Role of interleukin-6 in the paraneoplastic inflammatory syndrome associated with renal-cell carcinoma

We investigated the possible causative role of interleukin 6 (IL-6) in the paraneoplastic inflammatory syndrome and in paraneoplastic cholestasis (Stauffer syndrome) associated with renal-cell carcinoma in a series of 119 patients with metastases. IL-6 levels were found significantly higher in patients with paraneoplastic fever and weight loss. Patients with detectable serum IL-6 (n = 90, 76%) had significantly higher serum CRP, haptoglobin, and serum alkaline-phosphatase and gammaglutamyl-transferase levels. Platelets, polymorphonuclear neutrophil (PMN) and monocyte counts were also significantly higher in patients with detectable serum IL-6; in contrast, hemoglobin levels were significantly lower in patients with serum IL-6 over 80 pg/ml. Three of these patients were included in a phase-II trial of an anti-IL-6 monoclonal antibody given daily during 21 days. Reductions of CRP, haptoglobin and serum alkalin phosphatases were observed in all 3 patients during anti-IL-6 administration, with a subsequent increase up to or above pre-treatment levels after the end of anti-IL-6. Decrease of platelets, PMN and monocyte counts were also observed in the 3 patients during anti-IL-6 administration, with a normalization of cell counts in a patient with increased platelets, PMN and monocyte counts. Hemoglobin concentration, serum albumin concentration and lymphocyte counts remained stable in the 3 patients during and after anti-IL-6 administration. Serum IL-6, as evaluated by IRMA, decreased in the 3 patients during anti-IL-6 administration, but increased above pre-treatment levels after the end of anti-IL-6 administration. These results demonstrate that IL-6 is involved in the physiopathology of paraneoplastic syndromes observed in patients with metastatic renal-cell carcinoma, in particular CRP and haptoglobin increase, paraneoplastic cholestasis, also paraneoplastic thrombocytosis, neutrophilia and monocytosis. Int. J. Cancer 72:424–430, 1997. © 1997 Wiley-Liss, Inc.     

Castleman's disease in POEMS syndrome with elevated interleukin-6.

POEMS syndrome is a rare multisystem affliction known for its signs, from which it also takes its acronym name "peripheral neuropathy, organomegaly, endocrinopathy, monoclonal (M) protein, and skin lesions." Our study chronicles the course of this syndrome in a young woman with Castleman's disease (angiofollicular lymph node hyperplasia). Cerebrospinal fluid (CSF) and serum interleukin-6 (IL-6) levels were abnormally elevated at various times during a 9-month period. The authors conclude that the plasma cell dyscrasia associated with the POEMS syndrome of this patient was Castleman's disease. Elevation of serum IL-6 levels might contribute to the pathogenesis of the POEMS syndrome.     

Weight loss in a murine cachexia model is not associated with the cytokines tumour necrosis factor-alpha or interleukin-6.

Daily administration of an escalating dose of tumour necrosis factor-alpha (TNF-alpha) to female NMRI mice caused a progressive loss of body weight representing 12% of the original weight over a 6-day period. Weight loss was associated with a decreased food intake and pair-fed controls exhibited a weight loss of similar magnitude to that caused by TNF-alpha. However, weight loss in animals bearing a murine adenocarcinoma (MAC16) occurred without a change in energy intake and thus differed from that produced by TNF-alpha. Anti-TNF-alpha monoclonal antibodies at levels capable of protecting mice against lethal endotoxaemia were ineffective in reversing weight loss in animals bearing the MAC16 tumour and had no effect on the increase in tumour volume. Circulating levels of interleukin-6 were not elevated in animals bearing the MAC16 tumour and with a weight loss between 1.8 and 5.4 g. These results suggest that these cytokines are not involved in the cachexia produced by this murine tumour.     

Osteopontin and interleukin-8 expression is independently associated with prostate cancer recurrence.

PURPOSE: Lack of reliable biomarkers limits accurate prediction of prostate-specific antigen biochemical recurrence (disease progression) in prostate cancer. The two inflammatory chemokines, osteopontin and interleukin-8 (IL-8), are associated with tumor angiogenesis and metastasis. We investigated whether osteopontin and IL-8 expression in prostate cancer correlates with disease progression. EXPERIMENTAL DESIGN: Archival prostatectomy specimens (n = 103) were obtained from patients with minimum 72-month follow-up. Osteopontin and IL-8 expression was evaluated by immunohistochemistry and graded for intensity and the area. Association of osteopontin and IL-8 staining with biochemical recurrence was evaluated by univariate and multivariate models. RESULTS: In tumor cells, osteopontin and IL-8 staining was higher in the recurred group (203.2 +/- 78.4; 181.1 +/- 89.3) than in the nonrecurred group (122.7 +/- 76.6; 96.4 +/- 85.6; P < 0.001). Higher osteopontin and IL-8 staining was also observed in benign areas adjacent to tumor in the recurred group, than in nonrecurred group. In univariate analysis, except age, all preoperative and postoperative variables and osteopontin and IL-8 staining scores were significantly associated with biochemical recurrence (P < 0.05). In multivariate analysis, margin status and osteopontin staining independently associated with biochemical recurrence within 72 months. Osteopontin, either alone or with IL-8 and seminal vesicle invasion, was a significant variable in predicting biochemical recurrence within 24 months. Osteopontin and IL-8 staining predicted recurrence with high sensitivity (75.5%; 73.6%) and specificity (76%; 70.6%). CONCLUSION: In prostatectomy specimens, osteopontin expression is independently associated with biochemical recurrence. Both osteopontin and IL-8 may be predictors of early disease progression.     

Proliferation of immature myeloma cells by interleukin-6 is associated with CD45 expression in human multiple myeloma

Multiple myeloma (MM) is a hematologic malignancy of human plasma cells, and myeloma cells can be classified into several subpopulations according to phenotypic differences, such as CD38 MPC-1- CD49e- immature, CD38 MPC-1+ CD49e- intermediate and CD38 MPC-1+ CD49e+ mature myeloma cells. The expression of the CD45 molecule on myeloma cells is quite variable, and the physiological consequence of CD45 on myeloma cells is still unknown. Recently, we have found that a few MPC-1- immature myeloma cells express CD45 antigens while most myeloma cells do not express the CD45. MPC-1- CD45+ CD49e- but not MPC-1- CD45- CD49e- immature cells contain proliferating cells in response to interleukin-6 (IL-6). IL-6 can also induce expression of CD45 on the MPC-1- CD45- subpopulation of immature myeloma cells. In addition, myeloma cell lines responding to IL-6 express CD45, whereas cell lines proliferating independent of IL-6 do not express CD45. In the U266 cell line, IL-6 leads to the induction of CD45 expression and cell proliferation, indicating that IL-6-induced effects are closely linked to CD45 expression. Thus, there is a heterogeneity in human myeloma cells, and among these subpopulations immature myeloma cells expressing the CD45 molecules appear to proliferate in response to IL-6. In this review we propose the involvement of CD45 in MM pathogenesis, and the possible implications of CD45 as both a phenotypic marker and a functional molecule is discussed.     

Evidence that toxic injury is not always associated with induction of chemical carcinogenesis.

Long-term rodent bioassays with chemicals administered at maximum tolerated doses identify noncarcinogens as well as carcinogens. Thirty-one chemicals recently evaluated for carcinogenic potential by the National Toxicology Program provide unique data on the relationships between mutagenicity, toxicity, and carcinogenicity. Twenty-two substances were classified as carcinogens, and nine showed no evidence of carcinogenicity. Although cellular proliferation does play an intrinsic role in neoplastic processes, the responses associated with chronic toxicity in these studies were not always sufficient to induce neoplasia. Regardless of their mutagenic potential, 19 carcinogens induced toxic effects at sites that did not show neoplastic changes; similar toxic lesions were also seen among the mutagenic and nonmutagenic noncarcinogens. Although many nonmutagens induced neoplasia at sites that showed toxic effects, some of the same chemicals also exhibited toxicity at other sites that showed no neoplastic effect. These results suggest that for some chemicals, properties other than mutagenicity or toxicity may be responsible for their carcinogenic potential.     

Allele 2 of the interleukin-1 receptor antagonist gene is associated with early gastric cancer.

PURPOSE: In advanced gastric cancer (tumor stages T2-T4), associations with polymorphisms of the interleukin-1 (IL-1) gene cluster have been made. In early-stage gastric cancer, which we defined as adenocarcinoma confined to the mucosa or submucosa (stage T1), the role of host genetic susceptibility remains to be determined. PATIENTS AND METHODS: Eighty-eight patients with early-stage gastric cancer (stage T1, 77 positive for Helicobacter pylori) and 145 controls were genotyped for polymorphisms in the IL-1 gene cluster and the tumor necrosis factor alpha (TNF-A) gene. Statistical analysis was performed using the chi2 test and the Fisher's exact test, respectively. RESULTS: The homozygous genotype IL-1RN*2/2 of the IL-RN gene was strongly associated with early-stage gastric cancer (P < .0001), whereas further associations with the IL-1 gene cluster were not observed. A weak association of the TNF-A-308A allele with the diffuse type of early-stage gastric cancer, and an association with a composite of two or three proinflammatory polymorphisms, which predispose to increased production of the proinflammatory cytokines IL-1beta and TNF-alpha, could also be demonstrated. CONCLUSION: The genotype IL-1RN*2/2 seems to be associated with early-stage gastric cancer. As opposed to advanced-stage gastric cancer, further proinflammatory cytokine polymorphisms were not associated independently, but might act in combination and mirror early steps of gastric carcinogenesis in hosts colonized by Helicobacter pylori. However, these findings await confirmation in future trials and should be underscored by gene expression studies.     

The -174 G/C gene polymorphism in interleukin-6 is associated with an aggressive breast cancer phenotype

Serum and tissue levels of interleukin-6 (IL-6) have been implicated in the biological phenotype of breast carcinoma. A common G/C polymorphism at position -174 of the IL-6 promoter can influence the expression level of this gene. We therefore investigated for associations between this polymorphism and various phenotypic features in a series of 256 breast cancers. Individuals who were homozygous for the C allele (n=55) were more likely to have higher-grade tumours (P=0.039) with ductal histology (P=0.030) compared to those harbouring at least one wild-type G allele (n=201). Homozygosity for the C allele was also associated with significantly worse overall survival (P=0.031). We conclude that the -174 C allele of IL-6 is associated with a more aggressive breast cancer phenotype.     

S-phase induction by interleukin-6 followed by chemotherapy in patients with chronic lymphocytic leukemia and non-Hodgkin's lymphoma.

Interleukin-6 (IL-6) has in vitro demonstrated growth regulatory effects on tumor cells from patients with chronic lymphocytic leukemia (CLL) and lymphoma. The proliferation rate of these cells is usually very low and this is thought to be one of the reasons for the lack of a curative potential of cytostatic chemotherapy in CLL and low grade NHL. Recombinant human (rh) IL-6 might increase the in vivo proliferation rate leading to a higher sensitivity for chemotherapy. We tested this hypothesis by administering rhIL-6 to 9 CLL patients and 3 NHL patients in doses of 2.5 micrograms/kg, 5 micrograms/kg and 10 micrograms/kg s.c. daily for 5 days followed by CHOP chemotherapy on the last day of rhIL-6 injection. Six patients had two treatment cycles. The proportion of cells in S-phase was determined by the bromodeoxyuridine labeling index (LI). Three patients achieved a partial remission, one patient had progressive disease and the remaining patients demonstrated no change. Two patients, who received 10 micrograms/kg/day rhIL-6, demonstrated a significant increase in LI, one of these was first observed in the second treatment cycle. A significant decrease was seen in two patients receiving 2.5 micrograms/kg and 5 micrograms/kg respectively. Immunophenotypic assessment demonstrated that rhIL-6 increased the expression of CD20 in all CLL patients with a reversal after cessation of rhIL-6. We conclude that rhIL-6, in the dosage and schedule used in this study, did not increase the proportion of the cells in S-phase and that the growth stimulatory effects of rhIL-6 in CLL in vivo probably are insignificant. However, the role of rhIL-6 in CLL as inducer of increased CD20 expression prior to anti-CD20 antibody treatment remains to be determined.     

Metabolic syndrome is associated with colorectal cancer in men

Aim of the studyWe assessed the relation between metabolic syndrome (MetS) and its components and colorectal cancer.MethodsWe analysed data from a multicentre case–control study conducted in Italy and Switzerland, including 1378 cases of colon cancer, 878 cases of rectal cancer and 4661 controls. All cases were incident and histologically confirmed. Controls were subjects admitted to the same hospitals as cases with acute non-malignant conditions. MetS was defined according to the International Diabetes Federation criteria. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated by multiple logistic regression models, including terms for major identified confounding factors for colorectal cancer.ResultsWith reference to each component of the MetS, the ORs of colorectal cancer in men were 1.27 (95% CI, 0.95–1.69) for diabetes, 1.24 (95% CI, 1.03–1.48) for hypertension, 1.14 (95% CI, 0.93–1.40) for hypercholesterolaemia and 1.26 (95% CI, 1.08–1.48) for overweight at age 30. The corresponding ORs in women were 1.20 (95% CI, 0.82–1.75), 0.87 (95% CI, 0.71–1.06), 0.83 (95% CI, 0.66–1.03) and 1.06 (95% CI, 0.86–1.30). Colorectal cancer risk was increased in men (OR = 1.86; 95% CI, 1.21–2.86), but not in women (OR = 1.13; 95% CI, 0.66–1.93), with MetS. The ORs were 2.09 (95% CI, 1.38–3.18) in men and 1.15 (95% CI, 0.68–1.94) in women with ?3 components of the MetS, as compared to no component. Results were similar for colon and rectal cancers.ConclusionThis study supports a direct association between MetS and both colon and rectal cancers in men, but not in women.     

Serum interleukin-6 levels in patients with thrombocytosis.

Interleukin-6 (IL-6) has been shown to increase platelet counts in several animal models and to enhance megakaryocytopoiesis in vitro. In order to investigate the possible relationship between IL-6 and thrombocytosis, serum IL-6 levels in patients with platelet counts > or = 6 x 10(5)/microliters were measured using an IL-6-responsive bioassay. A cohort of healthy volunteers with normal platelet counts was used to establish a control mean serum IL-6 level [2.19 U/ml +/- 1.08 SD (range 0-5.5)]. Patients with primary thrombocytosis had a mean serum IL-6 level not significantly different from controls. In comparison, serum IL-6 levels of patients with reactive thrombocytosis were significantly greater than controls (38.3 U/ml +/- 94.6; range 0-933; P < 0.001). Although no significant correlation was observed between the degree of serum IL-6 elevation and the height of the platelet count in any individual, elevated serum IL-6 was highly correlated with reactive thrombocytosis.     

Soluble interleukin-6 receptor is released from receptor-bearing cell lines in vitro.

Soluble interleukin-6 receptor (sIL-6R) was found to be spontaneously released from human myeloma cell line U266 cells into culture supernatant, and was quantitatively measured with a fluorescence sandwich enzyme-linked immunosorbent assay employing antibodies specific to IL-6R. The supernatant IL-6R was generated only from IL-6R-positive cell lines; myeloma cell lines RPMI8226 and PRMI1788, and myelomonocytic cell lines U937, THP-1, and HL-60. In contrast, it was not released from the IL-6R-negative cells; T cell line Molt-4 and Burkitt lymphoma cell line Raji. SDS-PAGE analysis of the soluble IL-6R from U266 cells suggested a molecular weight of approximately 50-55 kDa, 25-30 kDa smaller than the mature cell surface receptor. These results suggest that the generation of soluble IL-6R may be a maker of myeloma cells and myelomonocytic cells.     

The soluble alpha chain of interleukin-15 receptor: a proinflammatory molecule associated with tumor progression in head and neck cancer

Interleukin (IL)-15 is a proinflammatory cytokine, as it induces the production of inflammatory cytokines [IL-6, tumor necrosis factor alpha (TNFalpha), IL-17, etc.]. A correlation between high intratumoral IL-15 concentrations and poor clinical outcome in lung and head and neck cancer patients has been recently reported. The purpose of this study was to investigate the role of the soluble alpha chain of IL-15 receptor (sIL-15Ralpha), a natural regulator of IL-15, in head and neck cancer. Fifty-three newly diagnosed untreated head and neck cancer patients were included in this study. Quantification of sIL-15Ralpha was performed with a newly developed RIA. Increased serum sIL-15Ralpha concentrations were found in head and neck cancer patients and were closely correlated with poor clinical outcome both in terms of locoregional control and survival even on multivariate analysis. sIL-15Ralpha was mainly produced by tumor cells via proteolytic cleavage of IL-15Ralpha mediated by ADAM-17. A correlation was observed between ADAM-17 expression in tumor cells and serum sIL-15Ralpha concentrations. Surprisingly, sIL-15Ralpha did not act in vitro as an IL-15 antagonist but rather as an enhancer of IL-15-induced proinflammatory cytokines (IL-6, TNFalpha, and IL-17) that may promote tumor progression. This new tumor evasion mechanism based on amplification of the intratumoral inflammatory reaction is probably not restricted to head and neck cancer, as other tumors have been shown to release sIL-15Ralpha. Overall, these results support for the first time an original protumor role of sIL-15Ralpha in cancer.     

CYP2B6*6 is associated with increased breast cancer risk

The cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of testosterone. Functional changes in this enzyme may influence endogenous hormone exposure, which has been associated with risk of breast cancer. To assess potential associations between two functional polymorphisms CYP2B6_516_G>T (rs3745274) and CYP2B6_785_A>G (rs2279343) and breast cancer risk, we established a specific matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry assay. The GENICA breast cancer case–control study showed associations between the variant genotypes CYP2B6_516_TT and CYP2B6_785_GG and breast cancer risk with odds ratios (ORs) of 1.34 (p = 0.001) and 1.31 (p = 0.002), respectively. A similar effect was observed for carriers of the CYP2B6_516_T allele in a validation study including four independent studies from Germany, Sweden and USA. In a pooled analysis of all five studies involving 4,638 breast cancer cases and 3,594 controls of European ancestry, carriers of the CYP2B6_516_G and the CYP2B6_785_G variant had an increased breast cancer risk with ORs of 1.10 (p = 0.027) and 1.10 (p = 0.031), respectively. We conclude that the genetic variants CYP2B6_516_G and CYP2B6_785_G (designated CYP2B6*6), which are known to decrease activity of the CYP2B6 enzyme, contribute to an increased breast cancer risk.     

Pretreatment tumor lysis syndrome associated with bulky retroperitoneal tumors. Recognition is the mainstay of therapy

Acute pretreatment tumor lysis syndrome is a rare complication of cancer. Early recognition and aggressive management are mandatory for prevention of the adverse sequelae of the syndrome. Here we present 2 cases of pretreatment tumor lysis syndrome, concluding that this clinical entity should be in the differential diagnosis of acute renal failure associated with malignancy, as early recognition is in fact the mainstay of treatment.