Pro-Inflammatory and T Cell Inhibitory Cytokines Are Secreted at High Levels in Tumor Cell Cultures of Human Renal Cell Carcinoma

Lahn, Michael; Fisch, Paul; Köhler, Gabriele; Kunzmann, Regina; Hentrich, I.; Jesuiter, Heike; Behringer, Dirk; Muschal, Birgit; Veelken, Hendrik; Kulmburg, P; Iklé, David; Lindemann, A.

doi:10.1159/000019821

Cited by 63 publications

(30 citation statements)

References 49 publications

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“…The significant upregulation of IL-6 and IL-l 0 we found in malignant but not in normal renal tissue, and the positive correlation between IL-6 and IL-IO proteins, reinforces the known differential role of the various cytokines in normal and tumor cells. The differential IL-6 and IL-I0 expression we found in benign tumors and RCCs --higher IL-6 epithelial and stromal immunoreactivity than IL-I0 in benign tumors (papillary adenoma and oncocytoma) and lower than IL-IO in RCCs --, fits in well with previous observations showing that RCCs produce large amounts of proinflammatory and T-cellinhibitory cytokines that may exert tumor-promoting and immunosuppressive effects (35)(36). IL-I0 has been traditionally regarded as an anti-inflammatory, immunosuppressivecytokinethatfavorstumorescape from immune surveillance and as a potent inhibitor of the synthesis of other cytokines, particularly IL-6 .…”

Section: Resultssupporting

confidence: 91%

Interleukin-6, Interleukin-10 and Heat Shock Protein-90 Expression in Renal Epithelial Neoplasias and Surrounding Normal-Appearing Renal Parenchyma

Cardillo

Ippoliti

2007

Int J Immunopathol Pharmacol

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Cytokines, notably the interleukins IL-6 and IL-IO, have an important role in the development and progression of renal-cell carcinomas, acting in the host-tumor interaction and in tumor bulk. Heat shock proteins (HSP), in particular HSP-90, may have a regulatory role in cytokine biosynthesis and prognostic implication in some tumors. To define the roles of the cytokines IL-6 and IL-IO and HSP-90 in the progression of renal-cell carcinoma we analyzed immunohistochemical expression of these proteins in human renal-cell carcinomas from 95 total nephrectomies. IL-6, IL-IO and HSP-90 proteins were more strongly expressed in epithelium and stroma of the renal tumoral compartment than in adjacent normal peritumoral tissue. But the difference reached significance only for HSP-90 protein. The percentage of cells expressing IL-6, IL-IO and HSP-90 immunoreactivity was higher in benign epithelial tumors, than in normal peritumoral tissue, but lower than in renal-cell carcinomas. Whereas HSP-90 immunoreactivity seemed higher in more aggressive histological phenotypes (collecting-duct carcinoma) of renal-cell carcinomas, IL-IO protein levels were higher in more advanced TNM stage (pT3) tumors. Our observation suggests that IL-6 and IL-IO and HSP-90 may be useful markers associated with the development and progression of renal-cell carcinomas and have independent functional roles in this malignant condition.

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Section: Resultssupporting

confidence: 91%

Interleukin-6, Interleukin-10 and Heat Shock Protein-90 Expression in Renal Epithelial Neoplasias and Surrounding Normal-Appearing Renal Parenchyma

Cardillo

Ippoliti

2007

Int J Immunopathol Pharmacol

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“…IL6, an inflammatory cytokine that acts as a growth factor for renal cells, and the chemoattractant IL8, known to interfere with the recruitment of immune cells (Lahn et al, 1999). RCC6 cells secreted high amounts of IL6 (42000 pg/ml) and IL8 (3000 pg/ml), and RCC4 cells produced 400 and 500 pg/ml of IL6 and IL8, respectively (Supplementary Figure 1).…”

Section: Vhl Status Of Rcc Cell Lines and Restoration Of Vhl Functionmentioning

confidence: 99%

Mutations of the von Hippel–Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma

et al. 2011

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The tumor suppressor gene von Hippel-Lindau (VHL) is involved in the development of sporadic clear-cell renal cell carcinoma (RCC). VHL interferes with angiogenesis and also controls cell adhesion and invasion. Therapies that target VHL-controlled genes are currently being evaluated in RCC patients. RCC is a immunogenic tumor and treatment with interleukin-2 (IL2) or interferon (IFN)-a results in regression in some patients. We used two renal tumor cell lines (RCC6 and RCC4) carrying VHL loss-of-function mutations to investigate the role of mutant VHL in susceptibility to natural killer (NK) cellmediated lysis. The RCC6 and RCC4 cell lines were transfected with the wild-type gene to restore the function of VHL. The presence of the gene in RCC cells downregulated hypoxia-inducible factor (HIF)-1a and subsequently decreased vascular endothelial growth factor (VEGF) production. Relative to control transfectants and parental cells, pVHL-transfected cell lines activated resting and IL2-activated NK cells less strongly, as assessed by IFNc secretion, NK degranulation and cell lysis. NKG2A, a human leukocyte antigen (HLA)-Ispecific inhibitory NK receptor, controls the lysis of tumor targets. We show that HLA-I expression in RCC-pVHL cells is stronger than that in parental and controls cells, although the expression of activating receptor NK ligands remains unchanged. Blocking NKG2A/HLA-I interactions substantially increased lysis of RCC-pVHL, but had little effect on the lysis of VHL-mutated RCC cell lines. In addition, in response to IFNa, the exponential growth of RCC-pVHL was inhibited more than that of RCC-pE cells, indicating that VHL mutations may be involved in IFNa resistance. These results indicate that a decreased expression of HLA-I molecules in mutated VHL renal tumor cells sensitizes them to NK-mediated lysis. These results suggest that combined immunotherapy with antiangiogenic drugs may be beneficial for patients with mutated VHL.

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“…and immortality (1)(2)(3)(4). Due to its delayed diagnosis until advanced stages, renal cell cancer (RCC) is known as the deadliest neoplasm of the urinary tract (1,5).…”

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confidence: 99%

MicroRNA-1 and MicroRNA-21 Individually Regulate Cellular Growth of Non-malignant and Malignant Renal Cells

Ahrend

Kaul

Ziegler

et al. 2017

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Abstract. Background/Aim: Due to its poor prognosis, it is increasingly necessary to understand the biology of renal cell cancer (RCC). Therefore, we investigated the role of microRNAs miR-1 and miR-21 in the growth of RCC cells compared to that of non-malignant renal cells. Materials and Methods: Four malignant cell lines RCC4, A498) Tumorigenesis gives cells an advantage in survival by an increase of proliferation, angiogenesis, immunomodulation and immortality (1-4). Due to its delayed diagnosis until advanced stages, renal cell cancer (RCC) is known as the deadliest neoplasm of the urinary tract (1, 5). Thus, it is more necessary than ever to understand its tumor biology and explore new targets for further therapeutic approaches and prognostic options (6). Former studies suggested that among others, a misguided microRNA expression pattern may be involved in tumor initiation and progression in RCC (7,8). Among such mechanisms, small regulatory RNAs, so-called microRNAs (miRs), can operate as controllers of different proccesses in tumorigenesis, such as cell migration and differentiation, as well as metastasis and apoptosis (9-11). miR-1 and miR-21 are two of numerous representatives of microRNAs. miR-1, initially found in cardiac muscle cells (12), but also found in various tissues (13-15), was strongly suspected of acting as a tumor suppressor due to its antioncogenic properties (16) in prostate, breast and colorectal cancer (13-15); interestingly, the type of tissue in fact determines the biological behavior of miR-1 (9). Sadly, the current data situation for the expression of miR-1 in RCC leaves much to be desired. For this reason, our study aimed to expand the first findings in order to gain a better understanding of the tumor biology of RCC. Similarly to miR-1, miR-21 was also detected in various malignant tissues, such as prostate and lung cancer and their metastases, pancreatic cancer and colorectal cancer (17-21). However, in contrast to miR-1, miR-21 appears to be an oncomir. There are preliminary investigations, showing miR-21 to appear as an oncomir in the case of RCC (22, 23).The fact that cancer cells have a further survival advantage by extending their chromosomal ends by means of endogenic telomerase, not only raises a problem, but also provides a therapeutic approach in cancer therapy (4).In order to gain deeper insight into these issues, as far as we are aware, we are the first to investigate one non-malignant 625 This article is freely accessible online. *These Authors contributed equally to this study. Materials and MethodsCell culture. Human RCC cell lines Caki-1, 786-O, A498 (all Cell Lines Service, Eppelheim, Germany), and RCC4 (Sigma-Aldrich, München, Germany) and the non-malignant renal cell line RC-124 (Cell Lines Service) were applied in this study. Caki-1 and A498 cells were propagated in minimum essential medium (MEM) supplemented with 79.6 mg/l non-essential amino acids, 2 mM L-glutamine, 1 mM sodium pyruvate, 1% penicillline/streptomycin (P/S), and 10% fetal bovine serum (FBS...

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Pro-Inflammatory and T Cell Inhibitory Cytokines Are Secreted at High Levels in Tumor Cell Cultures of Human Renal Cell Carcinoma

Cited by 63 publications

References 49 publications

Interleukin-6, Interleukin-10 and Heat Shock Protein-90 Expression in Renal Epithelial Neoplasias and Surrounding Normal-Appearing Renal Parenchyma

Interleukin-6, Interleukin-10 and Heat Shock Protein-90 Expression in Renal Epithelial Neoplasias and Surrounding Normal-Appearing Renal Parenchyma

Mutations of the von Hippel–Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma

MicroRNA-1 and MicroRNA-21 Individually Regulate Cellular Growth of Non-malignant and Malignant Renal Cells

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