor levels remained elevated. Additional observations included a rapid influx of neutrophilic leukocytes, followed by a prolonged presence of lymphocytes. These data indicate a broad and complex potential of the immune response in the central nervous system, as well as further define the cytokine cascade in response to IL-2 alone.     

Expression of hematopoietic growth factor RNAs in human mesenchymal cells from various organs.

Experiments were undertaken to study expression of hematopoietic growth factor RNAs in mesenchymal cells from a variety of organs including bone marrow, foreskin, gingiva, and lung. Cells from each organ had negligible expression of RNAs coding for granulocyte (G), macrophage (M), and granulocyte-macrophage (GM) colony stimulating factor (CSF), interleukin 1 beta (IL-1 beta), and IL-6. Fibroblasts from each tissue had a comparable ability to express the same cytokine RNAs. Surprisingly, the stimuli for expression of G-CSF RNA was disparate from the stimuli for expression of the other cytokine RNAs. While IL-1 beta enhanced accumulation of G-CSF RNA, tumor necrosis factor alpha (TNF) and 12-O-tetradecanoylphorbol-13-acetate (TPA) did not. In contrast, IL-1 beta, TNF, and TPA equally stimulated increased levels of M-CSF, GM-CSF, IL-1 beta and IL-6 RNAs.     

Intra-tumoral interleukin-6 down-regulation system and genetic mutations of tumor suppressor genes in colorectal carcinoma

BACKGROUND: The interleukin (IL)-1-IL-6 network, the most potent cascade of pro-inflammatory cytokines, plays an autocrine role in tumor growth. The IL-1-IL-6 network is down-regulated by a phased cytokine inhibitor IL-1 receptor antagonist (ra) and an anti-inflammatory cytokine IL-10. The current study evaluated this down-regulation system in colorectal carcinoma and its relation to the genetic alteration of tumor suppressor genes. METHODS: Seventy-four specimens of primary colorectal carcinoma and normal mucosa were collected to measure tissue concentrations of cytokines. Polymerase chain reaction amplification was performed to investigate the loss of heterozygosity of the microsatellite markers on chromosomes 17p and 18q. RESULTS: The IL-1ra/IL-6 ratio in the carcinoma specimens was lower than ratios in adenomas and normal mucosae and decreased with disease progression. The IL-1ra/IL-6 ratio in early cancers tended to be lower than that in adenomas and normal mucosae. However, the tissue concentrations of IL-1beta and IL-10 were not associated with any clinicopathologic parameters. The tissue IL-1ra concentration correlated with that of IL-6 only in adenomas and early cancers. Immunohistochemically, IL-1ra and IL-6 were localized in the tumor cytoplasm. A reduced tissue IL-1ra/IL-6 ratio in the carcinomas correlated with poor prognosis and was associated with the loss of heterozygosity of the microsatellite markers on chromosomes 18q. CONCLUSIONS: There is an IL-6-IL-1ra network system in colorectal tumors, but this system deteriorates with carcinogenesis and tumor growth. The deterioration of this network system was associated with the allelic loss of a portion of chromosome 18q, reflecting the genetic alteration of tumor suppressor genes.     

Decreased interleukin-1 receptor antagonist response following moderate exercise in patients with colorectal carcinoma after primary treatment

Clinical and experimental studies have shown that a moderately increased physical activity level may have beneficial effects in terms of exercise conditioning, resistance to infection and decreased relative risk of cancer. Modulation of the innate and adaptive components of the immune system with a shift of cytokines and their antagonists to a more pro- and less anti-inflammatory response was found to be a prominent feature in non-tumor patients and healthy volunteers. As quantitative data concerning the cytokine/antagonist response following exercise are not available for tumor patients, we compared the effects of a post-operative rehabilitation program with moderate exercise (ME) intensity (0.55-0.65 x maximal aerobic power) with a program with low exercise (LE) intensity (0.30-0.40 x maximal aerobic power) in patients with curatively treated colorectal carcinoma (UICC II and III) measuring pro- (IL-1beta, IL-6, tumour necrosis factor (TNF)) and anti-inflammatory cytokines (IL-1 receptor antagonist, sTNF receptors I and II). Twenty-three patients participated in this prospective trial, N = 13 in the ME group, N = 10 in the LE group. Exercise was performed daily 30-40 min for 2 weeks. Basal (circulating) and LPS-stimulated (phasic) cytokine and antagonist response was determined before exercise and after 1 and 2 weeks using appropriate ELISA tests. The LPS-stimulated interleukin-1 receptor antagonist (IL-1ra) response in the ME group gradually decreased from 31,532.6 (160.0-70,028.0) to 18,033.0 pg/ml (5040.0-52,570.0) after one and to 22,892.0 pg/ml (6376.0-34,726.0) after 2 weeks (P < 0.05) with a concomitant decrease of the corresponding IL-1ra/IL-6 and IL-1ra/IL-1beta ratio: 2.51-1.41 and 4.1-3.1, respectively. In contrast, in the LE group LPS-stimulated cytokines and antagonists did not significantly change during exercise. Circulating cytokines and antagonists remained unchanged in both groups. In providing quantitative data in patients with curatively-treated colorectal cancer, we demonstrated that a short-term rehabilitation program with moderate exercise leads to a decreased LPS-induced antagonist response with a shift to a more pro-inflammatory state (decreased antagonist/cytokine ratio). Whether this change of the phasic immune response to moderate exercise may be clinically beneficial (decreased rates of infection, relapses and/or second tumours) is possible, but has to be investigated in long-term studies.     

High establishment efficiency of lymph node stromal cells which spontaneously produce multiple cytokines derived from adult T-cell leukemia/lymphoma patients

Stromal cells isolated from lymph nodes of adult T-cell leukemia/lymphoma (ATL) patients were cultured. Such lymph node stromal cells (LNSC) could be maintained for more than one year, whereas LNSC from other lymphoproliferative disorders ceased to proliferate within months. The rate of human T lymphotropic virus type I (HTLV-I) integration in these LNSC was examined by nested polymerase chain reaction (PCR) and estimated to be about 1 genome per 100 cells. These LNSC showed the same combination of cytokine production irrespective of the patient origin, granulocyte-macrophage (GM)-CSF, G-CSF, interleukin (IL)-1 beta, IL-6, interferon (IFN)-gamma and IL-8, being positive but not M-CSF, IL-1 alpha, IFN-alpha, tumor necrosis factor (TNF)-alpha, IL-2, LD78 and the IL-1 receptor antagonist (IL-1ra). The results show that LNSC from ATL patients have pronounced proliferation activity and constitutively secrete various cytokines. They therefore provide useful models for studying the microenvironment of lymph nodes in vitro, and especially the growth mechanism of ATL cells.     

Serum monocyte colony-stimulating factor, erythropoietin and interleukin-6 in relation to pancytopenia in hairy cell leukemia.

In patients with hairy cell leukemia (HCL), we measured serum levels of monocyte colony-stimulating factor (M-CSF), interleukin-6 (IL-6), and erythropoietin during various degrees of pancytopenia characteristic for this disease. Serial sera from 12 HCL patients during various stages of the disease were analyzed. No correlation was found between the levels of M-CSF or IL-6 and the numbers of circulating monocytes or platelets, normal values of M-CSF (4 to 10 mg/l), and IL-6 (3-50 U/ml) being detected during all stages of the disease. In contrast, erythropoietin levels were inversely related with the hemoglobin concentration (r = -0.79), indicating the presence of a normal feedback mechanism for this factor in patients with HCL.     

An unexpected inverse correlation between soluble epidermal growth factor receptor and interleukin-6 in metastatic malignant melanoma patients

The exact role of the soluble form of epidermal growth factor receptor (sEGF-R) in melanoma disease remains to be determined. We focused this study on the detection of circulating levels of sEGF-R in metastatic malignant melanoma patients and on the possible relationship between sEGF-R and clinicobiological parameters including circulating interleukin-6 (IL-6) and survival. sEGF-R and IL-6 levels were determined using a highly sensitive enzyme-linked immunosorbent assay in serum from 75 metastatic malignant melanoma patients and 30 healthy controls. In our patients, median sEGF-R level was significantly elevated (P < 0.0001) compared with that of healthy controls (173.4 vs. 91.9 fm/ml). Age or sex was not associated with sEGF-R levels. Regarding tumor burden, in contrary to the detected IL-6 levels, we found that median sEGF-R levels were significantly (P = 0.045) lower in patients with high tumor burden (163 fm/ml) than in those with low tumor burden (193.8 fm/ml). An inverse correlation between IL-6 levels and sEGF-R was observed (r =-0.33; P = 0.040). No relationship between sEGF-R and time to progression or overall survival was observed while circulating IL-6 was found as a predictive factor of survival. Our results showed that sEGF-R level was elevated in metastatic malignant melanoma patients but not related to time to progression or survival and demonstrated an inverse correlation between sEGF-R and IL-6 levels. These findings imply a better understanding of EGF-R and IL-6 cross-talk function in melanoma.     

Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells

Previous investigations have shown that interleukin (IL)-11/IL-11 receptor alpha-chain (IL-11Ralpha), a member of the PI3K, MAPK and JAK-STAT activating family of cytokines/receptors, correlates with the regulation of tumor progression. In this study, we established the IL-11/IL-11Ralpha expression profile in human colorectal adenocarcinoma (CRC) and clarified its signaling pathway and role in the invasion activity of CRC cell lines. To elucidate the role of IL-11/IL-11Ralpha, we examined 103 cases of CRC and 24 cases of colorectal adenoma by immunohistochemistry. In addition, we investigated the invasive activity of cell signaling pathway of CRC cell lines. The IL-11Ralpha expression was correlated with tumor invasion and lymphatic infiltration (p<0.01, respectively). Recombinant human IL-11 (rhIL-11) promoted the migration and proliferation of HT-29 cells and activated the PI3K and p44/p42 MAPK pathways. Wortmannin, a PI3K inhibitor, and PD98059, a p44/p42 MAPK inhibitor, significantly reduced the promotion of invasion and proliferation activity by rhIL-11, respectively. In summary, the IL-11Ralpha expression was correlated with clinicopathological features and IL-11 promoted the invasion via the PI3K and up-regulated the proliferation via the p44/p42 MAPK in CRC cells. These findings suggested that the IL-11/IL-11R pathway plays an important role in the progression of CRC.     

结直肠癌患者血清中IL-17和IL-6的表达及其临床意义

目的:研究结直肠癌(colorectal carcinoma,CRC)患者血清中白细胞介素17(interleukin 17,IL-17)和IL-6的表达,探讨IL-17和IL-6与CRC发生和发展之间的关系.方法:采用ELISA方法检测56例CRC患者和30例健康志愿者(对照组)血清IL-17和IL-6的变化,分析IL-17和IL-6与CRC患者各临床病理特征之间的关系.结果:56例CRC患者血清IL-17为96.43±21.15 ng/L,IL-6为139.53±27.84 ng/L,均明显高于对照组(IL-17为16.88±5.07 ng/L,IL-6为39.21±7.46 ng/L,P＜0.01);IL-17和IL-6水平的上升与患者的性别和年龄无关(P＞0.05),而与肿瘤的大小、远处转移、Dukes分期及病理组织学分型明显相关(P＜0.01).结论:CRC患者血清中IL-17和IL-6水平随着肿瘤的进展而明显上升,预示IL-17和IL-6直接或间接参与了CRC的发生和发展.     

Carcinoembryonic antigen induction of IL-10 and IL-6 inhibits hepatic ischemic/reperfusion injury to colorectal carcinoma cells

Tumor cells cause ischemia/reperfusion (I/R) injury as they arrest within the hepatic microvasculature with the production of nitric oxide (NO) and reactive oxygen species (ROS) that kill both host liver and implanting tumor cells. Carcinoembryonic antigen (CEA) both facilitates the survival of experimental metastasis to nude mouse liver by weakly metastatic human colorectal carcinomas (CRCs) and induces the release of the proinflammatory cytokine IL-6. We hypothesized that CEA also stimulates the release of the antiinflammatory cytokine IL-10 causing inhibition of the toxicity of hepatic I/R injury and indirect stimulation of tumor cell colonization of the liver. Intravenous injection of CEA produced more than 1 ng/ml of IL-10 in the systemic circulation within 1 hr which subsided by 8 hr. The IL-10 response is specific to CEA since the pentapeptide sequence in CEA that binds to the CEA receptor stimulated isolated Kupffer cells to produce IL-10. IL-10, but not IL-6, increased the survival of weakly metastatic CRC cocultured with ischemic-reoxygenated liver fragments but did not affect the survival of CRC exposed to oxidative stress in the absence of any host cells. CEA, IL-6 and IL-10 pretreatment reduced expression of iNOS but only CEA and IL-10 strongly inhibited NO and total reactive species production by ischemic-rexoygenated liver. IL-6 was toxic to CRC exposed to oxidative stress while IL-10 did not have a direct effect on CRC. Thus, CEA stimulates production of IL-10 that may enhance metastasis by promoting the ability of circulating CRC cells to survive the I/R injury of implantation.     

Alterations of routine blood tests in adult patients with soft tissue sarcomas: Relationships to cytokine serum levels and prognostic significance

Background:It has been reported that malignancy is oftenaccompanied by hematological alterations and that such alterations maycorrelate with poor prognosis. It has also been demonstrated thatseveral cytokines may be synthesized by many malignant tumors and thatelevated serum levels of some cytokines are associated with changes inblood cell counts in cancer patients. However, so far little is knownabout the prognostic significance and mechanism of hematological changesin soft tissue sarcomas. The aim of the study was to evaluate theroutine blood tests of disturbances in patients with malignantsoft-tissue tumors prior to treatment and to correlate these resultswith selected cytokine serum levels, clinicopathological features of thetumors and patient survival. Patients and methods:145patients (75 males, 70 females; mean age 49.97 ± 16.9 yrs) withhistologically confirmed soft tissue sarcomas before treatment wereenrolled into the study. In all these patients we evaluated routineblood tests (hemoglobin level HGB, white blood cell count WBC, plateletcount PLT, white blood cell differential count–neutrocyte countNE, lymphocyte count LY, monocyte count MN, eosinophile count EO) andserum levels of 13 cytokines and soluble cytokine receptors (IL-6, IL-8,IL-10, TNF, G-CSF, M-CSF, bFGF, VEGF, IL-1ra, sIL-2R, sIL-6R, TNFRI, TNF RII) – ELISA method. Peripheral blood samples from 50healthy volunteers served as control. Statistical analysis was performedusing Kolmogorov–Smirnov and Mann–Whitney U-tests,² test (P < 0.05), whereappropriate. For survival analysis the Kaplan–Meier method,log-rank test and multivariate Cox analysis were applied. Results:Alterations of at least one of the standard bloodtests were found in 43.4% of all cases. The most frequentalterations were: neutrophilia (28.3% of cases), leukocytosis(27.6%), decreased HGB (25.5%), monocytosis (19.3%)and thrombocytosis (14.5%); they correlated strongly withelevated serum levels of several cytokines and soluble cytokinereceptors (particularly: sIL-2R, IL-6, IL-8, M-CSF, VEGF, TNF RI, TNFRII) (P < 0.001). Lymphocytopenia(LY < 1.0) found in 10.3% of patients correlatedstrongly with increased serum levels of IL-6, sIL-2R, TNF RI. Inparallel, we found a significant difference in serum levels of 11of 13 cytokines (IL-1ra, sIL-2R, IL-6, IL-8, IL-10, TNF RI, TNF RII,TNF, M-CSF, bFGF, VEGF) (P < 0.001) in softtissue sarcoma patients compared to healthy controls. Hematologicalalterations were significantly more frequent in patients with advancedtumors. In multivariate analysis we found no prognostic significance ofany of the routine blood tests in soft tissue sarcoma patients. Conclusion:The results of this study demonstrate thathematological alterations, which occur in over 40% of soft tissuesarcoma cases, are found more frequently in patients with advancedtumors. Strong correlations between the occurrence of hematologicalabnormalities and elevated serum levels of several cytokines and solublecytokine receptors, suggest that the former may develop as a result ofcytokine misbalance frequently detected in soft tissue sarcoma patients.However, the results of routine blood tests alone are no independentprognostic factor for survival of soft-tissue sarcoma patients.     

IL-6, M-CSF and IAP cytokines in ovarian cancer: simultaneous assessment of serum levels.

The aim of this study was to simultaneously determine IL-6, M-CSF and IAP levels in 61 serum samples of previously untreated ovarian cancer patients. A direct correlation between IL-6 and M-CSF has been found in our patient population (r = +0.41, p = 0.013), while IAP serum levels failed to correlate with M-CSF (r = +0.15, p = 0. 24) and IL-6 (r = +0.17, p = 0.18) levels. Since IL-6 and M-CSF have been demonstrated to be both induced in response to the same agents, it is conceivable that a mechanism of coregulation in the production of these cytokines by tumor cells and macrophages might occur. The direct correlation between IL-6 and M-CSF also suggests that tumor-derived cytokines can potentially lead to a self-maintaining cytokine network by recruiting cytokine-producing host cells and by perpetuating cytokine production.