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Schraml P, Frew IJ, Thoma CR, Boysen G, Struckmann K, Krek W et al.. Sporadic clear cell renal cell carcinoma but not the papillary type is characterized by severely reduced frequency of primary cilia. Mod Pathol 22: 31-36

Department of Pathology, Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
Modern Pathology (Impact Factor: 6.36). 01/2009; 22(1):31-6. DOI: 10.1038/modpathol.2008.132
Source: PubMed

ABSTRACT Renal cysts and clear cell renal cell carcinoma are common clinical manifestations of people with germ-line mutations of the von Hippel-Lindau tumor suppressor gene, VHL. Recent cell biological evidence suggests that the VHL gene product, pVHL, functions to maintain the primary cilium, a microtubule-based antenna-like structure whose functional integrity is believed to have an important role in cell-cycle control. As VHL mutations are common in sporadic clear cell renal cell carcinoma, but not papillary renal cell carcinoma, we asked whether there is an association between VHL status and primary cilia in vivo. VHL status was assessed in 20 cases of clear cell renal cell carcinoma and 9 cases of papillary renal cell carcinoma by DNA sequencing and by immunohistochemical staining for the hypoxia-inducible factor-alpha target gene products CA9 and GLUT-1. Of 20, 18 clear cell renal cell carcinomas, but only 1 of 9 papillary renal cell carcinomas, displayed evidence of VHL inactivation. In clear cell renal cell carcinoma the frequency of ciliated tumor cells ranged from 0 to 22% (median value 7.8+/-6.0%), whereas cilia frequency was significantly higher (P<0.0001) in papillary renal cell carcinoma (range 12-83%, median value 43.3+/-21.3%). There was no correlation between Ki-67 staining and cilia frequency, suggesting that the observed differences between the tumor types in cilia frequency are not accounted for by differences in cellular proliferation rates and that primary cilia degeneration in sporadic clear cell renal cell carcinoma depends on VHL inactivation. We propose that the different ciliation status of clear cell and papillary renal cell carcinoma may contribute, at least in part, to the different biological behaviors of these tumor types.

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    • "These include genetic disorders called ciliopathies but also many more pathologies , including obesity and cancer, reflecting the importance of proper assembly and maintenance of the cilium in developmental biology and tissue homeostasis (Marshall and Nonaka, 2006; Fliegauf et al., 2007). In cancer, loss of the primary cilium is observed in many tumor types (Schraml et al., 2009; Seeley et al., 2009; Yuan et al., 2010; Kim et al., 2011; Egeberg et al., 2012). It promotes aberrant cell signaling (Egeberg et al., 2012) and "
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    ABSTRACT: Distortion of primary cilia formation is increasingly recognized as a key event in many human pathologies. One of the underlying mechanisms involves aberrant activation of the lipogenic transcription factor Sterol Regulatory Element-binding Protein 1c (SREBP1c), as observed in cancer cells. To gain more insight into the molecular pathways by which SREBP1c suppresses primary ciliogenesis, we searched for overlap between known ciliogenesis regulators and targets of SREBP1. One of the candidate genes that was consistently upregulated in cellular models of SREBP1c-induced cilium repression was Phospholipase A2 group III (PLA2G3), a phospholipase that hydrolyses the sn-2 position of glycerophospholipids. Use of RNA interference and a chemical inhibitor of PLA2G3 rescued SREBP1c-induced cilium repression. Cilium repression by SREBP1c and PLA2G3 involved alterations in endosomal recycling and vesicular transport toward the cilium as revealed by aberrant transferrin and Rab11 localization and was largely mediated by an increase in lysophosphatidylcholine and lysophosphatidylethanolamine levels. Together, these findings indicate that aberrant activation of SREBP1c suppresses primary ciliogenesis by PLA2G3-mediated distortion of vesicular trafficking and suggest that PLA2G3 is a novel potential target to normalize ciliogenesis in SREBP1c-overexpressing cells, including cancer cells. © 2015 by The American Society for Cell Biology.
    Molecular biology of the cell 04/2015; 26(12). DOI:10.1091/mbc.E14-10-1472 · 5.98 Impact Factor
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    • "Mouse models demonstrate that loss of cilia can increase tumor incidence in basal cell carcinoma and medulloblastoma [5-7]. Cilia expression has been analyzed in some human cancers, demonstrating that pancreatic cancer, renal cell carcinoma, cholangiocarcinoma, melanoma, ovarian cancer, and prostate cancer all have a general loss of cilia [8-14]. These studies suggest that loss of cilia may promote cancer development in some tissues. "
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    ABSTRACT: Background Primary cilia are microtubule-based organelles that protrude from the cell surface. Primary cilia play a critical role in development and disease through regulation of signaling pathways including the Hedgehog pathway. Recent mouse models have also linked ciliary dysfunction to cancer. However, little is known about the role of primary cilia in breast cancer development. Primary cilia expression was characterized in cancer cells as well as their surrounding stromal cells from 86 breast cancer patients by counting cilia and measuring cilia length. In addition, we examined cilia expression in normal epithelial and stromal cells from reduction mammoplasties as well as histologically normal adjacent tissue for comparison. Results We observed a statistically significant decrease in the percentage of ciliated cells on both premalignant lesions as well as in invasive cancers. This loss of cilia does not correlate with increased proliferative index (Ki67-positive cells). However, we did detect rare ciliated cancer cells present in patients with invasive breast cancer and found that these express a marker of basaloid cancers that is associated with poor prognosis (Cytokeratin 5). Interestingly, the percentage of ciliated stromal cells associated with both premalignant and invasive cancers decreased when compared to stromal cells associated with normal tissue. To understand how cilia may be lost during cancer development we analyzed the expression of genes required for ciliogenesis and/or ciliary function and compared their expression in normal versus breast cancer samples. We found that expression of ciliary genes were frequently downregulated in human breast cancers. Conclusions These data suggest that primary cilia are lost early in breast cancer development on both the cancer cells and their surrounding stromal cells.
    Cilia 07/2014; 3:7. DOI:10.1186/2046-2530-3-7
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    • "We analyzed cilia frequency in renal tissue sections present in triplicate on a TMA of 110 patients, including RCC tissue and tissue obtained from the tumor parenchyma, and observed a severe reduction of cilia frequency in the various RCC subtypes. Our data supports, extends and confirms that the low ciliary frequency characteristic of renal cysts remains an evident characteristic of most renal tumors [22]. Potential effects on cilia function could not be analyzed in this approach, hence we cannot exclude whether cilia function in the normal tissue is also affected. "
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    ABSTRACT: Background Cilia are essential organelles in multiple organ systems, including the kidney where they serve as important regulators of renal homeostasis. Renal nephron cilia emanate from the apical membrane of epithelia, extending into the lumen where they function in flow-sensing and ligand-dependent signaling cascades. Ciliary dysfunction underlies renal cyst formation that is in part caused by deregulation of planar cell polarity and canonical Wnt signaling. Renal cancer pathologies occur sporadically or in heritable syndromes caused by germline mutations in tumor suppressor genes including VHL. Importantly, Von Hippel-Lindau (VHL) patients frequently develop complex renal cysts that can be considered a premalignant stage. One of the well-characterized molecular functions of VHL is its requirement for the maintenance of cilia. In this study, tissue from 110 renal cancer patients who underwent nephrectomy was analyzed to determine if lower ciliary frequency is a common hallmark of renal tumorigenesis by comparing cilia frequencies in both tumor and adjacent parenchymal tissue biopsies from the same kidney. Methods We stained sections of human renal material using markers for cilia. Preliminary staining was performed using an immunofluorescent approach and a combination of acetylated-α-tubulin and pericentrin antibodies and DAPI. After validation of an alternative, higher throughput approach using acetylated-α-tubulin immunohistochemistry, we continued to manually quantify cilia in all tissues. Nuclei were separately counted in an automated fashion in order to determine ciliary frequencies. Similar staining and scoring for Ki67 positive cells was performed to exclude that proliferation obscures cilia formation potential. Results Samples from renal cell carcinoma patients deposited in our hospital tissue bank were previously used to compose a tissue microarray containing three cores of both tumor and parenchymal tissue per patient. Cilia frequencies in a total of eighty-nine clear cell, eight papillary, five chromophobe renal cell carcinomas, two sarcomatoid renal tumors and six oncocytomas were determined. A marked decrease of primary cilia across renal cell carcinoma subtypes was observed compared to adjacent nontumorigenic tissue. Conclusions Our study shows that cilia are predominantly lost in renal cell carcinomas compared to tissue of the tumor parenchyma. These results suggest that ciliary loss is common in renal tumorigenesis, possibly participating in the sequence of cellular events leading to malignant tumor development. Future therapies aimed at restoring or circumventing cilia signaling might therefore aid in current treatment efficacy.
    Cilia 01/2013; 2(1):2. DOI:10.1186/2046-2530-2-2
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