scholarly journals Histological Tracking into the Third Dimension

2021 ◽  
Vol 8 (3) ◽  
pp. 5-14
Author(s):  
Mayyan Mubarak ◽  
Nayef Al Gharaibeh ◽  
Samuel Sommaruga ◽  
Jie Li ◽  
Alexander Vortmeyer
Keyword(s):  
Clear Cell ◽  
Three Dimensional ◽  
Kidney Tissue ◽  
Von Hippel Lindau ◽  
Targeted Sampling ◽  
Sequence Of Events ◽  
Third Dimension ◽  
Vhl Disease ◽  
Selective Analysis ◽  
Histologic Changes

Using a novel three-dimensional (3D) approach, we tracked histological changes to elucidate the earliest stages of renal clear cell neoplasia in normal kidney tissue of patients with von Hippel-Lindau (VHL) disease. Tissue blocks of interest were procured, serially sectioned, and 3D reconstruction of the entirety of pathologic events was performed. The results reveal an abundance of foci with aberrant clear cell proliferation that initially develop along the tubular lining, but have the potential to aggregate within individual tubules. This stage is followed by the extension of clear cell aggregates beyond the tubular basement membrane, which allows for the recruitment of angiogenesis derived from interstitial vasculature. The results suggest that the most frequent pathologic event in VHL kidneys is the presence of isolated or aggregated clear cells within the tubular epithelium, potentially developing further into a protracted process of neoplasia. The abundance of independent pathologic events in VHL kidneys confirms developmental mechanisms to precede tumor initiation. To our knowledge, this is the first report demonstrating that tracking of histologic changes in the 3rd dimension enables the confirmation of the sequence of events from the earliest pathologic change in the VHL kidney to the neoplastic stage. This approach is not only useful for visualization and quantification of pathologic changes but also for targeted sampling allowing selective analysis of the earliest stages of clear cell carcinogenesis.

scholarly journals USP37 promotes deubiquitination of HIF2α in kidney cancer

2020 ◽  
Vol 117 (23) ◽  
pp. 13023-13032
Author(s):  
Kai Hong ◽  
Lianxin Hu ◽  
Xijuan Liu ◽  
Jeremy M. Simon ◽  
Travis S. Ptacek ◽  
...  
Keyword(s):  
Clear Cell ◽  
Hypoxia Inducible Factor ◽  
Three Dimensional ◽  
Xenograft Model ◽  
Dependent Manner ◽  
Potential Therapeutic Target ◽  
Cell Renal Cell Carcinoma ◽  
Von Hippel Lindau ◽  
Orthotopic Xenograft Model ◽  
Factor Α

Clear cell renal cell carcinoma (ccRCC) is characterized by loss of tumor suppressor Von Hippel Lindau (VHL) function, which leads to accumulation of hypoxia inducible factor α (including HIF1α and HIF2α). HIF2α was previously reported to be one of the major oncogenic drivers in ccRCC, however, its therapeutic targets remain challenging. Here we performed a deubiquitinase (DUB) complementary DNA (cDNA) library binding screen and discovered that ubiquitin-specific peptidase 37 (USP37) is a DUB that binds HIF2α and promotes HIF2α deubiquitination. As a result, USP37 promotes HIF2α protein stability in an enzymatically dependent manner, and depletion of USP37 leads to HIF2α down-regulation in ccRCC. Functionally, USP37 depletion causes decreased cell proliferation measured by MTS, two-dimensional (2D) colony formation as well as three-dimensional (3D) anchorage- independent growth. USP37 is also essential for maintaining kidney tumorigenesis in an orthotopic xenograft model and its depletion leads to both decreased primary kidney tumorigenesis and spontaneous lung metastasis. Our results suggest that USP37 is a potential therapeutic target in ccRCC.

scholarly journals pVHL Modification by NEDD8 Is Required for Fibronectin Matrix Assembly and Suppression of Tumor Development

2004 ◽  
Vol 24 (8) ◽  
pp. 3251-3261 ◽  
Author(s):  
Natalie H. Stickle ◽  
Jacky Chung ◽  
Jeffery M. Klco ◽  
Richard P. Hill ◽  
William G. Kaelin ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Tumor Development ◽  
Three Dimensional ◽  
Suppressor Gene ◽  
Matrix Assembly ◽  
Von Hippel Lindau ◽  
Fibronectin Matrix ◽  
Matrix Expression ◽  
Vhl Disease ◽  
Hif Pathway

ABSTRACT Functional inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is the cause of the familial VHL disease and most sporadic renal clear-cell carcinomas (RCC). pVHL has been shown to play a role in the destruction of hypoxia-inducible factor α (HIF-α) subunits via ubiquitin-mediated proteolysis and in the regulation of fibronectin matrix assembly. Although most disease-causing pVHL mutations hinder the regulation of the HIF pathway, every disease-causing pVHL mutant tested to date has failed to promote the assembly of the fibronectin matrix, underscoring its potential importance in VHL disease. Here, we report that a ubiquitin-like molecule called NEDD8 covalently modifies pVHL. A nonneddylateable pVHL mutant, while retaining its ability to ubiquitylate HIF, failed to bind to and promote the assembly of the fibronectin matrix. Expression of the neddylation-defective pVHL in RCC cells, while restoring the regulation of HIF, failed to promote the differentiated morphology in a three-dimensional growth assay and was insufficient to suppress the formation of tumors in SCID mice. These results suggest that NEDD8 modification of pVHL plays an important role in fibronectin matrix assembly and that in the absence of such regulation, an intact HIF pathway is insufficient to prevent VHL-associated tumorigenesis.

scholarly journals Primary Clear Cell Microcystic Adenoma of the Sinonasal Cavity: Pathological or Fortuitous Association?

2017 ◽  
Vol 2017 ◽  
pp. 1-5
Author(s):  
Rosalin Cooper ◽  
Hannah Markham ◽  
Jeffery Theaker ◽  
Adrian Bateman ◽  
David Bunyan ◽  
...  
Keyword(s):  
Clear Cell ◽  
Surgical Excision ◽  
Loss Of Function ◽  
Cancer Syndrome ◽  
Cell Renal Cell Carcinoma ◽  
Inherited Cancer ◽  
Von Hippel Lindau ◽  
Microcystic Adenoma ◽  
Vhl Disease ◽  
Inherited Cancer Syndrome

Primary clear cell microcystic adenoma of the sinonasal cavity is rare. It has previously been described only as a VHL-associated tumour. Von Hippel-Lindau (VHL) syndrome is an inherited cancer syndrome characterised by an elevated risk of neoplasia including clear cell renal cell carcinoma (ccRCC), haemangioblastoma, and phaeochromocytoma. We describe the second reported case of a primary clear cell microcystic adenoma of the sinonasal cavity. The 39-year-old patient with VHL syndrome had previously undergone resection and ablation of ccRCC. He presented with epistaxis. Imaging demonstrated a mass in the ethmoid sinus. Initial clinical suspicion was of metastatic ccRCC. However, tumour morphology and immunoprofile were distinct from the previous ccRCC and supported a diagnosis of primary microcystic adenoma. Analysis of DNA extracted from sinonasal tumour tissue did not show loss of the wild-type allele at the VHL locus. Although this did not support tumour association with VHL disease, it was not possible to look for a loss-of-function mutation. The association of primary microcystic adenoma of the sinonasal cavity with VHL disease remains speculative. These lesions are benign but are likely to require regular surveillance. Such tumours may require repeated surgical excision.

Testosterone secreting clear cell ovarian tumor in a patient with Von Hippel Lindau (VHL) disease

2018 ◽  
Author(s):  
Tejhmal Rehman ◽  
Ali Hameed ◽  
Katie Snape ◽  
Shirley Hodgson ◽  
Gul Bano
Keyword(s):  
Ovarian Tumor ◽  
Clear Cell ◽  
Von Hippel Lindau ◽  
Vhl Disease

Tissue expression and plasma levels of adrenomedullin in renal cancer patients

2006 ◽  
Vol 111 (1) ◽  
pp. 61-70 ◽  
Author(s):  
Jens Michelsen ◽  
Helle Thiesson ◽  
Steen Walter ◽  
Peter D. Ottosen ◽  
Ole Skøtt ◽  
...  
Keyword(s):  
Clear Cell ◽  
Hypoxia Inducible Factor ◽  
Kidney Tissue ◽  
Tissue Expression ◽  
Tumour Marker ◽  
Cell Nuclei ◽  
Von Hippel Lindau ◽  
Hypoxia Inducible Factor 1 ◽  
Tumour Suppressor Protein ◽  
Peptide Expression

The peptide AM (adrenomedullin) is stimulated by hypoxia through HIF-1 (hypoxia-inducible factor-1). The majority of human CC-RCCs (clear cell renal cell carcinomas) display mutations in the tumour suppressor protein von Hippel–Lindau, which leads to constitutively elevated HIF-1. We hypothesized that AM is increased in CC-RCC tumours and that AM is a plasma biomarker for CC-RCC. Tumours and non-malignant kidney tissue were obtained from patients that underwent unilateral nephrectomy. Blood samples were drawn at the day of surgery, 3–6 days after surgery and 4–5 weeks after surgery. AM mRNA and peptide expression in tissue and AM plasma concentration were determined. HIF-1α was localized in tissue by immunohistochemistry. AM mRNA was elevated in CC-RCC compared with adjacent renal cortex (6-fold, n=18; P<0.02). There was no difference in AM mRNA between cortex and non-CC-RCC tissue (n=7). AM peptide concentration was elevated in CC-RCC tissue compared with adjacent cortex (4-fold, n=6; P<0.02), whereas there was no difference between cortex and non-CC-RCC tissue (n=5). HIF-1α immunoreactivity was detected in the majority of cell nuclei in 76% of CC-RCC, consistent with constitutive stabilization. In non-CC-RCC, HIF-1α staining was focal. Before surgery there was no difference in plasma AM concentration between tumour types. Nephrectomy increased plasma AM significantly after 3–6 days and a similar pre-surgery level was observed after 4–5 weeks in both groups of tumour patients. We conclude that elevated tissue AM is a distinguishing feature of CC-RCC compared with other kidney tumours. Plasma AM is not suited as a tumour marker for this disease.

Spectral Karyotyping (SKY) Of Early Clear Cell Carcinomas In Patients With Von Hippel Lindau (VHL) Disease

1999 ◽  
pp. 145
Author(s):  
John L. Phillips ◽  
Bijan M. Ghadimi ◽  
Danny Wangsa ◽  
Richard D. Klausner ◽  
W. Marston Linehan ◽  
...  
Keyword(s):  
Clear Cell ◽  
Spectral Karyotyping ◽  
Von Hippel Lindau ◽  
Vhl Disease

scholarly journals Hypoxia-Inducible Factor Linked to Differential Kidney Cancer Risk Seen with Type 2A and Type 2B VHL Mutations

2007 ◽  
Vol 27 (15) ◽  
pp. 5381-5392 ◽  
Author(s):  
Lianjie Li ◽  
Liang Zhang ◽  
Xiaoping Zhang ◽  
Qin Yan ◽  
Yoji Andrew Minamishima ◽  
...  
Keyword(s):  
Kidney Cancer ◽  
Clear Cell ◽  
Germ Line ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Cancer Type ◽  
Missense Mutations ◽  
Von Hippel Lindau ◽  
High Risk Type ◽  
Vhl Disease

ABSTRACT Clear cell carcinoma of the kidney is a major cause of mortality in patients with von Hippel-Lindau (VHL) disease, which is caused by germ line mutations that inactivate the VHL tumor suppressor gene. Biallelic VHL inactivation, due to mutations or hypermethylation, is also common in sporadic clear cell renal carcinomas. The VHL gene product, pVHL, is part of a ubiquitin ligase complex that targets the alpha subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF) for destruction under well-oxygenated conditions. All VHL mutations linked to classical VHL disease compromise this pVHL function although some missense mutations result in a low risk of kidney cancer (type 2A VHL disease) while others result in a high risk (type 2B VHL disease). We found that type 2A mutants were less defective than type 2B mutants when reintroduced into VHL −/− renal carcinoma cells with respect to HIF regulation. A stabilized version of HIF2α promoted tumor growth by VHL −/− cells engineered to produce type 2A mutants, while knock-down of HIF2α in cells producing type 2B mutants had the opposite effect. Therefore, quantitative differences with respect to HIF deregulation are sufficient to account for the differential risks of kidney cancer linked to VHL mutations.

Instrumentation For Quantitative Microscopy

1977 ◽  
Vol 35 ◽  
pp. 206-209
Author(s):  
B. Ralph ◽  
A.R. Jones
Keyword(s):  
Volume Fraction ◽  
Three Dimensional ◽  
Two Dimensional ◽  
Automatic Data ◽  
Phase Volume Fraction ◽  
Statistical Confidence ◽  
Resultant Data ◽  
Automatic Data Collection ◽  
Third Dimension ◽  
Evolution Of Microstructure

In all fields of microscopy there is an increasing interest in the quantification of microstructure. This interest may stem from a desire to establish quality control parameters or may have a more fundamental requirement involving the derivation of parameters which partially or completely define the three dimensional nature of the microstructure. This latter categorey of study may arise from an interest in the evolution of microstructure or from a desire to generate detailed property/microstructure relationships. In the more fundamental studies some convolution of two-dimensional data into the third dimension (stereological analysis) will be necessary.In some cases the two-dimensional data may be acquired relatively easily without recourse to automatic data collection and further, it may prove possible to perform the data reduction and analysis relatively easily. In such cases the only recourse to machines may well be in establishing the statistical confidence of the resultant data. Such relatively straightforward studies tend to result from acquiring data on the whole assemblage of features making up the microstructure. In this field data mode, when parameters such as phase volume fraction, mean size etc. are sought, the main case for resorting to automation is in order to perform repetitive analyses since each analysis is relatively easily performed.

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