Serial analysis of gene expression in renal carcinoma cells reveals VHL-dependent sensitivity to TNFα cytotoxicity

Caldwell, M.Craig; Hough, Colleen D.; Fürer, Stefanie; Linehan, W. Marston; Morin, Patrice J.; Gorospe, Myriam

doi:10.1038/sj.onc.1205140

Cited by 35 publications

(16 citation statements)

References 23 publications

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“…41 Therefore, loss of clusterin expression offers one explanation for why pVHL-defective tumor cells exhibit increased nuclear factor B signaling and resistance to tumor necrosis factor-␣. 57,58 Clusterin has also been shown to decrease prostate cancer cell proliferation and neuroblastoma cell invasion in vitro. 39 -41 Therefore, it is conceivable that clusterin contributes to tumor suppression by pVHL in addition to serving as a marker for its integrity.…”

Section: Discussionmentioning

confidence: 99%

Clusterin Is a Secreted Marker for a Hypoxia-Inducible Factor-Independent Function of the von Hippel-Lindau Tumor Suppressor Protein

Nakamura

Abreu-e-Lima

Awakura

et al. 2006

The American Journal of Pathology

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Germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene predispose people to renal cancer, hemangioblastomas, and pheochromocytomas in an allele-specific manner. The best documented function of the VHL gene product (pVHL) relates to its ability to polyubiquitinate, and hence target for destruction, the ␣ subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF). pVHL mutants linked to familial pheochromocyctoma (type 2C VHL disease), in contrast to classical VHL disease, appear to be normal with respect to HIF regulation. Using a simple method for identifying proteins that are differentially secreted by isogenic cell line pairs, we confirmed that the HIF targets IGBP3 and PAI-1 are overproduced by pVHLdefective renal carcinoma cells. In addition, cells lacking wild-type pVHL, including cells producing type 2C pVHL mutants, were defective with respect to expression and secretion of clusterin, which does not behave like a HIF target. Decreased clusterin secretion by pVHL-defective tumors was confirmed in vivo by immunohistochemistry. Therefore, clusterin is a secreted marker for a HIF-independent pVHL function that might be especially important in pheochromocytoma development. von Hippel-Lindau disease, caused by heterozygous germline inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, presents clinically as a hereditary cancer syndrome.1,2 Tumor development in this setting is due to somatic inactivation of the remaining wild-type VHL allele in a susceptible cell.3 The classical tumors observed in VHL disease are retinal and central nervous system (usually within the cerebellum or spinal cord) blood vessel proliferations called hemangioblastomas. These tumors, although benign, cause significant morbidity and mortality because of mass effect. Some VHL families also exhibit an increased risk of clear cell renal cell carcinoma or pheochromocytoma. In keeping with the Knudson 2-hit model, many sporadic hemangioblastomas and renal cell carcinomas are also due to VHL inactivation, as a result of either somatic mutations or hypermethylation.3,4 For reasons that are still unclear, somatic VHL mutations are rare in sporadic pheochromocytomas absent an occult germline VHL mutation, despite the fact that certain germline VHL mutations confer an increased risk of this tumor.Genotype-phenotype correlations have emerged in VHL disease. VHL families can be subdivided into type 1 (low risk of pheochromocytoma) and type 2 (high risk of pheochromocytoma). Type 2 disease can be subdivided into type 2A (low risk of renal cell carcinoma) and type 2B (high risk of renal cell carcinoma).1 Some VHL families exhibit an increased risk of pheochromocytoma without Supported in part by grants from the National Institutes of Health (to W.G.K.), the Kurozumi Medical Foundation (to E.N.), the Japanese Clinical Oncology Fund (to E.N.), the Ministry of Education, Culture, Sports, Science and Technology of Japan (to E.N. and O.O.), and the Murray Foundation (to W.G.K.

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Section: Discussionmentioning

confidence: 99%

Clusterin Is a Secreted Marker for a Hypoxia-Inducible Factor-Independent Function of the von Hippel-Lindau Tumor Suppressor Protein

Nakamura

Abreu-e-Lima

Awakura

et al. 2006

The American Journal of Pathology

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“…Although the wild-type VHL protein was known to modulate the expression of multiple gene products (19), it was only recently shown that TNF-␣ mRNA more avidly associates with polysomes in RCC cells harboring the mutation (27), explaining why many RCC tumors, but not normal kidney cells, synthesize that cytokine constitutively. Because immunohistological examination of many explanted RCC tumors reveals that a large percentage of the infiltrating T cells can be apoptotic, we asked whether transfection of cDNA encoding TNF-␣ into the comparatively nonapoptogenic, essentially TNF-␣-negative SK-RC-45 cells could enhance the line's capacity to kill resting T lymphocytes.…”

Section: Tnf-␣ Enhances the Ability Of Rcc Lines To Induce Apoptosis mentioning

confidence: 99%

“…It is now found that TNF-␣ produced at pathophysiological concentrations actually promotes tumor growth (17), suggesting that the cytokine may have different effects depending on the tumor type to which it is administered. Indeed, the effect of TNF-␣ on renal cancer cells is dependent on whether the tumor expresses the wild-type or mutant form of the von Hippel-Lindau (VHL) gene: wild-type tumors are typically susceptible to the toxicity of TNF-␣, although many VHL mutants are both resistant to and themselves produce the cytokine (18,19). The following studies were initiated upon determining that TNF-␣-producing RCC lines were significantly more apoptogenic for T cells than were nonproducers, and that nonapoptogenic lines could be converted to killers if first stimulated with TNF-␣.…”

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confidence: 99%

TNF-α Induction of GM2 Expression on Renal Cell Carcinomas Promotes T Cell Dysfunction

Raval

Biswas

Rayman

et al. 2007

The Journal of Immunology

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Previous studies from our laboratory demonstrated the role of tumor-derived gangliosides as important mediators of T cell apoptosis, and hence, as one mechanism by which tumors evade immune destruction. In this study, we report that TNF-α secreted by infiltrating inflammatory cells and/or genetically modified tumors augments tumor-associated GM2 levels, which leads to T cell death and immune dysfunction. The conversion of weakly apoptogenic renal cell carcinoma (RCC) clones to lines that can induce T cell death requires 3–5 days of TNF-α pretreatment, a time frame paralleling that needed for TNF-α to stimulate GM2 accumulation by SK-RC-45, SK-RC-54, and SK-RC-13. RCC tumor cell lines permanently transfected with the TNF-α transgene are similarly toxic for T lymphocytes, which correlates with their constitutively elevated levels of GM2. TNF-α increases GM2 ganglioside expression by enhancing the mRNA levels encoding its synthetic enzyme, GM2 synthase, as demonstrated by both RT-PCR and Southern analysis. The contribution of GM2 gangliosides to tumor-induced T cell death was supported by the finding that anti-GM2 Abs significantly blocked T cell apoptosis mediated by TNF-α-treated tumor cells, and by the observation that small interfering RNA directed against TNF-α abrogated GM2 synthase expression by TNF-transfected SK-RC-45, diminished its GM2 accumulation, and inhibited its apoptogenicity for T lymphocytes. Our results indicate that TNF-α signaling promotes RCC-induced killing of T cells by stimulating the acquisition of a distinct ganglioside assembly in RCC tumor cells.

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“…Several groups have profiled RCC cell lines (63)(64)(65)(66)(67)(68), seeking to dissect relevant tumorigenic pathways and the VHL protein (pVHL)-mediated hypoxia-signaling pathway. In view of the translational focus of this article, we review only those studies corroborated by clinical data.…”

Section: Tumor Biologymentioning

confidence: 99%

Gene Expression Profiling of Renal Cell Carcinoma

Tan

Rogers

Cooper

et al. 2004

Clinical Cancer Research

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Renal cell carcinoma (RCC) is a histologically diverse disease, with variable and often unpredictable clinical behavior. The prognosis worsens dramatically with the onset of clinical metastasis, and current regimens of systemic therapy yield only modest benefits for metastatic RCC. Gene expression profiling is a promising technique for refining the diagnosis and staging of RCC, as well as for highlighting potential therapeutic targets. We review the recent advances in expression profiling of RCC and discuss the clinical and biological insights obtained from these studies.

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Serial analysis of gene expression in renal carcinoma cells reveals VHL-dependent sensitivity to TNFα cytotoxicity

Cited by 35 publications

References 23 publications

Clusterin Is a Secreted Marker for a Hypoxia-Inducible Factor-Independent Function of the von Hippel-Lindau Tumor Suppressor Protein

Clusterin Is a Secreted Marker for a Hypoxia-Inducible Factor-Independent Function of the von Hippel-Lindau Tumor Suppressor Protein

TNF-α Induction of GM2 Expression on Renal Cell Carcinomas Promotes T Cell Dysfunction

Gene Expression Profiling of Renal Cell Carcinoma

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