Serum Levels of Interleukin-18 and sICAM-1 in Patients Affected by Breast Cancer: Preliminary Considerations

Merendino, Rosaria Alba; Gangemi, Sebastiano; Ruello, Antonella; Bene, A.; Losi, E.; Lonbardo, G.; Purello-D'Ambrosio, F

doi:10.1177/172460080101600207

Cited by 48 publications

(29 citation statements)

References 14 publications

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“…21 Nonetheless, IL-18 is increased in the circulation of patients with different types of cancer. [22][23][24][25][26] Intriguingly, in an experimental tumor model, IL-18 mediated tumor progression through the enhancement of cancer cells' adhesive properties to the vascular endothelium or through proangiogenic activity. 27 Thus, the role of IL-18 in tumor biology and therapy remains a controversial issue.…”

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confidence: 99%

Interleukin (IL)‐18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor

Orengo

Fabbi

Miglietta

et al. 2011

Intl Journal of Cancer

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Interleukin (IL)-18 is a proinflammatory and immune-enhancing cytokine, which exerts antitumor effects in vivo, mediated by the induction of interferon (IFN)c. We previously reported that IL-18 processing is defective in epithelial ovarian carcinoma (EOC) cells, which secrete an inactive precursor (pro-IL-18) in vitro. In addition, IL-18 was reported as a potential biomarker of EOC. Here, we further investigated its role as a serological marker in human EOC and addressed its possible biological activity in vivo. Our data indicate that immunoreactive IL-18 is increased in EOC patients' sera at diagnosis as compared with age-matched healthy women. IL-18 levels were higher in the ascitic fluids than in sera, suggesting a local production in the peritoneal cavity. Indeed, immunohistochemical analysis of tumors showed IL-18 expression in cytokeratine-positive neoplastic cells, although also scattered histiocytes and some lymphoid cells stained for IL-18. The detection of human IL-18 in sera and ascitic fluids of immunodeficient mice, orthotopically implanted with human EOC cells, further suggested that circulating IL-18 is tumor-derived. However, IL-18 is not an EOC specific biomarker, as increased serum levels were found also in some endometrial cancer patients. By means of a new monoclonal antibody, we characterized IL-18 present in the ascitic fluid as pro-IL-18, which is biologically inactive. Accordingly, IFNc was not increased in EOC patients' sera and ascitic fluids and showed no correlation with IL-18 levels. Altogether these data indicate that IL-18 in EOC fluids is predominantly tumor-derived and that its lack of biological activity may represent a mechanism of tumor-escape.

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confidence: 99%

Interleukin (IL)‐18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor

Orengo

Fabbi

Miglietta

et al. 2011

Intl Journal of Cancer

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“…3 Here we report elevated serum levels of bioactive IL-18 in patients afflicted with pancreatic carcinoma. In fact, elevated serum levels of IL-18 have been observed in other tumors including colon carcinoma, 55 lung cancer, 55 hematological malignancies, including myeloma, 56,57 breast cancer, 58,59 gastric carcinoma, 60 esophageal carcinoma, 61 bladder cancer, 62 renal cell carcinoma 63 and head and neck carcinoma. 64 Generally, IL-18 production has been linked to aggressive tumor development and shorter survival times.…”

Section: Discussionmentioning

confidence: 99%

Human pancreatic carcinoma cells secrete bioactive interleukin-18 after treatment with 5-fluorouracil: Implications for anti-tumor immune response

Carbone

Rodeck²,

Mauri³

et al. 2005

Cancer Biology & Therapy

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Recently we observed that pancreatic carcinoma cell lines constitutively express . Bioactive IL-18 induces Interferon (IFN)-γ production, Fas Ligand (FasL) expression, and inhibits angiogenesis, raising the issue of anti-tumor effects of a tumor-derived cytokine and motivating a more detailed analysis of IL-18 production in pancreatic carcinoma cells. This analysis included the study of effects of chemotherapeutic drugs (5-fluorouracil [5-FU], gemcitabine, cisplatin) commonly used in the treatment of pancreatic cancer patients on IL-18 production and processing. IL-18 expression and posttranslational processing were determined using RT-PCR, immunoblot and ELISA in pancreatic carcinoma cell lines and in tumor tissue and serum samples from pancreatic carcinoma patients in the presence and absence of chemotherapeutic drugs. We describe expression of IL-18 in pancreatic carcinoma cells and tissues associated with significantly elevated IL-18 levels in patients sera. Specifically, Capan-2 pancreatic tumor cells produced and secreted precursor IL-18 with no apparent biological activity. However, the chemotherapeutic agent 5-FU, by inducing Caspase-1 and Caspase-3 activation, induced secretion of proteolytically processed mature and degraded IL-18 species, respectively, in Capan-2 cells. Conditioned medium from 5-FU-treated but not control Capan-2 cells induced IFN-γ production by activated T cells in an IL-18-dependent manner. Furthermore, adjuvant polychemotherapy including 5-FU significantly increased serum levels of mature, bioactive IL-18 in pancreatic carcinoma patients. Treatment of pancreatic cancer cells with 5-FU induced Caspase-dependent processing of pro-IL18 leading to the secretion of biologically active IL-18. These findings delineate a novel mechanism by which chemotherapeutic agents may modulate local anti-tumor cell-mediated immune responses.

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“…Contrary to the anti-cancer effect of IL-18, its pro-cancerous effect has been recently suggested in gastric cancer patients, the analysis of the expression pattern of IL-18 and tumor progression revealed that IL-18 was expressed highly in the tumor region in comparison with non-tumor region and related with distant metastasis (Ye et al, 2007). Eissa et al (2005) and Merendino et al (2001) have reported that IL-18 is also an important marker of breast cancer progression because higher IL-18 levels were detected in serum from breast cancer patients with metastasis compared to healthy volunteers and breast cancer patients without metastasis.…”

Section: Discussionmentioning

confidence: 99%

HMGB1 Promotes the Synthesis of Pro-IL-1β and Pro-IL-18 by Activation of p38 MAPK and NF-κB Through Receptors for Advanced Glycation End-products in Macrophages

You²,

Li³

et al. 2012

Asian Pacific Journal of Cancer Prevention

105

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The high mobility group box-1 (HMGB1) protein and NALP3 inflammasome have been identified to play important roles in inflammation and cancer pathogenesis, but the relationships between the two and cancer remain unclear. The current study investigated the relationship between HMGB1 and the NALP3 inflammasome in THP-1 macrophages. HMGB1 was found unable to activate the NALP3 inflammasome and failed to induce the release of the IL-1β and IL-18 in THP-1 macrophages. HMGB1 was also found significantly enhanced the activity of ATP to induce IL-1β and IL-18 by the induction of increased expression of pro-IL-1β and pro-IL-18. This process was dependent on activation of RAGE, MAPK p38 and NF-κB signaling pathway. These results demonstrate that HMGB1 promotes the synthesis of pro-IL-1β and pro-IL-18 in THP-1 macrophages by the activation of p38 MAPK and NF-κB through RAGE. HMGB1 likely plays an important role in the first step of the release of the IL-1β and IL-18, preparing for other cytokines to induce excessive release of IL-1β and IL-18 which promote inflammation and cancer progression.

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Serum Levels of Interleukin-18 and sICAM-1 in Patients Affected by Breast Cancer: Preliminary Considerations

Cited by 48 publications

References 14 publications

Interleukin (IL)‐18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor

Interleukin (IL)‐18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor

Human pancreatic carcinoma cells secrete bioactive interleukin-18 after treatment with 5-fluorouracil: Implications for anti-tumor immune response

HMGB1 Promotes the Synthesis of Pro-IL-1β and Pro-IL-18 by Activation of p38 MAPK and NF-κB Through Receptors for Advanced Glycation End-products in Macrophages

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