Functional Intactness of Stimulatory and Inhibitory Autocrine Loops in Human Renal Carcinoma Cell Lines of the Clear Cell Type

Ramp, Uwe; Jaquet, Kai; Reinecke, Petra; Schardt, Cordula; Friebe, Ulrike; Nitsch, T.; Marx, Nikolaus; Gabbert, Helmut E.; Gerharz, C. D.

doi:10.1016/s0022-5347(01)64778-5

Cited by 36 publications

(14 citation statements)

References 19 publications

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“…Other investigators have examined human RCC lines and identified alterations in the expression of TGFb signaling pathway intermediaries such as TBR2 and the Smads (Engel et al, 1999), but these observations have not been validated in the clinical biology of RCC. Ramp et al (1997b) found that TBR3 mRNA was expressed in only 1/13 RCC cell lines examined. To our knowledge, few studies have methodically examined the expression of all three TBRs in patient samples at the protein and mRNA level, in an effort to correlate TBR expression to disease-specific states of RCC (i.e.…”

Section: Discussionmentioning

confidence: 96%

Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression

et al. 2003

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Renal cell carcinoma (RCC) is a major health issue. Whereas localized disease can be cured surgically, there is no effective therapy for metastatic disease. The development of an effective therapy will require an understanding of the pathways that are important in RCC carcinogenesis and progression. Using genomic profiling of patientmatched tissue, we have identified aberrations in the transforming growth factor b (TGFb) signaling pathway in RCC. We observed loss of type III TGFb receptor (TBR3) expression in all RCC samples. This suggests that TBR3 loss is an early event in RCC carcinogenesis and plays a sentinel role in the acquisition of a tumorigenic phenotype. We also observed subsequent loss of type II TGFb receptor (TBR2) expression in metastatic RCCs. We propose that loss of TBR3 is necessary for RCC carcinogenesis, and that loss of TBR2 leads to acquisition of a metastatic phenotype. To this end, we have identified a human renal cell carcinoma line (UMRC6) that is representative of localized, nonmetastatic RCC, reflecting a loss of TBR3, but not TBR2 expression. Another cell line, UMRC3, is highly metastatic, having lost TBR3 and TBR2 expression. We demonstrate functional loss of TGFb responsiveness in these cell lines as observed through phenotypic and transcriptional responsiveness to exogenous TGFb. Restoring TBR2 and TBR3 expression in UMRC3 cells attenuates cell proliferation, completely restores TGFb-mediated transcriptional responses, and completely blocks anchorage independent-growth: while restoration of TBR2 partially restores TGFb-mediated signaling. Based on these data, we propose that dysregulation in TGFb signaling, through stepwise loss in receptor expression, plays a prominent role in RCC carcinogenesis and progression. In addition, these studies unequivocably demonstrate a link between loss of TBR3 and a human disease.

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Section: Discussionmentioning

confidence: 96%

Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression

et al. 2003

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“…An elevated amount of insulin-and IGF-1 receptor expression with increased specific autophosphorylation and tyrosine-kinase activity in surgically resected samples has been reported (13). In contrast, others found no expression of IGF-1 and its receptors in RCC cell lines (14). Therefore, the role of IGF-1 in RCC is controversial.…”

Section: Discussionmentioning

confidence: 99%

Survivin associates with cell proliferation in renal cancer cells: Regulation of survivin expression by insulin-like growth factor-1, interferon-γ and a novel NF-κB inhibitor

Sato

Oya²,

Ito

et al. 2006

Int J Oncol

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Abstract. Although survivin has been widely recognized as an attractive target for cancer therapy, the exact mechanism regarding the regulation of survivin and its effect on cell proliferation have yet to be clearly defined in renal cell carcinoma (RCC). We investigated herein the association between survivin expression and cell proliferation in a RCC cell line, KU19-20. In KU19-20 cells, cell proliferation and survivin expression were significantly induced by IGF-1, whereas they were inhibited by a novel NF-κB inhibitor dehydroxymethyl-epoxyquinomicin (DHMEQ) and IFN-Á. The combination of DHMEQ and IFN-Á inhibited cell proliferation synergistically with a pronounced attenuation of survivin expression. Furthermore, treatment with survivinspecific siRNA reduced expression of survivin and significantly inhibited cell proliferation. Survivin expression was thus associated with cell proliferation in KU19-20 cells. The regulation of survivin by IFN-Á and/or an NF-κB inhibitor may therefore be a potential treatment modality for RCC.

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“…RCC cell lines have been shown to be capable of synthesizing several of such cytokines, including TNFa (Gogusev et al 1993). In addition, inhibitory autocrine loops involving cytokine secretion have been demonstrated in RCC (Ramp et al 1997). While the exact mechanisms of secretion for such cytokines remain largely unknown, Pgp has recently been shown to be involved in the transport of IL-2, IFNc and IL-4 (Drach et al 1996).…”

Section: Discussionmentioning

confidence: 99%

Interferon α2b differentially affects proliferation of two human renal cell carcinoma cell lines differing in the P-glycoprotein-associated multidrug-resistant phenotype

Frank

Pomer

1999

Journal of Cancer Research and Clinical Oncology

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Functional Intactness of Stimulatory and Inhibitory Autocrine Loops in Human Renal Carcinoma Cell Lines of the Clear Cell Type

Cited by 36 publications

References 19 publications

Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression

Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression

Survivin associates with cell proliferation in renal cancer cells: Regulation of survivin expression by insulin-like growth factor-1, interferon-γ and a novel NF-κB inhibitor

Interferon α2b differentially affects proliferation of two human renal cell carcinoma cell lines differing in the P-glycoprotein-associated multidrug-resistant phenotype

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