Cytokine Profile of Cervical Cancer Cells

Hazelbag, Suzanne; Fleuren, Gert Jan; Baelde, Hans J.; Schuuring, Ed; Kenter, Gemma G.; Gorter, Arko

doi:10.1006/gyno.2001.6378

Cited by 76 publications

(58 citation statements)

References 40 publications

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“…In disease IL-4 and TGF-␤ both play an important role in the development of atherosclerotic lesions by stimulating the development of a specific phenotype of macrophages (15)(16)(17). Tumor cells producing high levels of IL-4 and TGF-␤1 condition tumor infiltrating monocytes/macrophages to support tumor growth and immune escape (18,19). TGF-␤ acts via a well-defined signaling cascade activated by engagement of cell surface serine/threonine protein kinases known as type I and type II receptors.…”

mentioning

confidence: 99%

Activation of a TGF-β-Specific Multistep Gene Expression Program in Mature Macrophages Requires Glucocorticoid-Mediated Surface Expression of TGF-β Receptor II

Gratchev¹,

Kzhyshkowska²,

Kannookadan³

et al. 2008

The Journal of Immunology

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Alternatively activated (M2) macrophages regulate steady state-, cancer-, and inflammation-related tissue remodeling. They are induced by Th2-cytokines and glucocorticoids (GC). The responsiveness of mature macrophages to TGF-β, a cytokine involved in inflammation, cancer, and atherosclerosis, is currently controversial. Recently, we demonstrated that IL-17 receptor B is up-regulated in human monocyte-derived macrophages differentiated in the presence of Th2 cytokines IL-4 and TGF-β1. In this study, we show that mature human macrophages differentiated in the presence of IL-4, and dexamethasone (M2IL-4/GC) but not M2IL-4 responds to TGF-β1 which induced a gene expression program comprising 111 genes including transcriptional/signaling regulators (ID3 and RGS1), immune modulators (ALOX5AP and IL-17 receptor B) and atherosclerosis-related genes (ALOX5AP, ORL1, APOC1, APOC2, and APOE). Analysis of molecular mechanism underlying GC/TGF-β cooperation revealed that surface expression of TGF-βRII was high in M2GC and M2IL-4/GC, but absent from M2IL-4, whereas the expression of TGF-βRI/II mRNA, TGF-βRII total protein, and surface expression of TGF-βRIII were unchanged. GC dexamethasone was essential for increased surface expression of functional TGF-βRII because its effect was observed also in combination with IL-13, M-CSF, and GM-CSF. Prolonged Smad2-mediated signaling observed in TGF-β1-treated M2IL-4/GC was due to insufficient activity of negative feedback mechanism what can be explained by up-regulation of SIRT1, a negative regulator of Smad7, and the retention of TGF-βRII complex on the cell surface. In summary, mature human M2 macrophages made permissive to TGF-β by GC-induced surface expression of TGF-βRII activate in response to TGF-β1, a multistep gene expression program featuring traits of macrophages found within an atherosclerotic lesion.

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confidence: 99%

Activation of a TGF-β-Specific Multistep Gene Expression Program in Mature Macrophages Requires Glucocorticoid-Mediated Surface Expression of TGF-β Receptor II

Gratchev¹,

Kzhyshkowska²,

Kannookadan³

et al. 2008

The Journal of Immunology

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“…10,11 Cervical cancer cells are known to produce an extensive range of cytokines. 12,13 In addition to attracting inflammatory cells, these cytokines influence the activation status and function of the infiltrating antigen-presenting cells and the stroma and thus influence the course of the disease. 11,14 We have shown that expression of CCL2 (MCP-1) by the cervical cancer cells is associated with an increased number of macrophages and a decreased disease-free survival of cervical carcinoma patients.…”

mentioning

confidence: 99%

“…15 Furthermore, we have observed a down-regulation of the expression level of proinflammatory cytokines such as GM-CSF, TNF-a, and IL-12 in cervical carcinoma cell lines. 12 GM-CSF, TNF-a, and IL-12 are important in profiling immune reactivity. 10,16 GM-CSF and TNF-a are involved in differentiation and survival of dendritic cells (DC) and Langerhans cells (LHC) and IL-12 is known to stimulate effector cell populations such as cytotoxic T cells and natural killer cells.…”

mentioning

confidence: 99%

Role of tumor‐derived proinflammatory cytokines GM‐CSF, TNF‐α, and IL‐12 in the migration and differentiation of antigen‐presenting cells in cervical carcinoma

Zijlmans

Fleuren

Baelde

et al. 2006

Cancer

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BACKGROUND.Proinflammatory cytokines are important in modifying the activity, differentiation, and migration of antigen‐presenting cells and may influence the survival of cancer patients. The study assessed whether GM‐CSF, TNF‐α, and IL‐12, produced by cervical cancer cells, are important for the activity, differentiation, and migration of antigen‐presenting cells.METHODS.In 90 patients with cervical carcinoma the number of monocytes/tumor‐associated macrophages (TAM), mature dendritic cells (DC), and Langerhans cells (LHC) was determined using immunohistochemistry. An RNA in situ hybridization technique was used to measure the expression level of GM‐CSF, TNF‐α, IL‐12p35, and IL‐12p40.RESULTS.TAM were detected intraepithelial as well as in the stroma of the tumor. LHC were only detected intraepithelial and mature DC only in the tumor stroma. The number of TAM correlated positively with the number of mature DC. The expression levels of GM‐CSF and TNF‐α correlated positively with the number of TAM and DC. TNF‐α showed a negative correlation with the number of LHC. A significant correlation between the expression of functional IL‐12 (IL‐12p40) and stromal TAM was found. The expression of GM‐CSF, TNF‐α, and IL‐12p40 did not correlate significantly with disease‐free survival. However, high IL‐12p40 expression was associated with a favorable cumulative overall survival.CONCLUSIONS.The results suggest that GM‐CSF as well as TNF‐α, produced by cervical carcinoma cells, may play a role in the differentiation of monocytes into mature DC. Furthermore, TNF‐α may influence the migration of LHC from the tumor. Cancer 2007;109:556–565. © 2007 American Cancer Society.

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“…Furthermore, we tested a nutrition mixture that had inhibitory effects on MMP-2 and MMP-9 expression. Normal and cancerous ovarian and cervical cells produce immunomodulatory cytokines; however cytokine expression patterns change after malignant transformation (26,27). We chose cervical and ovarian cancer cell lines that express MMP-2 and MMP-9 to different extents.…”

Section: Effect Of the Nutrient Mixture (Nm) On Mmp-2 And Mmp-9 Exprementioning

confidence: 99%

In vitro modulation of MMP-2 and MMP-9 in human cervical and ovarian cancer cell lines by cytokines, inducers and inhibitors

Roomi

Monterrey²,

Kalinovsky³

et al. 2010

Oncol Rep

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Abstract. Matrix metalloproteinases (MMPs) secreted by cervical and ovarian cancer, especially MMP-2 and MMP-9, play crucial roles in tumor invasion and metastasis. We examined the effect of cytokines, mitogens, inducers and inhibitors on MMP-2 and MMP-9 expression in cervical and ovarian cancer cell lines. Human cervical (HeLa and DoTc2-4510) and ovarian (SK-OV-3) cell lines were cultured in appropriate media. At near confluence, the cells were washed with PBS and incubated in serum-free medium with various concentrations of several cytokines, mitogens and inhibitors. After 24 h the media were removed and analyzed for MMP-2 and MMP-9 by gelatinase zymography and quantitated by densitometry. HeLa and SK-OV-3 cell lines expressed MMP-2 whereas DoTc2-4510 cells expressed MMP-9. Treatment of cervical cancer cell lines (HeLa and DoTc2-4510) with PMA had no effect on MMP-2 expression and a moderate stimulatory effect in ovarian cancer cell line SK-OV-3. MMP-9 was stimulated by phorbol 12-myristate 13-acetate in HeLa cells and enhanced in DoTc2-4510. Tumor necrosis factor-· and interleukin-1ß, had slight inhibitory effect on HeLa cell expression of MMP-2 while lipopolysaccharide stimulated MMP-2 in HeLa cells. Doxycycline, epigallocatechin gallate, a nutrient mixture, actinomycin-D, cyclohexamide, retinoic acid and dexamethasone inhibited MMP-2 in HeLa and SK-OV-3 cell lines and inhibited MMP-9 in DoTc2-4510. Our results show that cytokines, mitogens, inducers and inhibitors have an up or down regulatory effect on MMP-2 and MMP-9 expression in ovarian and cervical cancer cell lines, suggesting these agents may be effective strategies to treat these cancers.

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Cytokine Profile of Cervical Cancer Cells

Cited by 76 publications

References 40 publications

Activation of a TGF-β-Specific Multistep Gene Expression Program in Mature Macrophages Requires Glucocorticoid-Mediated Surface Expression of TGF-β Receptor II

Activation of a TGF-β-Specific Multistep Gene Expression Program in Mature Macrophages Requires Glucocorticoid-Mediated Surface Expression of TGF-β Receptor II

Role of tumor‐derived proinflammatory cytokines GM‐CSF, TNF‐α, and IL‐12 in the migration and differentiation of antigen‐presenting cells in cervical carcinoma

In vitro modulation of MMP-2 and MMP-9 in human cervical and ovarian cancer cell lines by cytokines, inducers and inhibitors

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